https://www.wikidoc.org/api.php?action=feedcontributions&user=Deepika+Beereddy&feedformat=atomwikidoc - User contributions [en]2024-03-28T12:17:04ZUser contributionsMediaWiki 1.40.0https://www.wikidoc.org/index.php?title=Flutamide&diff=1059144Flutamide2015-01-23T17:05:00Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Flutamide<br />
|aOrAn=an<br />
|drugClass=androgen antagonist<br />
|indicationType=treatment<br />
|indication=carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=[[rash]], hot sweats, [[diarrhea]], [[nausea]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNINGS </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Hepatic Injury: </span></i><br />
<br />
*There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.<br />
<br />
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Carcinoma of prostate, Stage B2, C or D2, in combination with an LHRH agonist=====<br />
<br />
* Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression.<br />
<br />
* Dosing Information<br />
<br />
:* 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.<br />
<br />
Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).<br />
<br />
<!--Warnings--><br />
|warnings=Hepatic Injury<br />
<br />
See BOXED WARNINGS.<br />
<br />
Use in Women<br />
<br />
Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non-life threatening conditions.<br />
<br />
Fetal Toxicity<br />
<br />
Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy).<br />
<br />
Aniline Toxicity<br />
<br />
One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.<br />
Close<br />
PRECAUTIONS<br />
<br />
General<br />
<br />
In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.<br />
<br />
Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
<br />
Laboratory Tests<br />
<br />
Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen while continuing the LHRH analogue may be considered.<br />
|clinicalTrials=Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below.<br />
<br />
[[File:Flutamide adverse reactions 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + LHRH agonist versus placebo + LHRH agonist.<br />
<br />
The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table.<br />
<br />
[[File:Flutamide adverse reactions 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone.<br />
<br />
The only notable difference was the higher incidence of diarrhea in the flutamide + LHRH agonist group (12%), which was severe in 5% as opposed to the placebo + LHRH agonist (4%), which was severe in less than 1%.<br />
<br />
In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist.<br />
<br />
Cardiovascular System<br />
<br />
Hypertension in 1% of patients<br />
<br />
Central Nervous System<br />
<br />
CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients<br />
<br />
Gastrointestinal System<br />
<br />
Anorexia 4%, and other GI disorders occurred in 6% of patients<br />
<br />
Hematopoietic System<br />
<br />
Anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients<br />
<br />
Liver and Biliary System<br />
<br />
Hepatitis and jaundice in less than 1% of patients<br />
<br />
Skin<br />
<br />
Irritation at the injection site and rash occurred in 3% of patients<br />
<br />
Other<br />
<br />
Edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients.<br />
<br />
In addition, the following spontaneous adverse experiences have been reported during the marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis), and urine discoloration. The urine was noted to change to an amber or yellow-green appearance which can be attributed to the flutamide and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.<br />
<br />
Malignant breast neoplasms have occurred rarely in male patients being treated with flutamide.<br />
<br />
Abnormal Laboratory Test Values<br />
<br />
Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.<br />
|drugInteractions=Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin.<br />
|FDAPregCat=D<br />
|useInPregnancyFDA=Teratogenic Effects<br />
<br />
Pregnancy Category D<br />
<br />
There was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of cats treated with two higher doses. Feminization of the male cats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.<br />
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration=* The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg.<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia.<br />
<br />
Clinical trials have been conducted with flutamide in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.<br />
<br />
Flutamide is highly protein bound and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.<br />
|drugBox=[[File:Flutamide wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.<br />
|structure=Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula:<br />
<br />
[[File:Flutamide Structural Formula.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
C11H11F3N2O3 M.W. 276.21<br />
<br />
Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.<br />
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacokinetics--><br />
|PK=Absorption<br />
<br />
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.<br />
<br />
Distribution<br />
<br />
In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.<br />
<br />
Metabolism<br />
<br />
The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.<br />
<br />
Excretion<br />
<br />
Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours.<br />
<br />
[[File:Flutamide pk.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Special Populations<br />
<br />
Geriatric<br />
<br />
Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours.<br />
<br />
Race<br />
<br />
There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race.<br />
<br />
Renal Impairment<br />
<br />
Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.<br />
<br />
Hepatic Impairment<br />
<br />
No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).<br />
<br />
Women, Pediatrics<br />
<br />
Flutamide has not been studied in women or pediatric patients.<br />
<br />
Drug-Drug Interactions<br />
<br />
Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy (see PRECAUTIONS).<br />
<br />
Clinical Studies<br />
<br />
Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.<br />
<br />
The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.<br />
<br />
In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001).<br />
<br />
Stage D2 Prostatic Carcinoma<br />
<br />
To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.<br />
<br />
Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.<br />
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2 to 3, and 4 fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1 to 4 fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONS section).<br />
<br />
Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/Microsome Mutagenesis Assay. Dominant lethal tests in rats were negative.<br />
<br />
Reduced sperm counts were observed during a 6 week study of flutamide monotherapy in normal human volunteers.<br />
<br />
Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.<br />
<br />
Animal Toxicology<br />
<br />
Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2 to 4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1 to 12 fold greater than those observed in humans at therapeutic levels.<br />
|clinicalStudies=There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--How Supplied--><br />
|howSupplied=* Flutamide Capsules USP, 125 mg are available as light brown opaque oblong hard gelatin capsules, spin printed with<br />
Company logo<br />
<br />
and “4960” in black ink containing 125 mg flutamide packaged in bottles of 180 and 500 capsules.<br />
<br />
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).<br />
<br />
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.<br />
|storage=* Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].<br />
|packLabel=<!--Patient Counseling Information--><br />
|fdaPatientInfo=Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Eulexin<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059139Flutamide2015-01-23T17:01:05Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Flutamide<br />
|aOrAn=an<br />
|drugClass=androgen antagonist<br />
|indicationType=treatment<br />
|indication=carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=[[rash]], hot sweats, [[diarrhea]], [[nausea]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNINGS </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Hepatic Injury: </span></i><br />
<br />
*There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.<br />
<br />
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Carcinoma of prostate, Stage B2, C or D2, in combination with an LHRH agonist=====<br />
<br />
* Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression.<br />
<br />
* Dosing Information<br />
<br />
:* 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.<br />
<br />
Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).<br />
<br />
<!--Warnings--><br />
|warnings=Hepatic Injury<br />
<br />
See BOXED WARNINGS.<br />
<br />
Use in Women<br />
<br />
Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non-life threatening conditions.<br />
<br />
Fetal Toxicity<br />
<br />
Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy).<br />
<br />
Aniline Toxicity<br />
<br />
One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.<br />
Close<br />
PRECAUTIONS<br />
<br />
General<br />
<br />
In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.<br />
<br />
Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
<br />
Laboratory Tests<br />
<br />
Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen while continuing the LHRH analogue may be considered.<br />
|clinicalTrials=Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below.<br />
<br />
[[File:Flutamide adverse reactions 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + LHRH agonist versus placebo + LHRH agonist.<br />
<br />
The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table.<br />
<br />
[[File:Flutamide adverse reactions 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone.<br />
<br />
The only notable difference was the higher incidence of diarrhea in the flutamide + LHRH agonist group (12%), which was severe in 5% as opposed to the placebo + LHRH agonist (4%), which was severe in less than 1%.<br />
<br />
In addition, the following adverse reactions were reported during treatment with flutamide + LHRH agonist.<br />
<br />
Cardiovascular System<br />
<br />
Hypertension in 1% of patients<br />
<br />
Central Nervous System<br />
<br />
CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients<br />
<br />
Gastrointestinal System<br />
<br />
Anorexia 4%, and other GI disorders occurred in 6% of patients<br />
<br />
Hematopoietic System<br />
<br />
Anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients<br />
<br />
Liver and Biliary System<br />
<br />
Hepatitis and jaundice in less than 1% of patients<br />
<br />
Skin<br />
<br />
Irritation at the injection site and rash occurred in 3% of patients<br />
<br />
Other<br />
<br />
Edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients.<br />
<br />
In addition, the following spontaneous adverse experiences have been reported during the marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis), and urine discoloration. The urine was noted to change to an amber or yellow-green appearance which can be attributed to the flutamide and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide.<br />
<br />
Malignant breast neoplasms have occurred rarely in male patients being treated with flutamide.<br />
<br />
Abnormal Laboratory Test Values<br />
<br />
Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.<br />
<br />
|drugInteractions=Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin.<br />
|FDAPregCat=D<br />
|useInPregnancyFDA=Teratogenic Effects<br />
<br />
Pregnancy Category D<br />
<br />
There was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of cats treated with two higher doses. Feminization of the male cats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.<br />
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration=* Oral<br />
<br />
* Intravenous<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia.<br />
<br />
Clinical trials have been conducted with flutamide in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.<br />
<br />
Flutamide is highly protein bound and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.<br />
|drugBox=[[File:Flutamide wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.<br />
|structure=Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula:<br />
<br />
[[File:Flutamide Structural Formula.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
C11H11F3N2O3 M.W. 276.21<br />
<br />
Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.<br />
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacokinetics--><br />
|PK=Absorption<br />
<br />
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.<br />
<br />
Distribution<br />
<br />
In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.<br />
<br />
Metabolism<br />
<br />
The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.<br />
<br />
Excretion<br />
<br />
Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours.<br />
<br />
[[File:Flutamide pk.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Special Populations<br />
<br />
Geriatric<br />
<br />
Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours.<br />
<br />
Race<br />
<br />
There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race.<br />
<br />
Renal Impairment<br />
<br />
Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.<br />
<br />
Hepatic Impairment<br />
<br />
No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).<br />
<br />
Women, Pediatrics<br />
<br />
Flutamide has not been studied in women or pediatric patients.<br />
<br />
Drug-Drug Interactions<br />
<br />
Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy (see PRECAUTIONS).<br />
<br />
Clinical Studies<br />
<br />
Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.<br />
<br />
The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.<br />
<br />
In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001).<br />
<br />
Stage D2 Prostatic Carcinoma<br />
<br />
To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.<br />
<br />
Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.<br />
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2 to 3, and 4 fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1 to 4 fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONS section).<br />
<br />
Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/Microsome Mutagenesis Assay. Dominant lethal tests in rats were negative.<br />
<br />
Reduced sperm counts were observed during a 6 week study of flutamide monotherapy in normal human volunteers.<br />
<br />
Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.<br />
<br />
Animal Toxicology<br />
<br />
Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2 to 4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1 to 12 fold greater than those observed in humans at therapeutic levels.<br />
|clinicalStudies=There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--How Supplied--><br />
|howSupplied=*<br />
|packLabel=<!--Patient Counseling Information--><br />
|fdaPatientInfo=Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Eulexin<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
<br />
<!--Drug Shortage Status--><br />
|drugShortage=<br />
}}<br />
{{PillImage<br />
|fileName=No image.jpg<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
<!--Pill Image--><br />
<br />
<br />
<br />
<!--Label Display Image--><br />
<br />
<br />
<br />
<br />
<br />
<!--Category--><br />
<br />
[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059135Flutamide2015-01-23T16:58:34Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Flutamide<br />
|aOrAn=an<br />
|drugClass=androgen antagonist<br />
|indicationType=treatment<br />
|indication=carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=[[rash]], hot sweats, [[diarrhea]], [[nausea]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNINGS </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Hepatic Injury: </span></i><br />
<br />
*There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.<br />
<br />
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Carcinoma of prostate, Stage B2, C or D2, in combination with an LHRH agonist=====<br />
<br />
* Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression.<br />
<br />
* Dosing Information<br />
<br />
:* 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* Flutamide capsules are contraindicated in patients who are hypersensitive to flutamide or any component of this preparation.<br />
<br />
Flutamide capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).<br />
<br />
<!--Warnings--><br />
|warnings=Hepatic Injury<br />
<br />
See BOXED WARNINGS.<br />
<br />
Use in Women<br />
<br />
Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non-life threatening conditions.<br />
<br />
Fetal Toxicity<br />
<br />
Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy).<br />
<br />
Aniline Toxicity<br />
<br />
One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.<br />
Close<br />
PRECAUTIONS<br />
<br />
General<br />
<br />
In clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.<br />
<br />
Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
<br />
Laboratory Tests<br />
<br />
Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen while continuing the LHRH analogue may be considered.<br />
<br />
|clinicalTrials=[[File:Flutamide adverse reactions 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Flutamide adverse reactions 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|drugInteractions=Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin.<br />
|FDAPregCat=D<br />
|useInPregnancyFDA= Teratogenic Effects<br />
<br />
Pregnancy Category D<br />
<br />
There was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose). A slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of cats treated with two higher doses. Feminization of the male cats also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.<br />
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration=* Oral<br />
<br />
* Intravenous<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose====Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
* Description<br />
<br />
====Management====<br />
<br />
* Description<br />
<br />
===Chronic Overdose===<br />
<br />
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacology--><br />
<br />
<!--Drug box 2--><br />
|drugBox=[[File:Flutamide wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.<br />
|structure=Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula:<br />
<br />
[[File:Flutamide Structural Formula.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
C11H11F3N2O3 M.W. 276.21<br />
<br />
Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.<br />
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacokinetics--><br />
|PK=Absorption<br />
<br />
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.<br />
<br />
Distribution<br />
<br />
In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.<br />
<br />
Metabolism<br />
<br />
The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.<br />
<br />
Excretion<br />
<br />
Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours.<br />
<br />
[[File:Flutamide pk.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Special Populations<br />
<br />
Geriatric<br />
<br />
Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours.<br />
<br />
Race<br />
<br />
There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race.<br />
<br />
Renal Impairment<br />
<br />
Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.<br />
<br />
Hepatic Impairment<br />
<br />
No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).<br />
<br />
Women, Pediatrics<br />
<br />
Flutamide has not been studied in women or pediatric patients.<br />
<br />
Drug-Drug Interactions<br />
<br />
Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy (see PRECAUTIONS).<br />
<br />
Clinical Studies<br />
<br />
Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.<br />
<br />
The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.<br />
<br />
In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001).<br />
<br />
Stage D2 Prostatic Carcinoma<br />
<br />
To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.<br />
<br />
Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.<br />
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
In a 1-year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily oral doses of 10, 30, and 50 mg/kg/day were administered). These produce plasma Cmax values that are 1, 2 to 3, and 4 fold, respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for 1 year, tumors were still present after 1 year of a drug-free period, but the incidences were 43% to 47%. In a 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were 1 to 4 fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONS section).<br />
<br />
Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/Microsome Mutagenesis Assay. Dominant lethal tests in rats were negative.<br />
<br />
Reduced sperm counts were observed during a 6 week study of flutamide monotherapy in normal human volunteers.<br />
<br />
Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.<br />
<br />
Animal Toxicology<br />
<br />
Serious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for 2 to 4 years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were 1 to 12 fold greater than those observed in humans at therapeutic levels.<br />
<br />
|clinicalStudies=There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--How Supplied--><br />
|howSupplied=*<br />
|packLabel=<!--Patient Counseling Information--><br />
|fdaPatientInfo=Information for Patients<br />
<br />
Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.<br />
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Eulexin<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
<br />
<!--Drug Shortage Status--><br />
|drugShortage=<br />
}}<br />
{{PillImage<br />
|fileName=No image.jpg<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
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<!--Category--><br />
<br />
[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059129Flutamide2015-01-23T16:53:26Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Flutamide<br />
|aOrAn=an<br />
|drugClass=androgen antagonist<br />
|indicationType=treatment<br />
|indication=carcinoma of prostate, stage B2, C or D2, in combination with an LHRH agonist<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=[[rash]], hot sweats, [[diarrhea]], [[nausea]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNINGS </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Hepatic Injury: </span></i><br />
<br />
*There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.<br />
<br />
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Carcinoma of prostate, Stage B2, C or D2, in combination with an LHRH agonist=====<br />
<br />
* Flutamide capsules are indicated for use in combination with LHRH agonists for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
Treatment with flutamide capsules and the goserelin acetate implant should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
Stage D2 Metastatic Carcinoma<br />
<br />
To achieve benefit from treatment, flutamide capsules should be initiated with the LHRH agonist and continued until progression.<br />
<br />
* Dosing Information<br />
<br />
:* 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* Condition1<br />
<br />
<!--Warnings--><br />
|warnings=* Description<br />
<br />
====Precautions====<br />
<br />
* Description<br />
<br />
<!--Adverse Reactions--><br />
<br />
<!--Clinical Trials Experience--><br />
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.<br />
<br />
=====Body as a Whole=====<br />
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=====Cardiovascular=====<br />
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=====Endocrine=====<br />
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=====Hematologic and Lymphatic=====<br />
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=====Metabolic and Nutritional=====<br />
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<br />
=====Musculoskeletal=====<br />
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=====Neurologic=====<br />
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=====Respiratory=====<br />
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=====Skin and Hypersensitivy Reactions=====<br />
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<br />
<br />
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=====Special Senses=====<br />
<br />
<br />
<br />
<br />
=====Urogenital=====<br />
<br />
<br />
<br />
<br />
=====Miscellaneous=====<br />
<br />
<br />
<br />
<!--Postmarketing Experience--><br />
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.<br />
<br />
=====Body as a Whole=====<br />
<br />
<br />
<br />
=====Cardiovascular=====<br />
<br />
<br />
<br />
=====Digestive=====<br />
<br />
<br />
<br />
=====Endocrine=====<br />
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=====Hematologic and Lymphatic=====<br />
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=====Metabolic and Nutritional=====<br />
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=====Musculoskeletal=====<br />
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=====Neurologic=====<br />
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=====Respiratory=====<br />
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=====Skin and Hypersensitivy Reactions=====<br />
<br />
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<br />
=====Special Senses=====<br />
<br />
<br />
<br />
=====Urogenital=====<br />
<br />
<br />
<br />
=====Miscellaneous=====<br />
<br />
<br />
<br />
<!--Drug Interactions--><br />
|drugInteractions=* Drug<br />
:* Description<br />
<br />
<!--Use in Specific Populations--><br />
|useInPregnancyFDA=* '''Pregnancy Category'''<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.<br />
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration=* Oral<br />
<br />
* Intravenous<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose====Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
* Description<br />
<br />
====Management====<br />
<br />
* Description<br />
<br />
===Chronic Overdose===<br />
<br />
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacology--><br />
<br />
<!--Drug box 2--><br />
|drugBox=[[File:Flutamide wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.<br />
|structure=Flutamide Capsules USP contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, α,α,α-Trifluoro-2-methyl-4’-nitro-m-propionotoluidide and has the following structural formula:<br />
<br />
[[File:Flutamide Structural Formula.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
C11H11F3N2O3 M.W. 276.21<br />
<br />
Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.<br />
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacokinetics--><br />
|PK= Absorption<br />
<br />
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.<br />
<br />
Distribution<br />
<br />
In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins.<br />
<br />
Metabolism<br />
<br />
The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least 6 metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.<br />
<br />
Excretion<br />
<br />
Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours.<br />
<br />
[[File:Flutamide pk.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Special Populations<br />
<br />
Geriatric<br />
<br />
Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8.1 hours and at steady state in 9.6 hours.<br />
<br />
Race<br />
<br />
There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race.<br />
<br />
Renal Impairment<br />
<br />
Following a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax or AUC of the biologically active alpha-hydroxylated metabolite of flutamide. In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted.<br />
<br />
Hepatic Impairment<br />
<br />
No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury).<br />
<br />
Women, Pediatrics<br />
<br />
Flutamide has not been studied in women or pediatric patients.<br />
<br />
Drug-Drug Interactions<br />
<br />
Interactions between flutamide capsules and LHRH agonists have not occurred. Increases in prothrombin have been noted in patients receiving warfarin therapy (see PRECAUTIONS).<br />
<br />
Clinical Studies<br />
<br />
Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.<br />
<br />
The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH agonist as the sole therapy in stage D2 metastatic carcinoma.<br />
<br />
Stage B2-C Prostatic Carcinoma<br />
<br />
The effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.<br />
<br />
In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, P < 0.001). The combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, P = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs. 2.6 years, P < 0.001). Inclusion of normal PSA level as a criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, P < 0.001).<br />
<br />
Stage D2 Prostatic Carcinoma<br />
<br />
To study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide + flutamide, 306 leuprolide + placebo) with previously untreated advanced prostatic carcinoma were enrolled in a large multicentered, controlled clinical trial.<br />
<br />
Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.<br />
<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059121Flutamide2015-01-23T16:47:59Z<p>Deepika Beereddy: </p>
<hr />
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*There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.<br />
<br />
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.<br />
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<!--Administration and Monitoring--><br />
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====Signs and Symptoms====<br />
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<br />
[[File:Flutamide Structural Formula.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
C11H11F3N2O3 M.W. 276.21<br />
<br />
Flutamide is a buff to yellow powder. Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: black iron oxide, corn starch, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059047Flutamide2015-01-23T16:04:04Z<p>Deepika Beereddy: </p>
<hr />
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<br />
* Dosing Information<br />
<br />
:* 250 mg ORALLY every 8 hr in conjunction with a luteinizing hormone-releasing hormone (LHRH) agonist; begin 8 weeks prior to initiating radiation therapy and continue during radiation therapy.<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059038Flutamide2015-01-23T15:56:57Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059034Flutamide2015-01-23T15:53:44Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059029Flutamide2015-01-23T15:52:16Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059027Flutamide2015-01-23T15:50:49Z<p>Deepika Beereddy: </p>
<hr />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059023Flutamide2015-01-23T15:48:25Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
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=====Cardiovascular=====<br />
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=====Endocrine=====<br />
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=====Metabolic and Nutritional=====<br />
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=====Musculoskeletal=====<br />
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=====Neurologic=====<br />
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=====Respiratory=====<br />
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=====Special Senses=====<br />
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=====Body as a Whole=====<br />
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<br />
<br />
=====Cardiovascular=====<br />
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=====Digestive=====<br />
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=====Endocrine=====<br />
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=====Hematologic and Lymphatic=====<br />
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=====Metabolic and Nutritional=====<br />
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=====Musculoskeletal=====<br />
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=====Neurologic=====<br />
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=====Respiratory=====<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Flutamide&diff=1059022Flutamide2015-01-23T15:47:03Z<p>Deepika Beereddy: </p>
<hr />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Aplastic_anemia_causes&diff=1059002Aplastic anemia causes2015-01-23T15:23:59Z<p>Deepika Beereddy: /* Drug Side Effect */</p>
<hr />
<div>{{Aplastic anemia}}<br />
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]<br />
==Overview==<br />
The cause of the damage can be acquired or inherited. Acquired aplastic anemia is more common, and sometimes it's only temporary. Inherited aplastic anemia is rare. More than half of the cases of [[aplastic anemia]] are idiopathic. Chemicals, drugs, viral infections, [[collagen vascular disease]]s, and [[thymoma]] can be implicated as the causative factor in the other cases. Some research suggests that stem cell damage may occur because the body's immune system attacks its own cells by mistake.<br />
<br />
==Causes==<br />
===Acquired Causes===<br />
Many diseases, conditions, and factors can cause aplastic anemia, including:<br />
* Toxins, such as [[pesticides]], [[arsenic]], and [[benzene]].<br />
* Radiation and chemotherapy<br />
* Medicines, such as [[Albendazole]], [[Cefadroxil]], [[Chlorpromazine]], [[chloramphenicol]] (an antibiotic rarely used in the United States, [[Carbamazepine]], [[Hydroxychloroquine]], [[Methimazole]], [[Orphenadrine]], [[Oxcarbazepine]], [[Phenytoin]], [[Quinine]], [[Phenylbutazone]], [[Sulindac]], [[Sulfadiazine]], [[Sulfasalazine]], [[Valganciclovir hydrochloride]].<br />
* Infectious diseases, such as [[hepatitis]], [[Epstein-Barr virus]], [[cytomegalovirus]], [[parvovirus B19]], and [[HIV]].<br />
* [[Collagen vascular disease]]<br />
* [[Thymoma]]<br />
* Autoimmune disorders, such as lupus and [[rheumatoid arthritis]].<br />
* [[Pregnancy]] (aplastic anemia that occurs during pregnancy often goes away after delivery.)<br />
* Metastaic involvement of bone marrow<br />
<br />
===Inherited Causes===<br />
Certain inherited conditions can damage the stem cells and lead to aplastic anemia. Examples include:<br />
* [[Fanconi anemia]]<br />
* [[Shwachman-Diamond syndrome]]<br />
* [[Dyskeratosis congenita]] <br />
* [[Diamond-Blackfan anemia]].<br />
<br />
===Drug Side Effect===<br />
*[[Cefadroxil]]<br />
*[[Ceftazidime]] <br />
*[[Cefaclor]]<br />
*[[Cefaclor]]<br />
*[[Dapsone]]<br />
*[[Isoniazid]]<br />
*[[Meprobamate]]<br />
*[[Penicillamine]]<br />
*[[Probenecid]]<br />
*[[Tolbutamide]]<br />
*[[Sulfasalazine]]<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Needs content]]<br />
[[Category:Disease]]<br />
[[Category:Hematology]]<br />
[[Category:Autoimmune diseases]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Sulfadiazine&diff=1058983Sulfadiazine2015-01-23T15:12:39Z<p>Deepika Beereddy: </p>
<hr />
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|genericName=Sulfadiazine<br />
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|indication=[[chancroid]], [[trachoma]], [[inclusion conjunctivitis]], [[nocardiosis]], [[urinary tract infections]] (primarily [[pyelonephritis]], [[pyelitis]] and [[cystitis]]), [[toxoplasmosis encephalitis]] in patients with and without [[acquired immunodeficiency syndrome]], [[malaria]] due to chloroquine-resistant strains of plasmodium falciparum, prophylaxis of [[meningococcal meningitis]], [[meningococcal meningitis]], [[acute otitis media]] due to [[haemophilus influenzae]], prophylaxis against recurrences of [[rheumatic fever]], H. influenzae meningitis, as an adjunctive therapy<br />
|adverseReactions=[[rash]], [[abdominal pain]], [[diarrhea]], [[nausea]], [[vomiting]]<br />
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|fdaLIADAdult======Acute otitis media, Due to Haemophilus influenzae, in combination with penicillin=====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
=====Chancroid=====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
=====Haemophilus influenzae meningitis, In combination with parenteral streptomycin; Adjunct=====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Inclusion conjunctivitis====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Meningococcal meningitis; Treatment and Prophylaxis====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Nocardiosis====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:*Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Rheumatic fever, Recurrent; Prophylaxis====<br />
<br />
* Dosing Information<br />
<br />
:* Greater than 27 kg: 1 g ORALLY once a day; (27 kg or less) 500 mg ORALLY once a day (guideline dosing)<br />
<br />
:* Initial, 2 to 4 g ORALLY (manufacturer dosing)<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)<br />
<br />
====Toxoplasma encephalitis====<br />
<br />
* Dosing Information<br />
<br />
:* Initial 2 to 4 g ORALLY (manufacturer dosing) <br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours (manufacturer dosing)<br />
<br />
:* Less than 60 kg: 1000 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 50 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)<br />
<br />
:* 60 kg or greater: 1500 mg ORALLY every 6 hour plus pyrimethamine 200 mg ORALLY for 1 dose, then 75 mg ORALLY daily plus leucovorin 10 to 25 mg (can increase to 50 mg) ORALLY daily for at least 6 week (guideline dosing)<br />
<br />
:* 1000 to 1500 mg ORALLY every 6 hour plus atovaquone 1500 mg orally twice daily for at least 6 week (guideline dosing)<br />
<br />
====Trachoma====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
====Urinary tract infectious disease====<br />
<br />
* Dosing Information<br />
<br />
:* Initial, 2 to 4 g ORALLY<br />
<br />
:* Maintenance, 2 to 4 g ORALLY divided into 3 to 6 doses, every 24 hours<br />
<br />
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|fdaLIADPed======Acute otitis media, Due to Haemophilus influenzae, in combination with penicillin=====<br />
<br />
* Dosing Information<br />
<br />
:* 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
=====Chancroid=====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
=====Congenital toxoplasmosis; Adjunct=====<br />
<br />
* Dosing Information<br />
<br />
:* 2 months and older: Initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)<br />
<br />
:* 2 months and older: Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)<br />
<br />
:* (HIV) 50 mg/kg per dose ORALLY twice daily PLUS pyrimethamine 2 mg/kg ORALLY once daily for 2 days, then 1 mg/kg ORALLY once daily for 2 to 6 months, then 1 mg/kg ORALLY 3 times weekly PLUS leucovorin 10 mg ORALLY or IM with each dose of pyrimethamine; total treatment duration is 12 months (guideline dosing)<br />
<br />
====Haemophilus influenzae meningitis, In combination with parenteral streptomycin; Adjunct====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) Initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) Maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Inclusion conjunctivitis====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Malaria, due to chloroquine-resistant strains of Plasmodium falciparum; Adjunct====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Meningococcal meningitis; Treatment and Prophylaxis====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Nocardiosis====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Rheumatic fever, Recurrent; Prophylaxis====<br />
<br />
* Dosing Information<br />
<br />
:* (27 kg or less) 500 mg ORALLY once a day (guideline dosing)<br />
<br />
:* (greater than 27 kg) 1 g ORALLY once a day (guideline dosing)<br />
<br />
:* (less than 30 kg) 500 mg ORALLY every 24 hours (manufacturer dosing)<br />
<br />
:* (greater than 30 kg) 1 g ORALLY every 24 hours (manufacturer dosing)<br />
<br />
====Toxoplasma encephalitis====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY (manufacturer dosing)<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours (manufacturer dosing)<br />
<br />
:* (acquired toxoplasmosis in children with HIV) 25 to 50 mg/kg (MAX 1000 to 1500 mg/dose) ORALLY 4 times daily plus pyrimethamine 2 mg/kg (MAX 50 mg) ORALLY once daily for 3 days, then 1 mg/kg (MAX 25 mg) ORALLY once daily PLUS leucovorin 10 to 25 mg ORALLY daily; continue for at least 6 weeks, followed by secondary prophylaxis (guideline dosing)<br />
<br />
====Trachoma====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
====Urinary tract infectious disease====<br />
<br />
* Dosing Information<br />
<br />
:* (2 months and older) initial 75 mg/kg or 2 g/m(2) ORALLY<br />
<br />
:* (2 months and older) maintenance, 150 mg/kg/day or 4 g/m(2)/day ORALLY divided into 4 to 6 doses, every 24 hours; MAX 6 g every 24 hours<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=*Sulfadiazine is contraindicated in the following circumstances: Hypersensitivity to sulfonamides.<br />
<br />
*In infants less than 2 months of age (except as adjunctive therapy with [[pyrimethamine]] in the treatment of [[congenital toxoplasmosis]]).<br />
<br />
*In pregnancy at term and during the nursing period, because sulfonamides cross the placenta and are excreted in breast milk and may cause kernicterus.<br />
|warnings=* The sulfonamides should not be used for the treatment of group A betahemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as [[rheumatic fever]] and [[glomerulonephritis]].<br />
<br />
*Deaths associated with the administration of sulfonamides have been reported from [[hypersensitivity]] reactions, [[agranulocytosis]], [[aplastic anemia]] and other [[blood dyscrasias]].<br />
<br />
*The presence of such clinical signs as sore throat, [[fever]], [[pallor]], [[purpura]] or [[jaundice]] may be early indications of serious blood disorders.<br />
<br />
*The frequency of renal complications is considerably lower in patients receiving the more soluble sulfonamides.<br />
<br />
====Precautions====<br />
<br />
'''General'''<br />
<br />
*Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or [[bronchial asthma]].<br />
<br />
*[[Hemolysis]] may occur in individuals deficient in glucose-6-phosphate dehydrogenase. This reaction is dose related.<br />
<br />
*Adequate fluid intake must be maintained in order to prevent [[crystalluria]] and stone formation.<br />
<br />
'''Laboratory Tests'''<br />
<br />
*Complete blood counts and urinalyses with careful microscopic examinations should be done frequently in patients receiving sulfonamides.<br />
<br />
<!--Adverse Reactions--><br />
<br />
<!--Clinical Trials Experience--><br />
|clinicalTrials='''Blood Dyscrasias'''<br />
<br />
*[[Agranulocytosis]], [[aplastic anemia]], [[thrombocytopenia]], [[leukopenia]], [[hemolytic anemia]], [[purpura]], [[hypoprothrombinemia]] and [[methemoglobinemia]].<br />
<br />
'''Allergic Reactions'''<br />
<br />
*Erythema multiforme ([[Stevens-Johnson syndrome]]), generalized skin eruptions, [[epidermal necrolysis]], [[urticaria]], [[serum sickness]], [[pruritus]], [[exfoliative dermatitis]], [[anaphylactoid reactions]], [[periorbital edema]], conjunctival and scleral injection, [[photosensitization]], [[arthralgia]], [[allergic myocarditis]], drug fever and chills.<br />
<br />
'''Gastrointestinal Reactions'''<br />
<br />
*[[Nausea]], [[emesis]], [[abdominal pains]], [[hepatitis]], [[diarrhea]], [[anorexia]], [[pancreatitis]] and [[stomatitis]].<br />
<br />
'''C.N.S. Reactions'''<br />
<br />
*[[Headache]], [[peripheral neuritis]], mental depression, [[convulsions]], [[ataxia]], [[hallucinations]], [[tinnitus]], [[vertigo]] and [[insomnia]].<br />
<br />
'''Renal'''<br />
<br />
*[[Crystalluria]], stone formation, [[toxic nephrosis]] with [[oliguria]] and [[anuria]]; [[periarteritis nodosa]] and [[lupus erythematosus]] phenomenon have been noted.<br />
<br />
'''Miscellaneous Reactions'''<br />
<br />
*The sulfonamides bear certain chemical similarities to some goitrogens, diuretics ([[acetazolamide]] and the thiazides) and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents.<br />
|postmarketing=* There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Drug Interactions--><br />
|drugInteractions=* Administration of a sulfonamide may increase the effect of oral anticoagulants and methotrexate, probably by displacement of these drugs from binding sites on plasma albumin. Potentiation of the action of sulfonylurea hypoglycemic agents, thiazide diuretics and uricosuric agents may also be noted. This may also be due to displacement of the drugs from albumin or a pharmacodynamic mechanism may play a role. Conversely, agents such as [[indomethacin]], [[probenecid]] and [[salicylates]] may displace sulfonamides from plasma albumin and increase the concentrations of free drug in plasma.<br />
<br />
<!--Use in Specific Populations--><br />
|FDAPregCat=C<br />
|useInPregnancyFDA='''Teratogenic Effects'''<br />
<br />
'''Pregnancy Category C'''<br />
<br />
*The safe use of sulfonamides in pregnancy has not been established. The teratogenic potential of most sulfonamides has not been thoroughly investigated in either animals or humans. However, a significant increase in the incidence of cleft palate and other bony abnormalities in offspring has been observed when certain sulfonamides of the short, intermediate and long acting types were given to pregnant rats and mice in high oral doses (7 to 25 times the human therapeutic dose).<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*Sulfadiazine is contraindicated for use in nursing mothers because the sulfonamides cross the placenta, are excreted in breast milk and may cause kernicterus.<br />
<br />
*Because of the potential for serious adverse reactions in nursing infants from sulfadiazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. See CONTRAINDICATIONS.<br />
|useInPed=*Sulfadiazine is contraindicated in infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis). See CONTRAINDICATIONSand DOSAGE AND ADMINISTRATION.<br />
|useInGeri=*There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=*There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration=*SYSTEMIC SULFONAMIDES ARE CONTRAINDICATED IN INFANTS UNDER 2 MONTHS OF AGE except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis.<br />
<br />
*Usual Dosage for Infants over 2 Months of Age and Children<br />
<br />
*Initially, one-half the 24-hour dose. Maintenance, 150 mg/kg or 4 g/m2, divided into 4 to 6 doses, every 24 hours, with a maximum of 6 g every 24 hours. Rheumatic fever prophylaxis, under 30 kg (66 pounds), 500 mg every 24 hours; over 30 kg (66 pounds), 1 g every 24 hours.<br />
<br />
'''Usual Adult Dosage'''<br />
<br />
*Initially, 2 g to 4 g. Maintenance, 2 g to 4 g, divided into 3 to 6 doses, every 24 hours.<br />
|monitoring=*There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=*There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacology--><br />
<br />
<!--Drug box 2--><br />
|drugBox=[[File:Sulfadiazine wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* The systemic sulfonamides are bacteriostatic agents having a similar spectrum of activity. Sulfonamides competitively inhibit bacterial synthesis of folic acid (pteroylglutamic acid) from aminobenzoic acid. Resistant strains are capable of utilizing folic acid precursors or preformed folic acid.<br />
|structure=*Sulfadiazine is an oral sulfonamide anti-bacterial agent.<br />
<br />
*Each tablet, for oral administration, contains 500 mg sulfadiazine. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate and stearic acid.<br />
<br />
*Sulfadiazine occurs as a white or slightly yellow powder. It is odorless or nearly so and slowly darkens on exposure to light. It is practically insoluble in water and slightly soluble in alcohol. The chemical name of sulfadiazine is N1-2-pyrimidinylsulfanilamide. The molecular formula is C10H10N4O2S. It has a molecular weight of 250.27. The structural formula is shown below:<br />
<br />
[[File:Sulfadiazine structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Most sulfonamides slowly darken on exposure to light.<br />
|PD=*There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacokinetics--><br />
|PK=*Sulfonamides exist in the blood in 3 forms - free, conjugated (acetylated and possibly others) and protein bound. The free form is considered to be the therapeutically active one.<br />
<br />
*Sulfadiazine given orally is readily absorbed from the gastrointestinal tract. After a single 2 g oral dose, a peak of 6.04 mg/100 mL is reached in 4 hours; of this, 4.65 mg/100 mL is free drug.<br />
<br />
*When a dose of 100 mg/kg of body weight is given initially and followed by 50 mg/kg every 6 hours, blood levels of free sulfadiazine are about 7 mg/100mL. Protein binding is 38% to 48%. Sulfadiazine diffuses into the cerebrospinal fluid; free drug reaches 32% to 65% of blood levels and total drug 40% to 60%.<br />
<br />
*Sulfadiazine is excreted largely in the urine, where concentrations are 10 to 25 times greater than serum levels. Approximately 10% of a single oral dose is excreted in the first 6 hours, 50% within 24 hours and 60% to 85% in 48 to 72 hours. Of the amount excreted in the urine, 15% to 40% is in the acetyl form.<br />
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''<br />
<br />
*The sulfonamides bear certain chemical similarities to some goitrogens. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in rats.<br />
|clinicalStudies=*There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--How Supplied--><br />
|howSupplied=*SulfADIAZine Tablets USP for oral administration are available as:<br />
<br />
*500 mg: white, unscored, capsule-shaped tablets, debossed “E 757” on one face and supplied as:<br />
<br />
*NDC 0185-0757-30 bottles of 30<br />
<br />
*NDC 0185-0757-01 bottles of 100<br />
<br />
*NDC 0185-0757-10 bottles of 1000<br />
|storage=* Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].<br />
<br />
* Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.<br />
<br />
* To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.<br />
|packLabel=[[File:Sulfadiazine pdp.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Sulfadiazine label.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|fdaPatientInfo='''Information for Patients'''<br />
<br />
*Patients should be instructed to drink an eight ounce glass of water with each dose of medication and at frequent intervals throughout the day. Caution patients to report promptly the onset of sore throat, [[fever]], [[pallor]], [[purpura]] or [[jaundice]] when taking this drug, since these may be early indications of serious blood disorders.<br />
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=* ®<ref>{{Cite web | title = | url = }}</ref><br />
<br />
<!--Look-Alike Drug Names--><br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
<br />
<!--Drug Shortage Status--><br />
|drugShortage=<br />
}}<br />
{{PillImage<br />
|fileName=No image.jpg<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
{{LabelImage<br />
|fileName={{PAGENAME}}11.png<br />
}}<br />
<!--Pill Image--><br />
<br />
<br />
<br />
<!--Label Display Image--><br />
<br />
<br />
<br />
<br />
<br />
<!--Category--><br />
<br />
[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Aplastic_anemia_causes&diff=1058963Aplastic anemia causes2015-01-23T15:02:45Z<p>Deepika Beereddy: /* Acquired Causes */</p>
<hr />
<div>{{Aplastic anemia}}<br />
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]<br />
==Overview==<br />
The cause of the damage can be acquired or inherited. Acquired aplastic anemia is more common, and sometimes it's only temporary. Inherited aplastic anemia is rare. More than half of the cases of [[aplastic anemia]] are idiopathic. Chemicals, drugs, viral infections, [[collagen vascular disease]]s, and [[thymoma]] can be implicated as the causative factor in the other cases. Some research suggests that stem cell damage may occur because the body's immune system attacks its own cells by mistake.<br />
<br />
==Causes==<br />
===Acquired Causes===<br />
Many diseases, conditions, and factors can cause aplastic anemia, including:<br />
* Toxins, such as [[pesticides]], [[arsenic]], and [[benzene]].<br />
* Radiation and chemotherapy<br />
* Medicines, such as [[Albendazole]], [[Cefadroxil]], [[Chlorpromazine]], [[chloramphenicol]] (an antibiotic rarely used in the United States, [[Carbamazepine]], [[Hydroxychloroquine]], [[Methimazole]], [[Orphenadrine]], [[Oxcarbazepine]], [[Phenytoin]], [[Quinine]], [[Phenylbutazone]], [[Sulindac]], [[Sulfadiazine]], [[Sulfasalazine]], [[Valganciclovir hydrochloride]].<br />
* Infectious diseases, such as [[hepatitis]], [[Epstein-Barr virus]], [[cytomegalovirus]], [[parvovirus B19]], and [[HIV]].<br />
* [[Collagen vascular disease]]<br />
* [[Thymoma]]<br />
* Autoimmune disorders, such as lupus and [[rheumatoid arthritis]].<br />
* [[Pregnancy]] (aplastic anemia that occurs during pregnancy often goes away after delivery.)<br />
* Metastaic involvement of bone marrow<br />
<br />
===Inherited Causes===<br />
Certain inherited conditions can damage the stem cells and lead to aplastic anemia. Examples include:<br />
* [[Fanconi anemia]]<br />
* [[Shwachman-Diamond syndrome]]<br />
* [[Dyskeratosis congenita]] <br />
* [[Diamond-Blackfan anemia]].<br />
<br />
===Drug Side Effect===<br />
*[[Cefadroxil]]<br />
*[[Ceftazidime]] [[Cefaclor]]<br />
*[[Cefaclor]]<br />
*[[Dapsone]]<br />
*[[Isoniazid]]<br />
*[[Meprobamate]]<br />
*[[Penicillamine]]<br />
*[[Probenecid]]<br />
*[[Tolbutamide]]<br />
*[[Sulfasalazine]]<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Needs content]]<br />
[[Category:Disease]]<br />
[[Category:Hematology]]<br />
[[Category:Autoimmune diseases]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Drug_allergy_causes&diff=1058957Drug allergy causes2015-01-23T15:01:46Z<p>Deepika Beereddy: /* Causes by Specific Allergic Reactions{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy |...</p>
<hr />
<div>__NOTOC__<br />
{{Drug allergy}}<br />
{{CMG}}; {{AE}} {{CP}}, {{JM}}<br />
<br />
==Overview==<br />
The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.<br />
<br />
==Causes==<br />
===Common Causes===<br />
When a medication causes an allergic reaction, it is called an [[allergen]]. The following is a short list of the most common drug allergens<br />
*Antibiotics<br />
**[[Penicillin]]<br />
**[[Sulfonamide (medicine)|Sulfa drugs]]<br />
**[[Tetracycline]]<br />
*Analgesics<br />
**[[Codeine]]<br />
**[[Non-steroidal anti-inflammatory drug]]s (NSAIDs)<br />
*Anticonvulsives<br />
**[[Phenytoin|Dilantin]]<br />
**[[Carbamazepine|Tegretol]]<br />
<br />
===Causes by Organ System===<br />
<br />
{|style="width:75%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Effect'''<br />
|bgcolor="Beige"| [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Adapalene]], [[Adenosine]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Allopurinol]], [[Alteplase]], [[Amifostine]], [[Amiloride]], [[Aminocaproic acid]], [[Amiodarone]], [[Amlodipine]], [[Amlodipine besylate and Valsartan]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Antithrombin III]], [[Argatroban]], [[Aripiprazole]], [[Armodafinil]], [[Atazanavir]], [[Atenolol]], [[Atomoxetine]], [[Atorvastatin calcium]], [[Barbiturates]], [[Benazepril]], [[Bendamustine]], [[Benoxaprofen]], [[Betaxolol]], [[Bevacizumab]], [[Bisoprolol]], [[Botulinum toxin]], [[Brentuximab vedotin]], [[Brimonidine]], [[Brinzolamide]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Bumetanide]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[Cabergoline]], [[Captopril]], [[Carbamazepine]], [[Carbidopa and Levodopa]], [[Carteolol]], [[Carvedilol]], [[Cefdinir]], [[Celecoxib]], [[Cephalosporins]], [[Cetuximab]], [[Chlorambucil]], [[Chlormezanone]], [[Chlorothiazide]], [[Chlorthalidone]], [[Cholestyramine]], [[Ciclosporin]], [[Cilostazol]], [[Ciprofloxacin and Dexamethasone]], [[Citalopram Hydrobromide]], [[Clindamycin]], [[Clonidine]], [[Clopidogrel]], [[Coagulation factor VIIa]], [[Codeine]], [[Colestipol]], [[Conivaptan]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Danazol]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Dasatinib]], [[Denosumab]], [[Desirudin]], [[Desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diazoxide]], [[Diclofenac]], [[Diclofenamide]], [[Dofetilide]], [[Digoxin]], [[Digoxin immune fab]], [[Diltiazem]], [[Donepezil]], [[Dipyridamole]], [[Disopyramide]], [[Dobutamine]], [[Dorzolamide]], [[Doxycycline Hyclate]], [[Dronedarone]], [[Duloxetine]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]], [[Ethynodiol diacetate and ethinyl estradiol]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Eprosartan]], [[Eptifibatide]], [[Erlotinib]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]], [[Ethacrynic acid]], [[Ethambutol]], [[Ethotoin]], [[Etodolac]], [[Etravirine]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Ezetimibe And Simvastatin]], [[Factor IX complex]], [[Felodipine]], [[Fenofibrate]], [[Fenoldopam]], [[Filgrastim]], [[Flecainide]], [[Fluconazole]], [[Fluphenazine]], [[Fluticasone]], [[Fluticasone and Salmeterol]], [[Fluvastatin]], [[Fondaparinux]], [[Fosamprenavir]], [[Fosinopril]], [[Glimepiride]], [[Glyburide and Metformin]], [[Gold]], [[HPV Vaccine]], [[Hydrocodone bitartrate and Homatropine methylbromide]], [[Ibandronic acid]], [[Ibritumomab tiuxetan]], [[Ibuprofen]], [[Imiquimod]], [[Interferon beta-1b]], [[Ipilimumab]], [[Insulin]], [[Insulin glulisine]], [[Interferon beta-1a]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isoniazid]], [[Isotretinoin]], [[Ketorolac tromethamine]] [[Lamotrigine]], [[Leflunomide]], [[Lenalidomide]], [[levetiracetam]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Mesalamine]], [[Metformin]], [[Methimazole]], [[Methotrexate]], [[Methyldopa]], [[Methylphenidate]], [[Metronidazole]], [[Mirabegron]], [[Moxifloxacin]], [[Mupirocin]], [[Mycophenolate]], [[Nafarelin]], [[Naproxen sodium]], [[Nebivolol]], [[Nevirapine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[NSAIDs]], [[Nystatin]], [[Ofloxacin]], [[Oxycodone]], [[Oxytocin]], [[Pantoprazole]], [[Paroxetine]], [[Pemetrexed]], [[Penicillamine]], [[Pentosan polysulfate]], [[Phenacetin]], [[Phenobarbitol]], [[Phenylbutazone]], [[Piroxicam]], [[Prochlorperazine]], [[Progesterone]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Phenytoin]], [[Pioglitazone]], [[Potassium chloride]], [[Primidone]], [[Procainamide]], [[Quinidine]], [[Rifabutin]], [[Risedronate]], [[Rosiglitazone]], [[Rosuvastatin]], [[Sorafenib]], [[Streptomycin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfasalazine]], [[Sulfonamide]], [[Sulfonylurea]], [[Sumatriptan]], [[Suramin]], [[Tacrolimus]], [[Tamoxifen]], [[Terbinafine]], [[Tetracycline]], [[Thiabendazole]], [[Thioacetazone]], [[Tolterodine]], [[Tretinoin]], [[Triamcinolone]], [[Valsartan]], [[Vancomycin]], [[Vandetanib]], [[Varenicline]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]], [[Zonisamide]]<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
===Causes in Alphabetical Order===<br />
{{col-begin|width=80%}}<br />
{{col-break|width=33%}}<br />
<br />
* [[Abatacept]]<br />
* [[Abciximab]]<br />
* [[Acebutolol]]<br />
* [[Acetylcysteine]]<br />
* [[Acyclovir]]<br />
* [[Acetazolamide]]<br />
* [[Adalimumab]]<br />
* [[Adapalene]]<br />
* [[Adenosine]]<br />
* [[Albuterol]]<br />
* [[Alendronate]]<br />
* [[Aliskiren]]<br />
* [[Allopurinol]]<br />
* [[Alteplase]],<br />
* [[Amifostine]]<br />
* [[Amiloride]]<br />
* [[Aminocaproic acid]]<br />
* [[Amiodarone]]<br />
* [[Amlodipine]]<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Anastrozole]]<br />
* [[Antihemophilic factor]]<br />
* [[Anti-inhibitor coagulant complex]]<br />
* [[Antithrombin III]]<br />
* [[Argatroban]]<br />
* [[Aripiprazole]]<br />
* [[Armodafinil]]<br />
* [[Atazanavir]]<br />
* [[Atenolol]]<br />
* [[Atomoxetine]]<br />
* [[Atorvastatin calcium]]<br />
* [[Barbiturates]]<br />
* [[Benoxaprofen]]<br />
* [[Benazepril]]<br />
* [[Bendamustine]]<br />
* [[Betaxolol]]<br />
* [[Bevacizumab]]<br />
* [[Bisoprolol]]<br />
* [[Bivalirudin]]<br />
* [[Bortezomib]]<br />
* [[Brentuximab vedotin]]<br />
* [[Brimonidine]]<br />
* [[Brinzolamide]]<br />
* [[Budesonide And Formoterol Fumarate Dihydrate]]<br />
* [[Bumetanide]]<br />
* [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]]<br />
* [[Cabergoline]]<br />
* [[Candesartan]]<br />
* [[Capecitabine]]<br />
* [[Captopril]]<br />
* [[Carbamazepine]]<br />
* [[Carbidopa and Levodopa]]<br />
* [[Carteolol]]<br />
* [[Carvedilol]]<br />
* [[Cefdinir]]<br />
* [[Celecoxib]]<br />
* [[Cephalosporins]]<br />
* [[Cetuximab]]<br />
* [[Chlorambucil]]<br />
* [[Chlormezanone]]<br />
* [[Chlorothiazide]]<br />
* [[Chlorthalidone]]<br />
* [[Cholestyramine]]<br />
* [[Ciclosporin]]<br />
* [[Cilostazol]]<br />
* [[Ciprofloxacin and Dexamethasone]]<br />
* [[Citalopram Hydrobromide]]<br />
* [[Clindamycin]]<br />
* [[Clonidine]]<br />
* [[Clopidogrel]]<br />
* [[Coagulation factor VIIa]]<br />
* [[Codeine]]<br />
* [[Colestipol]]<br />
* [[Conivaptan]]<br />
* [[Crotamiton]]<br />
* [[Cyclobenzaprine]]<br />
* [[Cyclophosphamide]]<br />
* [[Dabigatran]]<br />
* [[Dalteparin]]<br />
* [[Danazol]]<br />
* [[Daptomycin]]<br />
* [[Darbepoetin Alfa]]<br />
* [[Darifenacin]]<br />
* [[Darunavir]]<br />
* [[Dasatinib]]<br />
* [[Denosumab]]<br />
* [[Desirudin]]<br />
* [[Desvenlafaxine]]<br />
* [[Dexamethasone]]<br />
* [[Dexlansoprazole]]<br />
* [[Dexmethylphenidate]]<br />
* [[Diazoxide]]<br />
* [[Diclofenac]]<br />
* [[Diclofenamide]]<br />
* [[Digoxin]]<br />
* [[Digoxin immune fab]]<br />
* [[Diltiazem]]<br />
* [[Dipyridamole]]<br />
* [[Disopyramide]]<br />
* [[Dobutamine]]<br />
* [[Dofetilide]]<br />
* [[Donepezil]]<br />
* [[Dorzolamide]]<br />
* [[Doxazosin]]<br />
* [[Doxycycline Hyclate]]<br />
* [[Dronedarone]]<br />
* [[Metronidazole]]<br />
* [[Duloxetine]]<br />
* [[Dutasteride]]<br />
* [[Dutasteride and Tamsulosin hydrochloride]]<br />
* [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]]<br />
* [[Enalapril maleate]]<br />
* [[Enoxaparin]]<br />
* [[Epoetin alfa]]<br />
* [[Eprosartan]]<br />
* [[Eptifibatide]]<br />
* [[Erlotinib]] <br />
* [[Erythropoietin]]<br />
* [[Esmolol]]<br />
* [[Esomeprazole]]<br />
* [[Eszopiclone]]<br />
* [[Etanercept]]<br />
* [[Ethacrynic acid]]<br />
* [[Ethambutol]]<br />
* [[Ethotoin]] <br />
* [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]]<br />
* [[Etravirine]]<br />
* [[Etodolac]]<br />
* [[Everolimus]]<br />
* [[Exenatide]] <br />
* [[Ezetimibe And Simvastatin]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Factor IX complex]]<br />
* [[Felodipine]]<br />
* [[Fenofibrate]]<br />
* [[Fenoldopam]]<br />
* [[Filgrastim]]<br />
* [[Flecainide]]<br />
* [[Fluconazole]]<br />
* [[Fluorometholone]]<br />
* [[Fluoxetine]]<br />
* [[Fluphenazine]]<br />
* [[Fluticasone]]<br />
* [[Fluticasone and Salmeterol]]<br />
* [[Fluvastatin]]<br />
* [[Fondaparinux]]<br />
* [[Fosamprenavir]]<br />
* [[Fosinopril]]<br />
* [[Glimepiride]]<br />
* [[Glyburide]]<br />
* [[Glipizide]]<br />
* [[Glucagon]]<br />
* [[Glyburide and Metformin]]<br />
* [[Gold]]<br />
* [[HPV Vaccine]]<br />
* [[Hydrocodone bitartrate and Homatropine methylbromide]]<br />
* [[Ibandronic acid]]<br />
* [[Ibritumomab tiuxetan]]<br />
* [[Ibuprofen]]<br />
* [[Imiquimod]]<br />
* [[Ipilimumab]]<br />
* [[Ipratropium Bromide And Albuterol]]<br />
* [[Insulin]]<br />
* [[Insulin glulisine]]<br />
* [[Interferon beta-1a]]<br />
* [[Interferon beta-1b]] <br />
* [[Irbesartan]]<br />
* [[Isoniazid]] <br />
* [[Isotretinoin]]<br />
* [[Ketorolac tromethamine]]<br />
* [[Lamotrigine]] <br />
* [[Leflunomide]]<br />
* [[Lenalidomide]]<br />
* [[Levetiracetam]] <br />
* [[Levonorgestrel and Ethinyl estradiol]]<br />
* [[Linagliptin]]<br />
* [[Linagliptin and Metformin hydrochloride]]<br />
* [[Lisinopril and Hydrochlorothiazide]]<br />
* [[Losartan and Hydrochlorothiazide]]<br />
* [[Medroxyprogesterone]]<br />
* [[Mefenamic acid]]<br />
* [[Meloxicam]]<br />
* [[Mesalamine]]<br />
* [[Metformin]]<br />
* [[Methotrexate]]<br />
* [[Methyldopa]] <br />
* [[Methylphenidate]]<br />
* [[Mirabegron]]<br />
* [[Moxifloxacin]]<br />
* [[Mupirocin]]<br />
* [[Mycophenolate]]<br />
* [[Nafarelin]]<br />
* [[Naproxen sodium]]<br />
* [[Nebivolol]] <br />
* [[Nevirapine]] <br />
* [[Nitrofurantoin]]<br />
* [[Norgestimate and Ethinyl estradiol]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[NSAIDs]]<br />
* [[Nystatin]]<br />
* [[Ofloxacin]]<br />
* [[Olmesartan]]<br />
* [[Oxycodone]]<br />
* [[Oxytocin]]<br />
* [[Pantoprazole]]<br />
* [[Paroxetine]]<br />
* [[Pemetrexed]]<br />
* [[Penicillamine]]<br />
* [[Pentosan polysulfate]]<br />
* [[Phenacetin]] <br />
* [[Phenobarbitol]] <br />
* [[Phenylbutazone]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Phenytoin]]<br />
* [[Pimecrolimus]] <br />
* [[Pioglitazone]]<br />
* [[Piroxicam]]<br />
* [[Potassium chloride]]<br />
* [[Primidone]] <br />
* [[Procainamide]] <br />
* [[Prochlorperazine]]<br />
* [[Progesterone]]<br />
* [[Quinidine]]<br />
* [[Rifabutin]]<br />
* [[Risedronate]]<br />
* [[Rosiglitazone]]<br />
* [[Rosuvastatin]] <br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
* [[Sorafenib]]<br />
* [[Streptomycin]]<br />
* [[Sulfacetamide sodium And Prednisolone acetate]] <br />
* [[Sulfasalazine]] <br />
* [[Sulfonamide]]<br />
* [[Sulfonylurea]]<br />
* [[Sumatriptan]]<br />
* [[Suramin]]<br />
* [[Tacrolimus]]<br />
* [[Tamoxifen]]<br />
* [[Terbinafine]] <br />
* [[Tetracycline]] <br />
* [[Thiabendazole]] <br />
* [[Thioacetazone]]<br />
* [[Tolterodine]]<br />
* [[Tretinoin]]<br />
* [[Triamcinolone]]<br />
* [[Valsartan]]<br />
* [[Vancomycin]] <br />
* [[Vandetanib]]<br />
* [[Venlafaxine]] <br />
* [[Varenicline]]<br />
* [[Zaleplon]]<br />
* [[Zanamivir]]<br />
* [[Zidovudine]]<br />
* [[Zolpidem]]<br />
* [[Zonisamide]]<br />
{{col-end}}<br />
<br />
===Causes by Specific Allergic Reactions<ref>{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy | journal = The Journal of Allergy and Clinical Immunology | date = 2010-02 | pmid = 20176256 }}</ref><ref>{{cite book | last = Lee | first = Anne | title = Adverse drug reactions | publisher = Pharmaceutical Press | location = London Chicago | year = 2006 | isbn = 0853696012 }}</ref>===<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Cutaneous reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Exanthems<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Delayed-type hypersensitivity <BR> ▸ Evolve over days after drug initiation <BR> ▸ Diffuse macules and papules <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[Amlodipine]], [[Amphotericin]], [[Barbiturates]], [[Captopril]], [[carbamazepine]], [[cephalosporins]], [[chloramphenicol]], [[Digoxin]], [[Erythromycin]], [[Furosemide]], [[gentamicin]], [[Glipizide]], [[gold salts]], [[Lithium]], [[Nalidixic acid]], [[Nitrofurantoin]], [[Penicillins]], [[Phenothiazines]], [[Phenylbutazone]], [[Phenytoin]], [[Sulfonamides]], [[Thiazides]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Urticaria/ angioedema<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Often IgE mediated <BR> ▸ Onset within minutes of drug initiation<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[ACE inhibitors]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Alteplase]], [[Aminosalicylic acid]], [[Amlodipine]], [[Amlodipine and Benazepril]], [[Anastrozole]], [[Anti-inhibitor coagulant complex]], [[Anticonvulsants]], [[Antihemophilic factor]], [[Antithrombin III]], [[Aripiprazole]], [[Armodafinil]], [[Aspirin]], [[Atomoxetine]], [[Atropine]], [[Beclometasone dipropionate]], [[Benazepril]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Captopril]], [[Carbidopa and Levodopa]], [[Carvedilol]], [[Celecoxib]], [[cephalosporins]], [[Cetuximab]], [[Cholestyramine]], [[Ciclosporin]], [[Cisplatin]], [[Clomifene]], [[Clonidine]], [[Clopidogrel]], [[Colestipol]], [[Cyclobenzaprine]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Darunavir]], [[Dasatinib]], [[Denosumab]], [[desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Dextran]], [[Diflunisal]], [[Digoxin immune fab]], [[Dofetilide]], [[Donepezil]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Erythropoietin]], [[Esomeprazole]], [[Eszopiclone]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Febuxostat]], [[Felodipine]], [[Fesoterodine]], [[Filgrastim]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fosinopril]], [[Frovatriptan]], [[Gemfibrozil]], [[Gentamicin]], [[Glimepiride]], [[Glipizide]], [[Glyburide]], [[Heparin]], [[Hydralazine]], [[Hydroxychloroquine]], [[Hyoscyamine]], [[Ibuprofen]], [[Indomethacin]], [[Interferon beta-1a]], [[Ipratropium bromide]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isotretinoin]], [[Isradipine]], [[Lamotrigine]], [[Levalbuterol]], [[Levonorgestrel and Ethinyl estradiol]], [[Levothyroxine]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Liraglutide]], [[Lisinopril]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Minocycline hydrochloride]], [[Moxifloxacin ophthalmic]], [[Mupirocin]], [[Losartan]], [[Meloxicam]], [[Metaxalone]], [[Methimazole]], [[Methocarbamol]], [[Methylphenidate]], [[Metoclopramide]], [[Metolazone]], [[Mirabegron]], [[Modafinil]], [[Moexipril hydrochloride]], [[Monoclonal antibodies]], [[Moxifloxacin]], [[Nabumetone]], [[Nafarelin]], [[Naltrexone]], [[Naproxen and esomeprazole magnesium]], [[Nisoldipine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Opioids]], [[Orphenadrine]], [[Oxcarbazepine]], [[Oxycodone]], [[Pantoprazole]], [[Pegfilgrastim]], [[Penicillins]], [[Pentamidine Isethionate]], [[Pentoxifylline]], [[Perindopril]], [[Phentermine]], [[Pramipexole]], [[Prochlorperazine]], [[Promethazine]], [[Rifaximin]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Sertraline]], [[Pitavastatin]], [[Procainamide]], [[Rizatriptan]], [[Quinidine sulfate]], [[Quinine]], [[Ramipril]], [[Ranolazine]], [[Repaglinide]], [[Risedronate]], [[Rosuvastatin]], [[Sitagliptin]], [[Sulfonamides]], [[Sumatriptan]], [[Tenofovir]], [[Tetracyclines]], [[Thalidomide]], [[Thiouracil]], [[Ticlopidine]], [[Tizanidine]], [[Tocilizumab]], [[Tolterodine]], [[Tubocurarine]], [[Ustekinumab]], [[Valacyclovir]], [[Valsartan]], [[Vancomycin]], [[Vardenafil]], [[Varenicline]], [[Zaleplon]], [[Zolmitriptan]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Fixed drug eruption<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hyperpigmented plaques that recur at same skin or mucosal site<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[ACE inhibitors]], [[adalimumab]], [[allopurinol]], [[amlodipine]], [[aspirin]], [[barbiturates]], [[benzodiazepines]], [[carbamazepine]], [[cephalosporins]], [[clindamycin]], [[co-trimoxazole]], [[dextromethorphan]], [[diltiazem]], [[fluconazole]], [[lamotrigine]], [[lansoprazole]], [[metronidazole]], [[NSAIDs]], [[paclitaxel]], [[paracetamol]], [[penicillin]], [[phenolphthalein]], [[omeprazole]], [[quinine]], [[salicylates]], [[sulfonamides]], [[terbinafine]], [[tetracyclines]], [[trimethoprim]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pustules<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Acute generalized eczematous pustulosis or acneiform rash<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[antibiotics]], [[calcium-channel blockers]], [[corticosteroids]], [[sirolimus]],[[Fluticasone]],[[Erlotinib]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Bullous<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Flaccid or tense blisters <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Argatroban]], [[Bendamustine]], [[Captopril]], [[Carbidopa and Levodopa]], [[Dasatinib]], [[Erlotinib]], [[Penicillamine]], [[Furosemide]], [[Risedronate]], [[Vancomycin]],[[Abciximab]],[[Warfarin]], [[Topiramate]],[[Linezolid]],[[Mirtazapine]],[[Dapsone]], [[Allopurinol]],[[Captopril ]],[[Captopril and Hydrochlorothiazide]],[[Clopidogrel]],[[Erlotinib]],[[Fosinopril]], [[Ibuprofen]], [[Imatinib]],[[Indapamide]],[[Risedronate]],[[Zolpidem]],[[Dasatinib]],[[Minoxidil]],[[Labetalol]],[[Phenytoin]],[[Dalteparin]],[[Bendamustine]],[[Tinzaparin]],[[Tamoxifen]],[[ clarithromycin]],[[Atorvastatin calcium]],[[Caduet]],[[Ticarcillin/Clavulanate]],[[Terbinafine]],[[Quinine]],[[Nevirapine]],[[Topiramate]],[[Perindopril]],[[Moexipril/Hydrochlorothiazide]], [[Naproxen sodium]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Cutaneous lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Erythematous/scaly plaques in photodistribution<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Hydrochlorothiazide]], [[calcium-channel blockers]], [[ACEIs]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Stevens-Johnson syndrome (SJS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Purpuric macules on face and trunk with &lt;10% epidermal detachment, fever, stomatitis, ocular involvement<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Antibiotics]], [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Beta-lactam|Β-lactam antibiotics]], [[Brinzolamide]], [[Carbamazepine]], [[Carvedilol]], [[Celecoxib]], [[Chlorpropamide]], [[Co-trimoxazole]], [[Darunavir]], [[Diflunisal]], [[Dorzolamide]], [[Duloxetine]], [[efavirenz, emtricitabine, and tenofovir disoproxil fumarate]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Fenofibrate]], [[Glimepiride]], [[Gold]], [[H2 Antagonist]]s, [[Histamine]], [[Hydroxychloroquine]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]],[[Lisinopril and Hydrochlorothiazide]], [[Macrolides]], [[Mefenamic acid]], [[Meloxicam]], [[Metolazone]], [[Mefloquine]], [[Methotrexate]], [[Mexiletine]], [[Minocycline hydrochloride]], [[Minoxidil]], [[Mirabegron]], [[Modafinil]], [[Naproxen and esomeprazole magnesium]], [[Piroxicam]], [[Moxifloxacin]], [[Nitrofurantoin]], [[NSAIDS]], [[Ofloxacin]], [[Olmesartan medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Phenothiazines]], [[Phenytoin]], [[Rifampicin]], [[Rivaroxaban]], [[Simvastatin]], [[Sitagliptin]], [[Spironolactone]], [[sulfacetamide sodium and prednisolone acetate]], [[Sulfonamides]], [[Tadalafil]], [[Tetracyclines]], [[Thalidomide]], [[Thiazides]], [[Ticlopidine]], [[Varenicline]], [[Zidovudine]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Toxic epidermal necrolysis (TEN)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Similar to SJS but >30% epidermal detachment<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Allopurinol]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Brinzolamide]], [[Carbamazepine]], [[Celecoxib]], [[Diflunisal]], [[Dorzolamide]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Finasteride]], [[Gold]], [[Griseofulvin]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]], [[Lisinopril and Hydrochlorothiazide]], [[Mefenamic acid]], [[Meloxicam]], [[Methotrexate]], [[Metolazone]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Naproxen and esomeprazole magnesium]], [[Nitrofurantoin]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Penicillins]], [[Phenytoin]], [[Piroxicam]], [[Salicylates]], [[Sitagliptin]], [[Spironolactone]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[tetracyclines]], [[Thalidomide]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Organ-specific reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pulmonary<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Pulmonary fibrosis, hypersensitivity pneumonitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Nitrofurantoin]], [[bleomycin]], [[Cabergoline]], [[Cetuximab]], [[Desvenlafaxine]], [[Dronedarone]], [[Erlotinib]], [[Hydrochlorothiazide]], [[Methyclothiazide]], [[Methotrexate]], [[Amiodarone]], [[Moxifloxacin]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hepatic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hepatitis, cholestasis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Aminosalicylic acid|Para-aminosalicylic acid]], [[Brinzolamide]], [[Dorzolamide]], [[Ofloxacin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[phenothiazines]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Renal<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Interstitial nephritis, membranous glomerulonephritis <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |[[Ofloxacin]], [[Penicillin]], [[sulfonamides]], [[gold]], [[penicillamine]], [[allopurinol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hematologic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hemolytic anemia, thrombocytopenia, granulocytopenia<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |<br />
▸ Hemolytic anemia — [[5-Azacytidine]], [[Acetophenazine]], [[Aclarubicin]], [[Actinomycin D]], [[Albendazole]], [[Alemtuzumab]], [[Aminopyrine]], [[Amitriptyline]], [[Amodiaquine]], [[Anakinra]], [[Antipyrine]], [[Azathioprine]], [[Bevacizumab]], [[Bortezomib]], [[Captopril]], [[Carbimazole]], [[Caspofungin]], [[Chloramphenicol]], [[Chlorpromazine]], [[Ciclosporin]], [[Cidofovir]], [[Cilazapril]], [[Clofarabine]], [[Clozapine]], [[Deferiprone]], [[Desipramine]], [[Docetaxel]], [[Dothiepin]], [[Doxorubicin]], [[Eflornithine]], [[Ethosuximide]], [[Erlotinib]], [[Ethotoin]], [[Flucytosine]], [[Fludarabine]], [[Fondaparinux]], [[Ganciclovir]], [[Gemcitabine]], [[Glimepiride]], [[Glyburide]], [[Glyburide and Metformin]], [[Gold salts]], [[Hydroxycarbamide]], [[Hypersplenism]], [[Ibritumomab tiuxetan]], [[Idarubicin]], [[Imatinib mesylate]], [[Interferon alpha]], [[Interferon beta]], [[Irinotecan]], [[Isoniazid]], [[Levomepromazine]], [[Lisinopril and Hydrochlorothiazide]], [[Mercaptopurine]], [[Methimazole]], [[Mirtazapine]], [[Mitoxantrone]], [[Nortriptyline]], [[Ofloxacin]], [[Paclitaxel]], [[Penicillamine]], [[Pentamidine]], [[Pentostatin]], [[Perazine]], [[Phenylbutazone]], [[Phenytoin]], [[Pipothiazine]], [[Procainamide]], [[Propylthiouracil]], [[Pyrimethamine]], [[Quinidine]], [[Remoxipride]], [[Riluzole]], [[Stiripentol]], [[Sulfasalazine]], [[Sulphonamides]], [[Ticlopidine]], [[Topotecan]], [[Trastuzumab]], [[Trimetrexate]], [[Valganciclovir]], [[Zidovudine]], [[Zileuton]]<br />
<br />
▸ Thrombocytopenia — [[Abciximab]], [[Aldesleukin]], [[Amobarbital]], [[Amrinone]], [[Armodafinil]], [[Capreomycin]], [[Carboplatin]], [[Cefotaxime]], [[Cefotetan]], [[Cefoxitin]], [[Ceftizoxime]], [[Chloramphenicol]], [[Chlorpropamide]], [[Ciclosporin]], [[Cinoxacin]], [[Claforan]], [[Diabinese]], [[Digoxin]], [[Disopyramide]], [[Enoxaparin]], [[Eptifibatide]], [[Erlotinib]], [[Estrogens]], [[Ethanol]], [[Exna]], [[Fondaparinux]], [[Glyburide]], [[Heparin]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Paraplatin]], [[Phenylbutazone]], [[Procainamide]], [[Proleukin]], [[Rifabutin]], [[Secobarbital]], [[Sulfonamides]], [[Thiazides]], [[Tuinal]]<br />
<br />
▸ Granulocytopenia — [[Acetazolamide]], [[Aripiprazole]], [[Benzthiazide]], [[Bortezomib]], [[Brinzolamide]], [[Bumetanide]], [[Capecitabine]], [[Captopril]], [[Carbamazepine]], [[Ceftazidime]], [[Celecoxib]], [[Chlorpropamide]], [[Dapsone]], [[Diabinese]], [[Disopyramide]], [[Dorzolamide]], [[Enalapril maleate]], [[Exna]], [[Fosinopril]], [[Fortaz]], [[Glyburide]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Penicillin]], [[quinine]], [[Rifabutin]], [[salicylate]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfadiazine]], [[sulfonamides]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Multiorgan reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Anaphylaxis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, angioedema, bronchospasm, gastrointestinal symptoms, hypotension<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Albuterol]], [[Aliskiren]], [[Alteplase]], [[Amlodipine and Benazepril]], [[Aminocaproic acid]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Aripiprazole]], [[Armodafinil]], [[Atomoxetine]], [[Beclometasone dipropionate]], [[Beta-lactam|β-lactam antibiotics]], [[Betaxolol]], [[Bisoprolol]], [[Bivalirudin]], [[Bortezomib]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[monoclonal antibodies]], [[adalimumab]], [[Benazepril]], [[Bendamustine]], [[Captopril]], [[Carteolol]], [[Carvedilol]], [[Celecoxib]], [[Ciclosporin]], [[Ciprofloxacin and Dexamethasone]], [[Cisplatin]], [[Clopidogrel]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Denosumab]], [[Desirudin]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diflunisal]], [[Digoxin]], [[Digoxin immune fab]], [[Dobutamine]], [[Enalapril maleate]], [[Enoxaparin]], [[epoetin alfa]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Ethambutol]], [[Etodolac]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Fenoldopam]], [[Fluconazole]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fondaparinux]], [[Furosemide]], [[Glimepiride]], [[Glucagon]], [[Heparin]], [[HPV Vaccine]], [[Hyoscyamine]], [[Ibandronic acid]], [[Infliximab]], [[Insulin glargine]], [[Insulin glulisine]], [[Insulin lispro]], [[Interferon beta-1a]], [[Interferon beta-1b]], [[Ipratropium Bromide And Albuterol]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Labetalol]], [[Levalbuterol]], [[Lepirudin]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Metaxalone]], [[Methylphenidate]], [[Methyltestosterone]], [[Metoclopramide]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Mupirocin]], [[Nabumetone]], [[Nadolol]], [[Nebivolol]], [[Nitrofurantoin]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Ondansetron]], [[Oxytocin]], [[Penbutolol]], [[Pindolol]], [[Prochlorperazine]], [[Propranolol]], [[Progesterone]], [[Protamine]], [[Rituximab]], [[Rivaroxaban]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Solifenacin]], [[Sumatriptan]], [[Tinzaparin]], [[Tocilizumab]], [[Trastuzumab]], [[Triamcinolone]], [[Triamterene]], [[Urokinase]], [[Valganciclovir hydrochloride]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Systemic lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Arthralgia, myalgias, fever, malaise<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Armodafinil]], [[Hydralazine]], [[procainamide]], [[isoniazid]], [[propafenone]], [[Levonorgestrel and Ethinyl estradiol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous or visceral vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[aspirin]], [[Beta-lactam|β-lactam antibiotics]], [[carbamazepine]], [[carbimazole]], [[co-trimoxazole]], [[diltiazem]], [[erythromycin]], [[gold]], [[G-CSF]], [[GM-CSF]], [[Hydralazine]], [[interferons]], [[methotrexate]], [[minocycline]], [[NSAIDs]], [[penicillamine]], [[propylthiouracil]], [[retinoids]], [[sulfasalazine]], [[sulfonamides]], [[thiazides]], [[thrombolytics]], [[Adalimumab]], [[Amiodarone]], [[Cefdinir]], [[Methyldopa]], [[Amoxapine]], [[Moxifloxacin]], [[Fluticasone]], [[Acyclovir]], [[Allopurinol]], [[Amlodipine]], [[Bortezomib]], [[Captopril]], [[Captopril and Hydrochlorothiazide]], [[Chlorothiazide]], [[Chlorthalidone]], [[Clopidogrel]], [[Delavirdine]], [[Enalapril maleate]], [[Filgrastim]], [[Fosinopril]], [[Furosemide]], [[Hydrochlorothiazide]],,[[Imatinib]], [[Isotretinoin]], [[Lisinopril]], [[Lisinopril/Hydrochlorothiazide]], [[Losartan]], [[Lovastatin]], [[Methyclothiazide]], [[Metolazone]], [[Ofloxacin]], [[Pravastatin]], [[Prazosin]], [[Ramipril]], [[Abatacept]], [[Spironolactone]], [[Spironolactone/Hydrochlorothiazide]], [[Ticlopidine]], [[Valsartan]], [[Colchicine]], [[Quinidine]], [[Quinidine gluconate]], [[Dronedarone]], [[Enoxaparin]], [[Thiazide]], [[Fluticasone/salmeterol]], [[Infliximab]], [[Sitagliptin]], [[Enalaprilat]], [[Fluoxetine]], [[Glyburide]], [[Hydrochloride]], [[Hydroflumethiazide]], [[Polythiazide]], [[Valaciclovir]], [[Simvastatin]], [[Losartan and Hydrochlorothiazide]], [[Methylphenidate]], [[Mirabegron]], [[Dexlansoprazole]], [[Sumatriptan]], [[Bisoprolol]], [[Rituximab]], [[Aggrenox]], [[Penicillin G]], [[Norfloxacin]], [[Isoniazid]], [[Penicillin G procaine]], [[Famciclovir]], [[Cefuroxime]], [[Rifampin isoniazid]], [[Rifampin]], [[Interferon alfa-2a]], [[Amoxicillin-clavulanate potassium]], [[Interferon alfa-2a]], [[Pegylated interferon alfa-2a]], [[vancomycin]], [[Atovaquone proguanil]], [[Terbinafine]], [[Indinavir]], [[Ciprofloxacin Hydrochloride]], [[Lamivudine zidovudine]], [[Interferon alfa-2b]], [[Gemifloxacin mesylate]], [[Pentamidine Isethionate]], [[Abacavir lamivudine zidovudine]], [[Nitrofurantoin]], [[Zidovudine]], [[Quinine Sulfate]], [[Valproic acid]], [[Divalproex]], [[Niacin/Simvastatin]], [[Ezetimibe/Simvastatin]], [[Felodipine]], [[Fosinopril/Hydrochlorothiazide]], [[Moexipril/Hydrochlorothiazide]], [[Quinapril/Hydrochlorothiazide]], [[Enalapril maleate/Hydrochlorothiazide]], [[Enalapril/Felodipine]], [[Perindopril]] ,[[Fluvastatin]], [[Diltiazem]], [[Metoprolol succinate and hydrochlorothiazide]], [[Nebivolol]], [[Amiodarone]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Amlodipine Besylate]], [[Divalproex]], [[Pioglitazone/Glimepiride]], [[Aspirin/Dipyridamole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Serum sickness<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, arthralgia, fever<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Heterologous]] [[antibodies]], [[infliximab]], [[Cefdinir]], [[Bupropion]], [[Levothyroxine]], [[Tetracycline hydrochloride]], [[Antivenom]], [[Glatiramer acetate]], [[Antivenin]],,[[Measles]], [[Ticlopidine]], [[Clopidogrel]], [[Novobiocin]], [[Epinephrine]], [[Omalizumab]], [[Rituximab]], [[Immunosuppressive drug]], [[Digoxin]], [[Levothyroxine]], [[Ciprofloxacin]], [[Cefprozil]], [[Cefaclor]], [[Oxacillin]], [[Amoxicillin]], [[Ofloxacin]], [[Penicillin G benzathine]], [[Ampicillin]], [[Ceftibuten]], [[Cefpodoxime]], [[Terbinafine]], [[Gemifloxacin]], [[Metronidazole]], [[Cefadroxil]], [[Doxycycline]], [[Levofloxacin]], [[Minocycline]], [[Moxifloxacin]], [[Sulfadiazine]], [[Lincomycin]], [[Sulfamethoxazole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Drug reaction with eosinophilia and systemic symptoms (DRESS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[anticonvulsant]]s, [[Armodafinil]], [[atazanavir]], [[Carbamazepine]], [[minocycline]], [[sulfonamide]]s, [[spironolactone]]<br />
|}<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Allergology]]<br />
[[Category:Immunology]]<br />
[[Category:Emergency medicine]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Drug_allergy_causes&diff=1058951Drug allergy causes2015-01-23T14:57:05Z<p>Deepika Beereddy: /* Causes by Specific Allergic Reactions{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy |...</p>
<hr />
<div>__NOTOC__<br />
{{Drug allergy}}<br />
{{CMG}}; {{AE}} {{CP}}, {{JM}}<br />
<br />
==Overview==<br />
The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.<br />
<br />
==Causes==<br />
===Common Causes===<br />
When a medication causes an allergic reaction, it is called an [[allergen]]. The following is a short list of the most common drug allergens<br />
*Antibiotics<br />
**[[Penicillin]]<br />
**[[Sulfonamide (medicine)|Sulfa drugs]]<br />
**[[Tetracycline]]<br />
*Analgesics<br />
**[[Codeine]]<br />
**[[Non-steroidal anti-inflammatory drug]]s (NSAIDs)<br />
*Anticonvulsives<br />
**[[Phenytoin|Dilantin]]<br />
**[[Carbamazepine|Tegretol]]<br />
<br />
===Causes by Organ System===<br />
<br />
{|style="width:75%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Effect'''<br />
|bgcolor="Beige"| [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Adapalene]], [[Adenosine]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Allopurinol]], [[Alteplase]], [[Amifostine]], [[Amiloride]], [[Aminocaproic acid]], [[Amiodarone]], [[Amlodipine]], [[Amlodipine besylate and Valsartan]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Antithrombin III]], [[Argatroban]], [[Aripiprazole]], [[Armodafinil]], [[Atazanavir]], [[Atenolol]], [[Atomoxetine]], [[Atorvastatin calcium]], [[Barbiturates]], [[Benazepril]], [[Bendamustine]], [[Benoxaprofen]], [[Betaxolol]], [[Bevacizumab]], [[Bisoprolol]], [[Botulinum toxin]], [[Brentuximab vedotin]], [[Brimonidine]], [[Brinzolamide]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Bumetanide]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[Cabergoline]], [[Captopril]], [[Carbamazepine]], [[Carbidopa and Levodopa]], [[Carteolol]], [[Carvedilol]], [[Cefdinir]], [[Celecoxib]], [[Cephalosporins]], [[Cetuximab]], [[Chlorambucil]], [[Chlormezanone]], [[Chlorothiazide]], [[Chlorthalidone]], [[Cholestyramine]], [[Ciclosporin]], [[Cilostazol]], [[Ciprofloxacin and Dexamethasone]], [[Citalopram Hydrobromide]], [[Clindamycin]], [[Clonidine]], [[Clopidogrel]], [[Coagulation factor VIIa]], [[Codeine]], [[Colestipol]], [[Conivaptan]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Danazol]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Dasatinib]], [[Denosumab]], [[Desirudin]], [[Desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diazoxide]], [[Diclofenac]], [[Diclofenamide]], [[Dofetilide]], [[Digoxin]], [[Digoxin immune fab]], [[Diltiazem]], [[Donepezil]], [[Dipyridamole]], [[Disopyramide]], [[Dobutamine]], [[Dorzolamide]], [[Doxycycline Hyclate]], [[Dronedarone]], [[Duloxetine]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]], [[Ethynodiol diacetate and ethinyl estradiol]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Eprosartan]], [[Eptifibatide]], [[Erlotinib]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]], [[Ethacrynic acid]], [[Ethambutol]], [[Ethotoin]], [[Etodolac]], [[Etravirine]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Ezetimibe And Simvastatin]], [[Factor IX complex]], [[Felodipine]], [[Fenofibrate]], [[Fenoldopam]], [[Filgrastim]], [[Flecainide]], [[Fluconazole]], [[Fluphenazine]], [[Fluticasone]], [[Fluticasone and Salmeterol]], [[Fluvastatin]], [[Fondaparinux]], [[Fosamprenavir]], [[Fosinopril]], [[Glimepiride]], [[Glyburide and Metformin]], [[Gold]], [[HPV Vaccine]], [[Hydrocodone bitartrate and Homatropine methylbromide]], [[Ibandronic acid]], [[Ibritumomab tiuxetan]], [[Ibuprofen]], [[Imiquimod]], [[Interferon beta-1b]], [[Ipilimumab]], [[Insulin]], [[Insulin glulisine]], [[Interferon beta-1a]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isoniazid]], [[Isotretinoin]], [[Ketorolac tromethamine]] [[Lamotrigine]], [[Leflunomide]], [[Lenalidomide]], [[levetiracetam]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Mesalamine]], [[Metformin]], [[Methimazole]], [[Methotrexate]], [[Methyldopa]], [[Methylphenidate]], [[Metronidazole]], [[Mirabegron]], [[Moxifloxacin]], [[Mupirocin]], [[Mycophenolate]], [[Nafarelin]], [[Naproxen sodium]], [[Nebivolol]], [[Nevirapine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[NSAIDs]], [[Nystatin]], [[Ofloxacin]], [[Oxycodone]], [[Oxytocin]], [[Pantoprazole]], [[Paroxetine]], [[Pemetrexed]], [[Penicillamine]], [[Pentosan polysulfate]], [[Phenacetin]], [[Phenobarbitol]], [[Phenylbutazone]], [[Piroxicam]], [[Prochlorperazine]], [[Progesterone]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Phenytoin]], [[Pioglitazone]], [[Potassium chloride]], [[Primidone]], [[Procainamide]], [[Quinidine]], [[Rifabutin]], [[Risedronate]], [[Rosiglitazone]], [[Rosuvastatin]], [[Sorafenib]], [[Streptomycin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfasalazine]], [[Sulfonamide]], [[Sulfonylurea]], [[Sumatriptan]], [[Suramin]], [[Tacrolimus]], [[Tamoxifen]], [[Terbinafine]], [[Tetracycline]], [[Thiabendazole]], [[Thioacetazone]], [[Tolterodine]], [[Tretinoin]], [[Triamcinolone]], [[Valsartan]], [[Vancomycin]], [[Vandetanib]], [[Varenicline]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]], [[Zonisamide]]<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
===Causes in Alphabetical Order===<br />
{{col-begin|width=80%}}<br />
{{col-break|width=33%}}<br />
<br />
* [[Abatacept]]<br />
* [[Abciximab]]<br />
* [[Acebutolol]]<br />
* [[Acetylcysteine]]<br />
* [[Acyclovir]]<br />
* [[Acetazolamide]]<br />
* [[Adalimumab]]<br />
* [[Adapalene]]<br />
* [[Adenosine]]<br />
* [[Albuterol]]<br />
* [[Alendronate]]<br />
* [[Aliskiren]]<br />
* [[Allopurinol]]<br />
* [[Alteplase]],<br />
* [[Amifostine]]<br />
* [[Amiloride]]<br />
* [[Aminocaproic acid]]<br />
* [[Amiodarone]]<br />
* [[Amlodipine]]<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Anastrozole]]<br />
* [[Antihemophilic factor]]<br />
* [[Anti-inhibitor coagulant complex]]<br />
* [[Antithrombin III]]<br />
* [[Argatroban]]<br />
* [[Aripiprazole]]<br />
* [[Armodafinil]]<br />
* [[Atazanavir]]<br />
* [[Atenolol]]<br />
* [[Atomoxetine]]<br />
* [[Atorvastatin calcium]]<br />
* [[Barbiturates]]<br />
* [[Benoxaprofen]]<br />
* [[Benazepril]]<br />
* [[Bendamustine]]<br />
* [[Betaxolol]]<br />
* [[Bevacizumab]]<br />
* [[Bisoprolol]]<br />
* [[Bivalirudin]]<br />
* [[Bortezomib]]<br />
* [[Brentuximab vedotin]]<br />
* [[Brimonidine]]<br />
* [[Brinzolamide]]<br />
* [[Budesonide And Formoterol Fumarate Dihydrate]]<br />
* [[Bumetanide]]<br />
* [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]]<br />
* [[Cabergoline]]<br />
* [[Candesartan]]<br />
* [[Capecitabine]]<br />
* [[Captopril]]<br />
* [[Carbamazepine]]<br />
* [[Carbidopa and Levodopa]]<br />
* [[Carteolol]]<br />
* [[Carvedilol]]<br />
* [[Cefdinir]]<br />
* [[Celecoxib]]<br />
* [[Cephalosporins]]<br />
* [[Cetuximab]]<br />
* [[Chlorambucil]]<br />
* [[Chlormezanone]]<br />
* [[Chlorothiazide]]<br />
* [[Chlorthalidone]]<br />
* [[Cholestyramine]]<br />
* [[Ciclosporin]]<br />
* [[Cilostazol]]<br />
* [[Ciprofloxacin and Dexamethasone]]<br />
* [[Citalopram Hydrobromide]]<br />
* [[Clindamycin]]<br />
* [[Clonidine]]<br />
* [[Clopidogrel]]<br />
* [[Coagulation factor VIIa]]<br />
* [[Codeine]]<br />
* [[Colestipol]]<br />
* [[Conivaptan]]<br />
* [[Crotamiton]]<br />
* [[Cyclobenzaprine]]<br />
* [[Cyclophosphamide]]<br />
* [[Dabigatran]]<br />
* [[Dalteparin]]<br />
* [[Danazol]]<br />
* [[Daptomycin]]<br />
* [[Darbepoetin Alfa]]<br />
* [[Darifenacin]]<br />
* [[Darunavir]]<br />
* [[Dasatinib]]<br />
* [[Denosumab]]<br />
* [[Desirudin]]<br />
* [[Desvenlafaxine]]<br />
* [[Dexamethasone]]<br />
* [[Dexlansoprazole]]<br />
* [[Dexmethylphenidate]]<br />
* [[Diazoxide]]<br />
* [[Diclofenac]]<br />
* [[Diclofenamide]]<br />
* [[Digoxin]]<br />
* [[Digoxin immune fab]]<br />
* [[Diltiazem]]<br />
* [[Dipyridamole]]<br />
* [[Disopyramide]]<br />
* [[Dobutamine]]<br />
* [[Dofetilide]]<br />
* [[Donepezil]]<br />
* [[Dorzolamide]]<br />
* [[Doxazosin]]<br />
* [[Doxycycline Hyclate]]<br />
* [[Dronedarone]]<br />
* [[Metronidazole]]<br />
* [[Duloxetine]]<br />
* [[Dutasteride]]<br />
* [[Dutasteride and Tamsulosin hydrochloride]]<br />
* [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]]<br />
* [[Enalapril maleate]]<br />
* [[Enoxaparin]]<br />
* [[Epoetin alfa]]<br />
* [[Eprosartan]]<br />
* [[Eptifibatide]]<br />
* [[Erlotinib]] <br />
* [[Erythropoietin]]<br />
* [[Esmolol]]<br />
* [[Esomeprazole]]<br />
* [[Eszopiclone]]<br />
* [[Etanercept]]<br />
* [[Ethacrynic acid]]<br />
* [[Ethambutol]]<br />
* [[Ethotoin]] <br />
* [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]]<br />
* [[Etravirine]]<br />
* [[Etodolac]]<br />
* [[Everolimus]]<br />
* [[Exenatide]] <br />
* [[Ezetimibe And Simvastatin]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Factor IX complex]]<br />
* [[Felodipine]]<br />
* [[Fenofibrate]]<br />
* [[Fenoldopam]]<br />
* [[Filgrastim]]<br />
* [[Flecainide]]<br />
* [[Fluconazole]]<br />
* [[Fluorometholone]]<br />
* [[Fluoxetine]]<br />
* [[Fluphenazine]]<br />
* [[Fluticasone]]<br />
* [[Fluticasone and Salmeterol]]<br />
* [[Fluvastatin]]<br />
* [[Fondaparinux]]<br />
* [[Fosamprenavir]]<br />
* [[Fosinopril]]<br />
* [[Glimepiride]]<br />
* [[Glyburide]]<br />
* [[Glipizide]]<br />
* [[Glucagon]]<br />
* [[Glyburide and Metformin]]<br />
* [[Gold]]<br />
* [[HPV Vaccine]]<br />
* [[Hydrocodone bitartrate and Homatropine methylbromide]]<br />
* [[Ibandronic acid]]<br />
* [[Ibritumomab tiuxetan]]<br />
* [[Ibuprofen]]<br />
* [[Imiquimod]]<br />
* [[Ipilimumab]]<br />
* [[Ipratropium Bromide And Albuterol]]<br />
* [[Insulin]]<br />
* [[Insulin glulisine]]<br />
* [[Interferon beta-1a]]<br />
* [[Interferon beta-1b]] <br />
* [[Irbesartan]]<br />
* [[Isoniazid]] <br />
* [[Isotretinoin]]<br />
* [[Ketorolac tromethamine]]<br />
* [[Lamotrigine]] <br />
* [[Leflunomide]]<br />
* [[Lenalidomide]]<br />
* [[Levetiracetam]] <br />
* [[Levonorgestrel and Ethinyl estradiol]]<br />
* [[Linagliptin]]<br />
* [[Linagliptin and Metformin hydrochloride]]<br />
* [[Lisinopril and Hydrochlorothiazide]]<br />
* [[Losartan and Hydrochlorothiazide]]<br />
* [[Medroxyprogesterone]]<br />
* [[Mefenamic acid]]<br />
* [[Meloxicam]]<br />
* [[Mesalamine]]<br />
* [[Metformin]]<br />
* [[Methotrexate]]<br />
* [[Methyldopa]] <br />
* [[Methylphenidate]]<br />
* [[Mirabegron]]<br />
* [[Moxifloxacin]]<br />
* [[Mupirocin]]<br />
* [[Mycophenolate]]<br />
* [[Nafarelin]]<br />
* [[Naproxen sodium]]<br />
* [[Nebivolol]] <br />
* [[Nevirapine]] <br />
* [[Nitrofurantoin]]<br />
* [[Norgestimate and Ethinyl estradiol]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[NSAIDs]]<br />
* [[Nystatin]]<br />
* [[Ofloxacin]]<br />
* [[Olmesartan]]<br />
* [[Oxycodone]]<br />
* [[Oxytocin]]<br />
* [[Pantoprazole]]<br />
* [[Paroxetine]]<br />
* [[Pemetrexed]]<br />
* [[Penicillamine]]<br />
* [[Pentosan polysulfate]]<br />
* [[Phenacetin]] <br />
* [[Phenobarbitol]] <br />
* [[Phenylbutazone]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Phenytoin]]<br />
* [[Pimecrolimus]] <br />
* [[Pioglitazone]]<br />
* [[Piroxicam]]<br />
* [[Potassium chloride]]<br />
* [[Primidone]] <br />
* [[Procainamide]] <br />
* [[Prochlorperazine]]<br />
* [[Progesterone]]<br />
* [[Quinidine]]<br />
* [[Rifabutin]]<br />
* [[Risedronate]]<br />
* [[Rosiglitazone]]<br />
* [[Rosuvastatin]] <br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
* [[Sorafenib]]<br />
* [[Streptomycin]]<br />
* [[Sulfacetamide sodium And Prednisolone acetate]] <br />
* [[Sulfasalazine]] <br />
* [[Sulfonamide]]<br />
* [[Sulfonylurea]]<br />
* [[Sumatriptan]]<br />
* [[Suramin]]<br />
* [[Tacrolimus]]<br />
* [[Tamoxifen]]<br />
* [[Terbinafine]] <br />
* [[Tetracycline]] <br />
* [[Thiabendazole]] <br />
* [[Thioacetazone]]<br />
* [[Tolterodine]]<br />
* [[Tretinoin]]<br />
* [[Triamcinolone]]<br />
* [[Valsartan]]<br />
* [[Vancomycin]] <br />
* [[Vandetanib]]<br />
* [[Venlafaxine]] <br />
* [[Varenicline]]<br />
* [[Zaleplon]]<br />
* [[Zanamivir]]<br />
* [[Zidovudine]]<br />
* [[Zolpidem]]<br />
* [[Zonisamide]]<br />
{{col-end}}<br />
<br />
===Causes by Specific Allergic Reactions<ref>{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy | journal = The Journal of Allergy and Clinical Immunology | date = 2010-02 | pmid = 20176256 }}</ref><ref>{{cite book | last = Lee | first = Anne | title = Adverse drug reactions | publisher = Pharmaceutical Press | location = London Chicago | year = 2006 | isbn = 0853696012 }}</ref>===<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Cutaneous reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Exanthems<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Delayed-type hypersensitivity <BR> ▸ Evolve over days after drug initiation <BR> ▸ Diffuse macules and papules <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[Amlodipine]], [[Amphotericin]], [[Barbiturates]], [[Captopril]], [[carbamazepine]], [[cephalosporins]], [[chloramphenicol]], [[Digoxin]], [[Erythromycin]], [[Furosemide]], [[gentamicin]], [[Glipizide]], [[gold salts]], [[Lithium]], [[Nalidixic acid]], [[Nitrofurantoin]], [[Penicillins]], [[Phenothiazines]], [[Phenylbutazone]], [[Phenytoin]], [[Sulfonamides]], [[Thiazides]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Urticaria/ angioedema<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Often IgE mediated <BR> ▸ Onset within minutes of drug initiation<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[ACE inhibitors]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Alteplase]], [[Aminosalicylic acid]], [[Amlodipine]], [[Amlodipine and Benazepril]], [[Anastrozole]], [[Anti-inhibitor coagulant complex]], [[Anticonvulsants]], [[Antihemophilic factor]], [[Antithrombin III]], [[Aripiprazole]], [[Armodafinil]], [[Aspirin]], [[Atomoxetine]], [[Atropine]], [[Beclometasone dipropionate]], [[Benazepril]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Captopril]], [[Carbidopa and Levodopa]], [[Carvedilol]], [[Celecoxib]], [[cephalosporins]], [[Cetuximab]], [[Cholestyramine]], [[Ciclosporin]], [[Cisplatin]], [[Clomifene]], [[Clonidine]], [[Clopidogrel]], [[Colestipol]], [[Cyclobenzaprine]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Darunavir]], [[Dasatinib]], [[Denosumab]], [[desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Dextran]], [[Diflunisal]], [[Digoxin immune fab]], [[Dofetilide]], [[Donepezil]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Erythropoietin]], [[Esomeprazole]], [[Eszopiclone]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Febuxostat]], [[Felodipine]], [[Fesoterodine]], [[Filgrastim]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fosinopril]], [[Frovatriptan]], [[Gemfibrozil]], [[Gentamicin]], [[Glimepiride]], [[Glipizide]], [[Glyburide]], [[Heparin]], [[Hydralazine]], [[Hydroxychloroquine]], [[Hyoscyamine]], [[Ibuprofen]], [[Indomethacin]], [[Interferon beta-1a]], [[Ipratropium bromide]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isotretinoin]], [[Isradipine]], [[Lamotrigine]], [[Levalbuterol]], [[Levonorgestrel and Ethinyl estradiol]], [[Levothyroxine]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Liraglutide]], [[Lisinopril]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Minocycline hydrochloride]], [[Moxifloxacin ophthalmic]], [[Mupirocin]], [[Losartan]], [[Meloxicam]], [[Metaxalone]], [[Methimazole]], [[Methocarbamol]], [[Methylphenidate]], [[Metoclopramide]], [[Metolazone]], [[Mirabegron]], [[Modafinil]], [[Moexipril hydrochloride]], [[Monoclonal antibodies]], [[Moxifloxacin]], [[Nabumetone]], [[Nafarelin]], [[Naltrexone]], [[Naproxen and esomeprazole magnesium]], [[Nisoldipine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Opioids]], [[Orphenadrine]], [[Oxcarbazepine]], [[Oxycodone]], [[Pantoprazole]], [[Pegfilgrastim]], [[Penicillins]], [[Pentamidine Isethionate]], [[Pentoxifylline]], [[Perindopril]], [[Phentermine]], [[Pramipexole]], [[Prochlorperazine]], [[Promethazine]], [[Rifaximin]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Sertraline]], [[Pitavastatin]], [[Procainamide]], [[Rizatriptan]], [[Quinidine sulfate]], [[Quinine]], [[Ramipril]], [[Ranolazine]], [[Repaglinide]], [[Risedronate]], [[Rosuvastatin]], [[Sitagliptin]], [[Sulfonamides]], [[Sumatriptan]], [[Tenofovir]], [[Tetracyclines]], [[Thalidomide]], [[Thiouracil]], [[Ticlopidine]], [[Tizanidine]], [[Tocilizumab]], [[Tolterodine]], [[Tubocurarine]], [[Ustekinumab]], [[Valacyclovir]], [[Valsartan]], [[Vancomycin]], [[Vardenafil]], [[Varenicline]], [[Zaleplon]], [[Zolmitriptan]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Fixed drug eruption<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hyperpigmented plaques that recur at same skin or mucosal site<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[ACE inhibitors]], [[adalimumab]], [[allopurinol]], [[amlodipine]], [[aspirin]], [[barbiturates]], [[benzodiazepines]], [[carbamazepine]], [[cephalosporins]], [[clindamycin]], [[co-trimoxazole]], [[dextromethorphan]], [[diltiazem]], [[fluconazole]], [[lamotrigine]], [[lansoprazole]], [[metronidazole]], [[NSAIDs]], [[paclitaxel]], [[paracetamol]], [[penicillin]], [[phenolphthalein]], [[omeprazole]], [[quinine]], [[salicylates]], [[sulfonamides]], [[terbinafine]], [[tetracyclines]], [[trimethoprim]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pustules<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Acute generalized eczematous pustulosis or acneiform rash<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[antibiotics]], [[calcium-channel blockers]], [[corticosteroids]], [[sirolimus]],[[Fluticasone]],[[Erlotinib]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Bullous<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Flaccid or tense blisters <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Argatroban]], [[Bendamustine]], [[Captopril]], [[Carbidopa and Levodopa]], [[Dasatinib]], [[Erlotinib]], [[Penicillamine]], [[Furosemide]], [[Risedronate]], [[Vancomycin]],[[Abciximab]],[[Warfarin]], [[Topiramate]],[[Linezolid]],[[Mirtazapine]],[[Dapsone]], [[Allopurinol]],[[Captopril ]],[[Captopril and Hydrochlorothiazide]],[[Clopidogrel]],[[Erlotinib]],[[Fosinopril]], [[Ibuprofen]], [[Imatinib]],[[Indapamide]],[[Risedronate]],[[Zolpidem]],[[Dasatinib]],[[Minoxidil]],[[Labetalol]],[[Phenytoin]],[[Dalteparin]],[[Bendamustine]],[[Tinzaparin]],[[Tamoxifen]],[[ clarithromycin]],[[Atorvastatin calcium]],[[Caduet]],[[Ticarcillin/Clavulanate]],[[Terbinafine]],[[Quinine]],[[Nevirapine]],[[Topiramate]],[[Perindopril]],[[Moexipril/Hydrochlorothiazide]], [[Naproxen sodium]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Cutaneous lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Erythematous/scaly plaques in photodistribution<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Hydrochlorothiazide]], [[calcium-channel blockers]], [[ACEIs]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Stevens-Johnson syndrome (SJS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Purpuric macules on face and trunk with &lt;10% epidermal detachment, fever, stomatitis, ocular involvement<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Antibiotics]], [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Beta-lactam|Β-lactam antibiotics]], [[Brinzolamide]], [[Carbamazepine]], [[Carvedilol]], [[Celecoxib]], [[Chlorpropamide]], [[Co-trimoxazole]], [[Darunavir]], [[Diflunisal]], [[Dorzolamide]], [[Duloxetine]], [[efavirenz, emtricitabine, and tenofovir disoproxil fumarate]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Fenofibrate]], [[Glimepiride]], [[Gold]], [[H2 Antagonist]]s, [[Histamine]], [[Hydroxychloroquine]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]],[[Lisinopril and Hydrochlorothiazide]], [[Macrolides]], [[Mefenamic acid]], [[Meloxicam]], [[Metolazone]], [[Mefloquine]], [[Methotrexate]], [[Mexiletine]], [[Minocycline hydrochloride]], [[Minoxidil]], [[Mirabegron]], [[Modafinil]], [[Naproxen and esomeprazole magnesium]], [[Piroxicam]], [[Moxifloxacin]], [[Nitrofurantoin]], [[NSAIDS]], [[Ofloxacin]], [[Olmesartan medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Phenothiazines]], [[Phenytoin]], [[Rifampicin]], [[Rivaroxaban]], [[Simvastatin]], [[Sitagliptin]], [[Spironolactone]], [[sulfacetamide sodium and prednisolone acetate]], [[Sulfonamides]], [[Tadalafil]], [[Tetracyclines]], [[Thalidomide]], [[Thiazides]], [[Ticlopidine]], [[Varenicline]], [[Zidovudine]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Toxic epidermal necrolysis (TEN)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Similar to SJS but >30% epidermal detachment<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Allopurinol]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Brinzolamide]], [[Carbamazepine]], [[Celecoxib]], [[Diflunisal]], [[Dorzolamide]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Finasteride]], [[Gold]], [[Griseofulvin]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]], [[Lisinopril and Hydrochlorothiazide]], [[Mefenamic acid]], [[Meloxicam]], [[Methotrexate]], [[Metolazone]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Naproxen and esomeprazole magnesium]], [[Nitrofurantoin]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Penicillins]], [[Phenytoin]], [[Piroxicam]], [[Salicylates]], [[Sitagliptin]], [[Spironolactone]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[tetracyclines]], [[Thalidomide]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Organ-specific reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pulmonary<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Pulmonary fibrosis, hypersensitivity pneumonitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Nitrofurantoin]], [[bleomycin]], [[Cabergoline]], [[Cetuximab]], [[Desvenlafaxine]], [[Dronedarone]], [[Erlotinib]], [[Hydrochlorothiazide]], [[Methyclothiazide]], [[Methotrexate]], [[Amiodarone]], [[Moxifloxacin]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hepatic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hepatitis, cholestasis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Aminosalicylic acid|Para-aminosalicylic acid]], [[Brinzolamide]], [[Dorzolamide]], [[Ofloxacin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[phenothiazines]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Renal<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Interstitial nephritis, membranous glomerulonephritis <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |[[Ofloxacin]], [[Penicillin]], [[sulfonamides]], [[gold]], [[penicillamine]], [[allopurinol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hematologic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hemolytic anemia, thrombocytopenia, granulocytopenia<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |<br />
▸ Hemolytic anemia — [[5-Azacytidine]], [[Acetophenazine]], [[Aclarubicin]], [[Actinomycin D]], [[Albendazole]], [[Alemtuzumab]], [[Aminopyrine]], [[Amitriptyline]], [[Amodiaquine]], [[Anakinra]], [[Antipyrine]], [[Azathioprine]], [[Bevacizumab]], [[Bortezomib]], [[Captopril]], [[Carbimazole]], [[Caspofungin]], [[Chloramphenicol]], [[Chlorpromazine]], [[Ciclosporin]], [[Cidofovir]], [[Cilazapril]], [[Clofarabine]], [[Clozapine]], [[Deferiprone]], [[Desipramine]], [[Docetaxel]], [[Dothiepin]], [[Doxorubicin]], [[Eflornithine]], [[Ethosuximide]], [[Erlotinib]], [[Ethotoin]], [[Flucytosine]], [[Fludarabine]], [[Fondaparinux]], [[Ganciclovir]], [[Gemcitabine]], [[Glimepiride]], [[Glyburide]], [[Glyburide and Metformin]], [[Gold salts]], [[Hydroxycarbamide]], [[Hypersplenism]], [[Ibritumomab tiuxetan]], [[Idarubicin]], [[Imatinib mesylate]], [[Interferon alpha]], [[Interferon beta]], [[Irinotecan]], [[Isoniazid]], [[Levomepromazine]], [[Lisinopril and Hydrochlorothiazide]], [[Mercaptopurine]], [[Methimazole]], [[Mirtazapine]], [[Mitoxantrone]], [[Nortriptyline]], [[Ofloxacin]], [[Paclitaxel]], [[Penicillamine]], [[Pentamidine]], [[Pentostatin]], [[Perazine]], [[Phenylbutazone]], [[Phenytoin]], [[Pipothiazine]], [[Procainamide]], [[Propylthiouracil]], [[Pyrimethamine]], [[Quinidine]], [[Remoxipride]], [[Riluzole]], [[Stiripentol]], [[Sulfasalazine]], [[Sulphonamides]], [[Ticlopidine]], [[Topotecan]], [[Trastuzumab]], [[Trimetrexate]], [[Valganciclovir]], [[Zidovudine]], [[Zileuton]]<br />
<br />
▸ Thrombocytopenia — [[Abciximab]], [[Aldesleukin]], [[Amobarbital]], [[Amrinone]], [[Armodafinil]], [[Capreomycin]], [[Carboplatin]], [[Cefotaxime]], [[Cefotetan]], [[Cefoxitin]], [[Ceftizoxime]], [[Chloramphenicol]], [[Chlorpropamide]], [[Ciclosporin]], [[Cinoxacin]], [[Claforan]], [[Diabinese]], [[Digoxin]], [[Disopyramide]], [[Enoxaparin]], [[Eptifibatide]], [[Erlotinib]], [[Estrogens]], [[Ethanol]], [[Exna]], [[Fondaparinux]], [[Glyburide]], [[Heparin]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Paraplatin]], [[Phenylbutazone]], [[Procainamide]], [[Proleukin]], [[Rifabutin]], [[Secobarbital]], [[Sulfonamides]], [[Thiazides]], [[Tuinal]]<br />
<br />
▸ Granulocytopenia — [[Acetazolamide]], [[Aripiprazole]], [[Benzthiazide]], [[Bortezomib]], [[Brinzolamide]], [[Bumetanide]], [[Capecitabine]], [[Captopril]], [[Carbamazepine]], [[Ceftazidime]], [[Celecoxib]], [[Chlorpropamide]], [[Dapsone]], [[Diabinese]], [[Disopyramide]], [[Dorzolamide]], [[Enalapril maleate]], [[Exna]], [[Fosinopril]], [[Fortaz]], [[Glyburide]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Penicillin]], [[quinine]], [[Rifabutin]], [[salicylate]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Multiorgan reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Anaphylaxis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, angioedema, bronchospasm, gastrointestinal symptoms, hypotension<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Albuterol]], [[Aliskiren]], [[Alteplase]], [[Amlodipine and Benazepril]], [[Aminocaproic acid]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Aripiprazole]], [[Armodafinil]], [[Atomoxetine]], [[Beclometasone dipropionate]], [[Beta-lactam|β-lactam antibiotics]], [[Betaxolol]], [[Bisoprolol]], [[Bivalirudin]], [[Bortezomib]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[monoclonal antibodies]], [[adalimumab]], [[Benazepril]], [[Bendamustine]], [[Captopril]], [[Carteolol]], [[Carvedilol]], [[Celecoxib]], [[Ciclosporin]], [[Ciprofloxacin and Dexamethasone]], [[Cisplatin]], [[Clopidogrel]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Denosumab]], [[Desirudin]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diflunisal]], [[Digoxin]], [[Digoxin immune fab]], [[Dobutamine]], [[Enalapril maleate]], [[Enoxaparin]], [[epoetin alfa]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Ethambutol]], [[Etodolac]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Fenoldopam]], [[Fluconazole]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fondaparinux]], [[Furosemide]], [[Glimepiride]], [[Glucagon]], [[Heparin]], [[HPV Vaccine]], [[Hyoscyamine]], [[Ibandronic acid]], [[Infliximab]], [[Insulin glargine]], [[Insulin glulisine]], [[Insulin lispro]], [[Interferon beta-1a]], [[Interferon beta-1b]], [[Ipratropium Bromide And Albuterol]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Labetalol]], [[Levalbuterol]], [[Lepirudin]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Metaxalone]], [[Methylphenidate]], [[Methyltestosterone]], [[Metoclopramide]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Mupirocin]], [[Nabumetone]], [[Nadolol]], [[Nebivolol]], [[Nitrofurantoin]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Ondansetron]], [[Oxytocin]], [[Penbutolol]], [[Pindolol]], [[Prochlorperazine]], [[Propranolol]], [[Progesterone]], [[Protamine]], [[Rituximab]], [[Rivaroxaban]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Solifenacin]], [[Sumatriptan]], [[Tinzaparin]], [[Tocilizumab]], [[Trastuzumab]], [[Triamcinolone]], [[Triamterene]], [[Urokinase]], [[Valganciclovir hydrochloride]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Systemic lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Arthralgia, myalgias, fever, malaise<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Armodafinil]], [[Hydralazine]], [[procainamide]], [[isoniazid]], [[propafenone]], [[Levonorgestrel and Ethinyl estradiol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous or visceral vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[aspirin]], [[Beta-lactam|β-lactam antibiotics]], [[carbamazepine]], [[carbimazole]], [[co-trimoxazole]], [[diltiazem]], [[erythromycin]], [[gold]], [[G-CSF]], [[GM-CSF]], [[Hydralazine]], [[interferons]], [[methotrexate]], [[minocycline]], [[NSAIDs]], [[penicillamine]], [[propylthiouracil]], [[retinoids]], [[sulfasalazine]], [[sulfonamides]], [[thiazides]], [[thrombolytics]], [[Adalimumab]], [[Amiodarone]], [[Cefdinir]], [[Methyldopa]], [[Amoxapine]], [[Moxifloxacin]], [[Fluticasone]], [[Acyclovir]], [[Allopurinol]], [[Amlodipine]], [[Bortezomib]], [[Captopril]], [[Captopril and Hydrochlorothiazide]], [[Chlorothiazide]], [[Chlorthalidone]], [[Clopidogrel]], [[Delavirdine]], [[Enalapril maleate]], [[Filgrastim]], [[Fosinopril]], [[Furosemide]], [[Hydrochlorothiazide]],,[[Imatinib]], [[Isotretinoin]], [[Lisinopril]], [[Lisinopril/Hydrochlorothiazide]], [[Losartan]], [[Lovastatin]], [[Methyclothiazide]], [[Metolazone]], [[Ofloxacin]], [[Pravastatin]], [[Prazosin]], [[Ramipril]], [[Abatacept]], [[Spironolactone]], [[Spironolactone/Hydrochlorothiazide]], [[Ticlopidine]], [[Valsartan]], [[Colchicine]], [[Quinidine]], [[Quinidine gluconate]], [[Dronedarone]], [[Enoxaparin]], [[Thiazide]], [[Fluticasone/salmeterol]], [[Infliximab]], [[Sitagliptin]], [[Enalaprilat]], [[Fluoxetine]], [[Glyburide]], [[Hydrochloride]], [[Hydroflumethiazide]], [[Polythiazide]], [[Valaciclovir]], [[Simvastatin]], [[Losartan and Hydrochlorothiazide]], [[Methylphenidate]], [[Mirabegron]], [[Dexlansoprazole]], [[Sumatriptan]], [[Bisoprolol]], [[Rituximab]], [[Aggrenox]], [[Penicillin G]], [[Norfloxacin]], [[Isoniazid]], [[Penicillin G procaine]], [[Famciclovir]], [[Cefuroxime]], [[Rifampin isoniazid]], [[Rifampin]], [[Interferon alfa-2a]], [[Amoxicillin-clavulanate potassium]], [[Interferon alfa-2a]], [[Pegylated interferon alfa-2a]], [[vancomycin]], [[Atovaquone proguanil]], [[Terbinafine]], [[Indinavir]], [[Ciprofloxacin Hydrochloride]], [[Lamivudine zidovudine]], [[Interferon alfa-2b]], [[Gemifloxacin mesylate]], [[Pentamidine Isethionate]], [[Abacavir lamivudine zidovudine]], [[Nitrofurantoin]], [[Zidovudine]], [[Quinine Sulfate]], [[Valproic acid]], [[Divalproex]], [[Niacin/Simvastatin]], [[Ezetimibe/Simvastatin]], [[Felodipine]], [[Fosinopril/Hydrochlorothiazide]], [[Moexipril/Hydrochlorothiazide]], [[Quinapril/Hydrochlorothiazide]], [[Enalapril maleate/Hydrochlorothiazide]], [[Enalapril/Felodipine]], [[Perindopril]] ,[[Fluvastatin]], [[Diltiazem]], [[Metoprolol succinate and hydrochlorothiazide]], [[Nebivolol]], [[Amiodarone]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Amlodipine Besylate]], [[Divalproex]], [[Pioglitazone/Glimepiride]], [[Aspirin/Dipyridamole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Serum sickness<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, arthralgia, fever<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Heterologous]] [[antibodies]], [[infliximab]], [[Cefdinir]], [[Bupropion]], [[Levothyroxine]], [[Tetracycline hydrochloride]], [[Antivenom]], [[Glatiramer acetate]], [[Antivenin]],,[[Measles]], [[Ticlopidine]], [[Clopidogrel]], [[Novobiocin]], [[Epinephrine]], [[Omalizumab]], [[Rituximab]], [[Immunosuppressive drug]], [[Digoxin]], [[Levothyroxine]], [[Ciprofloxacin]], [[Cefprozil]], [[Cefaclor]], [[Oxacillin]], [[Amoxicillin]], [[Ofloxacin]], [[Penicillin G benzathine]], [[Ampicillin]], [[Ceftibuten]], [[Cefpodoxime]], [[Terbinafine]], [[Gemifloxacin]], [[Metronidazole]], [[Cefadroxil]], [[Doxycycline]], [[Levofloxacin]], [[Minocycline]], [[Moxifloxacin]], [[Sulfadiazine]], [[Lincomycin]], [[Sulfamethoxazole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Drug reaction with eosinophilia and systemic symptoms (DRESS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[anticonvulsant]]s, [[Armodafinil]], [[atazanavir]], [[Carbamazepine]], [[minocycline]], [[sulfonamide]]s, [[spironolactone]]<br />
|}<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Allergology]]<br />
[[Category:Immunology]]<br />
[[Category:Emergency medicine]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Drug_allergy_causes&diff=1058944Drug allergy causes2015-01-23T14:54:44Z<p>Deepika Beereddy: /* Causes by Specific Allergic Reactions{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy |...</p>
<hr />
<div>__NOTOC__<br />
{{Drug allergy}}<br />
{{CMG}}; {{AE}} {{CP}}, {{JM}}<br />
<br />
==Overview==<br />
The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.<br />
<br />
==Causes==<br />
===Common Causes===<br />
When a medication causes an allergic reaction, it is called an [[allergen]]. The following is a short list of the most common drug allergens<br />
*Antibiotics<br />
**[[Penicillin]]<br />
**[[Sulfonamide (medicine)|Sulfa drugs]]<br />
**[[Tetracycline]]<br />
*Analgesics<br />
**[[Codeine]]<br />
**[[Non-steroidal anti-inflammatory drug]]s (NSAIDs)<br />
*Anticonvulsives<br />
**[[Phenytoin|Dilantin]]<br />
**[[Carbamazepine|Tegretol]]<br />
<br />
===Causes by Organ System===<br />
<br />
{|style="width:75%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Effect'''<br />
|bgcolor="Beige"| [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Adapalene]], [[Adenosine]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Allopurinol]], [[Alteplase]], [[Amifostine]], [[Amiloride]], [[Aminocaproic acid]], [[Amiodarone]], [[Amlodipine]], [[Amlodipine besylate and Valsartan]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Antithrombin III]], [[Argatroban]], [[Aripiprazole]], [[Armodafinil]], [[Atazanavir]], [[Atenolol]], [[Atomoxetine]], [[Atorvastatin calcium]], [[Barbiturates]], [[Benazepril]], [[Bendamustine]], [[Benoxaprofen]], [[Betaxolol]], [[Bevacizumab]], [[Bisoprolol]], [[Botulinum toxin]], [[Brentuximab vedotin]], [[Brimonidine]], [[Brinzolamide]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Bumetanide]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[Cabergoline]], [[Captopril]], [[Carbamazepine]], [[Carbidopa and Levodopa]], [[Carteolol]], [[Carvedilol]], [[Cefdinir]], [[Celecoxib]], [[Cephalosporins]], [[Cetuximab]], [[Chlorambucil]], [[Chlormezanone]], [[Chlorothiazide]], [[Chlorthalidone]], [[Cholestyramine]], [[Ciclosporin]], [[Cilostazol]], [[Ciprofloxacin and Dexamethasone]], [[Citalopram Hydrobromide]], [[Clindamycin]], [[Clonidine]], [[Clopidogrel]], [[Coagulation factor VIIa]], [[Codeine]], [[Colestipol]], [[Conivaptan]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Danazol]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Dasatinib]], [[Denosumab]], [[Desirudin]], [[Desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diazoxide]], [[Diclofenac]], [[Diclofenamide]], [[Dofetilide]], [[Digoxin]], [[Digoxin immune fab]], [[Diltiazem]], [[Donepezil]], [[Dipyridamole]], [[Disopyramide]], [[Dobutamine]], [[Dorzolamide]], [[Doxycycline Hyclate]], [[Dronedarone]], [[Duloxetine]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]], [[Ethynodiol diacetate and ethinyl estradiol]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Eprosartan]], [[Eptifibatide]], [[Erlotinib]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]], [[Ethacrynic acid]], [[Ethambutol]], [[Ethotoin]], [[Etodolac]], [[Etravirine]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Ezetimibe And Simvastatin]], [[Factor IX complex]], [[Felodipine]], [[Fenofibrate]], [[Fenoldopam]], [[Filgrastim]], [[Flecainide]], [[Fluconazole]], [[Fluphenazine]], [[Fluticasone]], [[Fluticasone and Salmeterol]], [[Fluvastatin]], [[Fondaparinux]], [[Fosamprenavir]], [[Fosinopril]], [[Glimepiride]], [[Glyburide and Metformin]], [[Gold]], [[HPV Vaccine]], [[Hydrocodone bitartrate and Homatropine methylbromide]], [[Ibandronic acid]], [[Ibritumomab tiuxetan]], [[Ibuprofen]], [[Imiquimod]], [[Interferon beta-1b]], [[Ipilimumab]], [[Insulin]], [[Insulin glulisine]], [[Interferon beta-1a]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isoniazid]], [[Isotretinoin]], [[Ketorolac tromethamine]] [[Lamotrigine]], [[Leflunomide]], [[Lenalidomide]], [[levetiracetam]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Mesalamine]], [[Metformin]], [[Methimazole]], [[Methotrexate]], [[Methyldopa]], [[Methylphenidate]], [[Metronidazole]], [[Mirabegron]], [[Moxifloxacin]], [[Mupirocin]], [[Mycophenolate]], [[Nafarelin]], [[Naproxen sodium]], [[Nebivolol]], [[Nevirapine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[NSAIDs]], [[Nystatin]], [[Ofloxacin]], [[Oxycodone]], [[Oxytocin]], [[Pantoprazole]], [[Paroxetine]], [[Pemetrexed]], [[Penicillamine]], [[Pentosan polysulfate]], [[Phenacetin]], [[Phenobarbitol]], [[Phenylbutazone]], [[Piroxicam]], [[Prochlorperazine]], [[Progesterone]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Phenytoin]], [[Pioglitazone]], [[Potassium chloride]], [[Primidone]], [[Procainamide]], [[Quinidine]], [[Rifabutin]], [[Risedronate]], [[Rosiglitazone]], [[Rosuvastatin]], [[Sorafenib]], [[Streptomycin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfasalazine]], [[Sulfonamide]], [[Sulfonylurea]], [[Sumatriptan]], [[Suramin]], [[Tacrolimus]], [[Tamoxifen]], [[Terbinafine]], [[Tetracycline]], [[Thiabendazole]], [[Thioacetazone]], [[Tolterodine]], [[Tretinoin]], [[Triamcinolone]], [[Valsartan]], [[Vancomycin]], [[Vandetanib]], [[Varenicline]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]], [[Zonisamide]]<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
===Causes in Alphabetical Order===<br />
{{col-begin|width=80%}}<br />
{{col-break|width=33%}}<br />
<br />
* [[Abatacept]]<br />
* [[Abciximab]]<br />
* [[Acebutolol]]<br />
* [[Acetylcysteine]]<br />
* [[Acyclovir]]<br />
* [[Acetazolamide]]<br />
* [[Adalimumab]]<br />
* [[Adapalene]]<br />
* [[Adenosine]]<br />
* [[Albuterol]]<br />
* [[Alendronate]]<br />
* [[Aliskiren]]<br />
* [[Allopurinol]]<br />
* [[Alteplase]],<br />
* [[Amifostine]]<br />
* [[Amiloride]]<br />
* [[Aminocaproic acid]]<br />
* [[Amiodarone]]<br />
* [[Amlodipine]]<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Anastrozole]]<br />
* [[Antihemophilic factor]]<br />
* [[Anti-inhibitor coagulant complex]]<br />
* [[Antithrombin III]]<br />
* [[Argatroban]]<br />
* [[Aripiprazole]]<br />
* [[Armodafinil]]<br />
* [[Atazanavir]]<br />
* [[Atenolol]]<br />
* [[Atomoxetine]]<br />
* [[Atorvastatin calcium]]<br />
* [[Barbiturates]]<br />
* [[Benoxaprofen]]<br />
* [[Benazepril]]<br />
* [[Bendamustine]]<br />
* [[Betaxolol]]<br />
* [[Bevacizumab]]<br />
* [[Bisoprolol]]<br />
* [[Bivalirudin]]<br />
* [[Bortezomib]]<br />
* [[Brentuximab vedotin]]<br />
* [[Brimonidine]]<br />
* [[Brinzolamide]]<br />
* [[Budesonide And Formoterol Fumarate Dihydrate]]<br />
* [[Bumetanide]]<br />
* [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]]<br />
* [[Cabergoline]]<br />
* [[Candesartan]]<br />
* [[Capecitabine]]<br />
* [[Captopril]]<br />
* [[Carbamazepine]]<br />
* [[Carbidopa and Levodopa]]<br />
* [[Carteolol]]<br />
* [[Carvedilol]]<br />
* [[Cefdinir]]<br />
* [[Celecoxib]]<br />
* [[Cephalosporins]]<br />
* [[Cetuximab]]<br />
* [[Chlorambucil]]<br />
* [[Chlormezanone]]<br />
* [[Chlorothiazide]]<br />
* [[Chlorthalidone]]<br />
* [[Cholestyramine]]<br />
* [[Ciclosporin]]<br />
* [[Cilostazol]]<br />
* [[Ciprofloxacin and Dexamethasone]]<br />
* [[Citalopram Hydrobromide]]<br />
* [[Clindamycin]]<br />
* [[Clonidine]]<br />
* [[Clopidogrel]]<br />
* [[Coagulation factor VIIa]]<br />
* [[Codeine]]<br />
* [[Colestipol]]<br />
* [[Conivaptan]]<br />
* [[Crotamiton]]<br />
* [[Cyclobenzaprine]]<br />
* [[Cyclophosphamide]]<br />
* [[Dabigatran]]<br />
* [[Dalteparin]]<br />
* [[Danazol]]<br />
* [[Daptomycin]]<br />
* [[Darbepoetin Alfa]]<br />
* [[Darifenacin]]<br />
* [[Darunavir]]<br />
* [[Dasatinib]]<br />
* [[Denosumab]]<br />
* [[Desirudin]]<br />
* [[Desvenlafaxine]]<br />
* [[Dexamethasone]]<br />
* [[Dexlansoprazole]]<br />
* [[Dexmethylphenidate]]<br />
* [[Diazoxide]]<br />
* [[Diclofenac]]<br />
* [[Diclofenamide]]<br />
* [[Digoxin]]<br />
* [[Digoxin immune fab]]<br />
* [[Diltiazem]]<br />
* [[Dipyridamole]]<br />
* [[Disopyramide]]<br />
* [[Dobutamine]]<br />
* [[Dofetilide]]<br />
* [[Donepezil]]<br />
* [[Dorzolamide]]<br />
* [[Doxazosin]]<br />
* [[Doxycycline Hyclate]]<br />
* [[Dronedarone]]<br />
* [[Metronidazole]]<br />
* [[Duloxetine]]<br />
* [[Dutasteride]]<br />
* [[Dutasteride and Tamsulosin hydrochloride]]<br />
* [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]]<br />
* [[Enalapril maleate]]<br />
* [[Enoxaparin]]<br />
* [[Epoetin alfa]]<br />
* [[Eprosartan]]<br />
* [[Eptifibatide]]<br />
* [[Erlotinib]] <br />
* [[Erythropoietin]]<br />
* [[Esmolol]]<br />
* [[Esomeprazole]]<br />
* [[Eszopiclone]]<br />
* [[Etanercept]]<br />
* [[Ethacrynic acid]]<br />
* [[Ethambutol]]<br />
* [[Ethotoin]] <br />
* [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]]<br />
* [[Etravirine]]<br />
* [[Etodolac]]<br />
* [[Everolimus]]<br />
* [[Exenatide]] <br />
* [[Ezetimibe And Simvastatin]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Factor IX complex]]<br />
* [[Felodipine]]<br />
* [[Fenofibrate]]<br />
* [[Fenoldopam]]<br />
* [[Filgrastim]]<br />
* [[Flecainide]]<br />
* [[Fluconazole]]<br />
* [[Fluorometholone]]<br />
* [[Fluoxetine]]<br />
* [[Fluphenazine]]<br />
* [[Fluticasone]]<br />
* [[Fluticasone and Salmeterol]]<br />
* [[Fluvastatin]]<br />
* [[Fondaparinux]]<br />
* [[Fosamprenavir]]<br />
* [[Fosinopril]]<br />
* [[Glimepiride]]<br />
* [[Glyburide]]<br />
* [[Glipizide]]<br />
* [[Glucagon]]<br />
* [[Glyburide and Metformin]]<br />
* [[Gold]]<br />
* [[HPV Vaccine]]<br />
* [[Hydrocodone bitartrate and Homatropine methylbromide]]<br />
* [[Ibandronic acid]]<br />
* [[Ibritumomab tiuxetan]]<br />
* [[Ibuprofen]]<br />
* [[Imiquimod]]<br />
* [[Ipilimumab]]<br />
* [[Ipratropium Bromide And Albuterol]]<br />
* [[Insulin]]<br />
* [[Insulin glulisine]]<br />
* [[Interferon beta-1a]]<br />
* [[Interferon beta-1b]] <br />
* [[Irbesartan]]<br />
* [[Isoniazid]] <br />
* [[Isotretinoin]]<br />
* [[Ketorolac tromethamine]]<br />
* [[Lamotrigine]] <br />
* [[Leflunomide]]<br />
* [[Lenalidomide]]<br />
* [[Levetiracetam]] <br />
* [[Levonorgestrel and Ethinyl estradiol]]<br />
* [[Linagliptin]]<br />
* [[Linagliptin and Metformin hydrochloride]]<br />
* [[Lisinopril and Hydrochlorothiazide]]<br />
* [[Losartan and Hydrochlorothiazide]]<br />
* [[Medroxyprogesterone]]<br />
* [[Mefenamic acid]]<br />
* [[Meloxicam]]<br />
* [[Mesalamine]]<br />
* [[Metformin]]<br />
* [[Methotrexate]]<br />
* [[Methyldopa]] <br />
* [[Methylphenidate]]<br />
* [[Mirabegron]]<br />
* [[Moxifloxacin]]<br />
* [[Mupirocin]]<br />
* [[Mycophenolate]]<br />
* [[Nafarelin]]<br />
* [[Naproxen sodium]]<br />
* [[Nebivolol]] <br />
* [[Nevirapine]] <br />
* [[Nitrofurantoin]]<br />
* [[Norgestimate and Ethinyl estradiol]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[NSAIDs]]<br />
* [[Nystatin]]<br />
* [[Ofloxacin]]<br />
* [[Olmesartan]]<br />
* [[Oxycodone]]<br />
* [[Oxytocin]]<br />
* [[Pantoprazole]]<br />
* [[Paroxetine]]<br />
* [[Pemetrexed]]<br />
* [[Penicillamine]]<br />
* [[Pentosan polysulfate]]<br />
* [[Phenacetin]] <br />
* [[Phenobarbitol]] <br />
* [[Phenylbutazone]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Phenytoin]]<br />
* [[Pimecrolimus]] <br />
* [[Pioglitazone]]<br />
* [[Piroxicam]]<br />
* [[Potassium chloride]]<br />
* [[Primidone]] <br />
* [[Procainamide]] <br />
* [[Prochlorperazine]]<br />
* [[Progesterone]]<br />
* [[Quinidine]]<br />
* [[Rifabutin]]<br />
* [[Risedronate]]<br />
* [[Rosiglitazone]]<br />
* [[Rosuvastatin]] <br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
* [[Sorafenib]]<br />
* [[Streptomycin]]<br />
* [[Sulfacetamide sodium And Prednisolone acetate]] <br />
* [[Sulfasalazine]] <br />
* [[Sulfonamide]]<br />
* [[Sulfonylurea]]<br />
* [[Sumatriptan]]<br />
* [[Suramin]]<br />
* [[Tacrolimus]]<br />
* [[Tamoxifen]]<br />
* [[Terbinafine]] <br />
* [[Tetracycline]] <br />
* [[Thiabendazole]] <br />
* [[Thioacetazone]]<br />
* [[Tolterodine]]<br />
* [[Tretinoin]]<br />
* [[Triamcinolone]]<br />
* [[Valsartan]]<br />
* [[Vancomycin]] <br />
* [[Vandetanib]]<br />
* [[Venlafaxine]] <br />
* [[Varenicline]]<br />
* [[Zaleplon]]<br />
* [[Zanamivir]]<br />
* [[Zidovudine]]<br />
* [[Zolpidem]]<br />
* [[Zonisamide]]<br />
{{col-end}}<br />
<br />
===Causes by Specific Allergic Reactions<ref>{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy | journal = The Journal of Allergy and Clinical Immunology | date = 2010-02 | pmid = 20176256 }}</ref><ref>{{cite book | last = Lee | first = Anne | title = Adverse drug reactions | publisher = Pharmaceutical Press | location = London Chicago | year = 2006 | isbn = 0853696012 }}</ref>===<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Cutaneous reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Exanthems<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Delayed-type hypersensitivity <BR> ▸ Evolve over days after drug initiation <BR> ▸ Diffuse macules and papules <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[Amlodipine]], [[Amphotericin]], [[Barbiturates]], [[Captopril]], [[carbamazepine]], [[cephalosporins]], [[chloramphenicol]], [[Digoxin]], [[Erythromycin]], [[Furosemide]], [[gentamicin]], [[Glipizide]], [[gold salts]], [[Lithium]], [[Nalidixic acid]], [[Nitrofurantoin]], [[Penicillins]], [[Phenothiazines]], [[Phenylbutazone]], [[Phenytoin]], [[Sulfonamides]], [[Thiazides]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Urticaria/ angioedema<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Often IgE mediated <BR> ▸ Onset within minutes of drug initiation<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[ACE inhibitors]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Alteplase]], [[Aminosalicylic acid]], [[Amlodipine]], [[Amlodipine and Benazepril]], [[Anastrozole]], [[Anti-inhibitor coagulant complex]], [[Anticonvulsants]], [[Antihemophilic factor]], [[Antithrombin III]], [[Aripiprazole]], [[Armodafinil]], [[Aspirin]], [[Atomoxetine]], [[Atropine]], [[Beclometasone dipropionate]], [[Benazepril]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Captopril]], [[Carbidopa and Levodopa]], [[Carvedilol]], [[Celecoxib]], [[cephalosporins]], [[Cetuximab]], [[Cholestyramine]], [[Ciclosporin]], [[Cisplatin]], [[Clomifene]], [[Clonidine]], [[Clopidogrel]], [[Colestipol]], [[Cyclobenzaprine]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Darunavir]], [[Dasatinib]], [[Denosumab]], [[desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Dextran]], [[Diflunisal]], [[Digoxin immune fab]], [[Dofetilide]], [[Donepezil]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Erythropoietin]], [[Esomeprazole]], [[Eszopiclone]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Febuxostat]], [[Felodipine]], [[Fesoterodine]], [[Filgrastim]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fosinopril]], [[Frovatriptan]], [[Gemfibrozil]], [[Gentamicin]], [[Glimepiride]], [[Glipizide]], [[Glyburide]], [[Heparin]], [[Hydralazine]], [[Hydroxychloroquine]], [[Hyoscyamine]], [[Ibuprofen]], [[Indomethacin]], [[Interferon beta-1a]], [[Ipratropium bromide]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isotretinoin]], [[Isradipine]], [[Lamotrigine]], [[Levalbuterol]], [[Levonorgestrel and Ethinyl estradiol]], [[Levothyroxine]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Liraglutide]], [[Lisinopril]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Minocycline hydrochloride]], [[Moxifloxacin ophthalmic]], [[Mupirocin]], [[Losartan]], [[Meloxicam]], [[Metaxalone]], [[Methimazole]], [[Methocarbamol]], [[Methylphenidate]], [[Metoclopramide]], [[Metolazone]], [[Mirabegron]], [[Modafinil]], [[Moexipril hydrochloride]], [[Monoclonal antibodies]], [[Moxifloxacin]], [[Nabumetone]], [[Nafarelin]], [[Naltrexone]], [[Naproxen and esomeprazole magnesium]], [[Nisoldipine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Opioids]], [[Orphenadrine]], [[Oxcarbazepine]], [[Oxycodone]], [[Pantoprazole]], [[Pegfilgrastim]], [[Penicillins]], [[Pentamidine Isethionate]], [[Pentoxifylline]], [[Perindopril]], [[Phentermine]], [[Pramipexole]], [[Prochlorperazine]], [[Promethazine]], [[Rifaximin]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Sertraline]], [[Pitavastatin]], [[Procainamide]], [[Rizatriptan]], [[Quinidine sulfate]], [[Quinine]], [[Ramipril]], [[Ranolazine]], [[Repaglinide]], [[Risedronate]], [[Rosuvastatin]], [[Sitagliptin]], [[Sulfonamides]], [[Sumatriptan]], [[Tenofovir]], [[Tetracyclines]], [[Thalidomide]], [[Thiouracil]], [[Ticlopidine]], [[Tizanidine]], [[Tocilizumab]], [[Tolterodine]], [[Tubocurarine]], [[Ustekinumab]], [[Valacyclovir]], [[Valsartan]], [[Vancomycin]], [[Vardenafil]], [[Varenicline]], [[Zaleplon]], [[Zolmitriptan]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Fixed drug eruption<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hyperpigmented plaques that recur at same skin or mucosal site<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[ACE inhibitors]], [[adalimumab]], [[allopurinol]], [[amlodipine]], [[aspirin]], [[barbiturates]], [[benzodiazepines]], [[carbamazepine]], [[cephalosporins]], [[clindamycin]], [[co-trimoxazole]], [[dextromethorphan]], [[diltiazem]], [[fluconazole]], [[lamotrigine]], [[lansoprazole]], [[metronidazole]], [[NSAIDs]], [[paclitaxel]], [[paracetamol]], [[penicillin]], [[phenolphthalein]], [[omeprazole]], [[quinine]], [[salicylates]], [[sulfonamides]], [[terbinafine]], [[tetracyclines]], [[trimethoprim]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pustules<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Acute generalized eczematous pustulosis or acneiform rash<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[antibiotics]], [[calcium-channel blockers]], [[corticosteroids]], [[sirolimus]],[[Fluticasone]],[[Erlotinib]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Bullous<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Flaccid or tense blisters <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Argatroban]], [[Bendamustine]], [[Captopril]], [[Carbidopa and Levodopa]], [[Dasatinib]], [[Erlotinib]], [[Penicillamine]], [[Furosemide]], [[Risedronate]], [[Vancomycin]],[[Abciximab]],[[Warfarin]], [[Topiramate]],[[Linezolid]],[[Mirtazapine]],[[Dapsone]], [[Allopurinol]],[[Captopril ]],[[Captopril and Hydrochlorothiazide]],[[Clopidogrel]],[[Erlotinib]],[[Fosinopril]], [[Ibuprofen]], [[Imatinib]],[[Indapamide]],[[Risedronate]],[[Zolpidem]],[[Dasatinib]],[[Minoxidil]],[[Labetalol]],[[Phenytoin]],[[Dalteparin]],[[Bendamustine]],[[Tinzaparin]],[[Tamoxifen]],[[ clarithromycin]],[[Atorvastatin calcium]],[[Caduet]],[[Ticarcillin/Clavulanate]],[[Terbinafine]],[[Quinine]],[[Nevirapine]],[[Topiramate]],[[Perindopril]],[[Moexipril/Hydrochlorothiazide]], [[Naproxen sodium]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Cutaneous lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Erythematous/scaly plaques in photodistribution<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Hydrochlorothiazide]], [[calcium-channel blockers]], [[ACEIs]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Stevens-Johnson syndrome (SJS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Purpuric macules on face and trunk with &lt;10% epidermal detachment, fever, stomatitis, ocular involvement<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Antibiotics]], [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Beta-lactam|Β-lactam antibiotics]], [[Brinzolamide]], [[Carbamazepine]], [[Carvedilol]], [[Celecoxib]], [[Chlorpropamide]], [[Co-trimoxazole]], [[Darunavir]], [[Diflunisal]], [[Dorzolamide]], [[Duloxetine]], [[efavirenz, emtricitabine, and tenofovir disoproxil fumarate]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Fenofibrate]], [[Glimepiride]], [[Gold]], [[H2 Antagonist]]s, [[Histamine]], [[Hydroxychloroquine]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]],[[Lisinopril and Hydrochlorothiazide]], [[Macrolides]], [[Mefenamic acid]], [[Meloxicam]], [[Metolazone]], [[Mefloquine]], [[Methotrexate]], [[Mexiletine]], [[Minocycline hydrochloride]], [[Minoxidil]], [[Modafinil]], [[Naproxen and esomeprazole magnesium]], [[Piroxicam]], [[Moxifloxacin]], [[Nitrofurantoin]], [[NSAIDS]], [[Ofloxacin]], [[Olmesartan medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Phenothiazines]], [[Phenytoin]], [[Rifampicin]], [[Rivaroxaban]], [[Simvastatin]], [[Sitagliptin]], [[Spironolactone]], [[sulfacetamide sodium and prednisolone acetate]], [[Sulfonamides]], [[Tadalafil]], [[Tetracyclines]], [[Thalidomide]], [[Thiazides]], [[Ticlopidine]], [[Varenicline]], [[Zidovudine]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Toxic epidermal necrolysis (TEN)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Similar to SJS but >30% epidermal detachment<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Allopurinol]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Brinzolamide]], [[Carbamazepine]], [[Celecoxib]], [[Diflunisal]], [[Dorzolamide]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Finasteride]], [[Gold]], [[Griseofulvin]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]], [[Lisinopril and Hydrochlorothiazide]], [[Mefenamic acid]], [[Meloxicam]], [[Methotrexate]], [[Metolazone]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Naproxen and esomeprazole magnesium]], [[Nitrofurantoin]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Penicillins]], [[Phenytoin]], [[Piroxicam]], [[Salicylates]], [[Sitagliptin]], [[Spironolactone]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[tetracyclines]], [[Thalidomide]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Organ-specific reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pulmonary<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Pulmonary fibrosis, hypersensitivity pneumonitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Nitrofurantoin]], [[bleomycin]], [[Cabergoline]], [[Cetuximab]], [[Desvenlafaxine]], [[Dronedarone]], [[Erlotinib]], [[Hydrochlorothiazide]], [[Methyclothiazide]], [[Methotrexate]], [[Amiodarone]], [[Moxifloxacin]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hepatic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hepatitis, cholestasis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Aminosalicylic acid|Para-aminosalicylic acid]], [[Brinzolamide]], [[Dorzolamide]], [[Ofloxacin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[phenothiazines]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Renal<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Interstitial nephritis, membranous glomerulonephritis <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |[[Ofloxacin]], [[Penicillin]], [[sulfonamides]], [[gold]], [[penicillamine]], [[allopurinol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hematologic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hemolytic anemia, thrombocytopenia, granulocytopenia<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |<br />
▸ Hemolytic anemia — [[5-Azacytidine]], [[Acetophenazine]], [[Aclarubicin]], [[Actinomycin D]], [[Albendazole]], [[Alemtuzumab]], [[Aminopyrine]], [[Amitriptyline]], [[Amodiaquine]], [[Anakinra]], [[Antipyrine]], [[Azathioprine]], [[Bevacizumab]], [[Bortezomib]], [[Captopril]], [[Carbimazole]], [[Caspofungin]], [[Chloramphenicol]], [[Chlorpromazine]], [[Ciclosporin]], [[Cidofovir]], [[Cilazapril]], [[Clofarabine]], [[Clozapine]], [[Deferiprone]], [[Desipramine]], [[Docetaxel]], [[Dothiepin]], [[Doxorubicin]], [[Eflornithine]], [[Ethosuximide]], [[Erlotinib]], [[Ethotoin]], [[Flucytosine]], [[Fludarabine]], [[Fondaparinux]], [[Ganciclovir]], [[Gemcitabine]], [[Glimepiride]], [[Glyburide]], [[Glyburide and Metformin]], [[Gold salts]], [[Hydroxycarbamide]], [[Hypersplenism]], [[Ibritumomab tiuxetan]], [[Idarubicin]], [[Imatinib mesylate]], [[Interferon alpha]], [[Interferon beta]], [[Irinotecan]], [[Isoniazid]], [[Levomepromazine]], [[Lisinopril and Hydrochlorothiazide]], [[Mercaptopurine]], [[Methimazole]], [[Mirtazapine]], [[Mitoxantrone]], [[Nortriptyline]], [[Ofloxacin]], [[Paclitaxel]], [[Penicillamine]], [[Pentamidine]], [[Pentostatin]], [[Perazine]], [[Phenylbutazone]], [[Phenytoin]], [[Pipothiazine]], [[Procainamide]], [[Propylthiouracil]], [[Pyrimethamine]], [[Quinidine]], [[Remoxipride]], [[Riluzole]], [[Stiripentol]], [[Sulfasalazine]], [[Sulphonamides]], [[Ticlopidine]], [[Topotecan]], [[Trastuzumab]], [[Trimetrexate]], [[Valganciclovir]], [[Zidovudine]], [[Zileuton]]<br />
<br />
▸ Thrombocytopenia — [[Abciximab]], [[Aldesleukin]], [[Amobarbital]], [[Amrinone]], [[Armodafinil]], [[Capreomycin]], [[Carboplatin]], [[Cefotaxime]], [[Cefotetan]], [[Cefoxitin]], [[Ceftizoxime]], [[Chloramphenicol]], [[Chlorpropamide]], [[Ciclosporin]], [[Cinoxacin]], [[Claforan]], [[Diabinese]], [[Digoxin]], [[Disopyramide]], [[Enoxaparin]], [[Eptifibatide]], [[Erlotinib]], [[Estrogens]], [[Ethanol]], [[Exna]], [[Fondaparinux]], [[Glyburide]], [[Heparin]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Paraplatin]], [[Phenylbutazone]], [[Procainamide]], [[Proleukin]], [[Rifabutin]], [[Secobarbital]], [[Sulfonamides]], [[Thiazides]], [[Tuinal]]<br />
<br />
▸ Granulocytopenia — [[Acetazolamide]], [[Aripiprazole]], [[Benzthiazide]], [[Bortezomib]], [[Brinzolamide]], [[Bumetanide]], [[Capecitabine]], [[Captopril]], [[Carbamazepine]], [[Ceftazidime]], [[Celecoxib]], [[Chlorpropamide]], [[Dapsone]], [[Diabinese]], [[Disopyramide]], [[Dorzolamide]], [[Enalapril maleate]], [[Exna]], [[Fosinopril]], [[Fortaz]], [[Glyburide]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Penicillin]], [[quinine]], [[Rifabutin]], [[salicylate]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Multiorgan reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Anaphylaxis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, angioedema, bronchospasm, gastrointestinal symptoms, hypotension<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Albuterol]], [[Aliskiren]], [[Alteplase]], [[Amlodipine and Benazepril]], [[Aminocaproic acid]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Aripiprazole]], [[Armodafinil]], [[Atomoxetine]], [[Beclometasone dipropionate]], [[Beta-lactam|β-lactam antibiotics]], [[Betaxolol]], [[Bisoprolol]], [[Bivalirudin]], [[Bortezomib]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[monoclonal antibodies]], [[adalimumab]], [[Benazepril]], [[Bendamustine]], [[Captopril]], [[Carteolol]], [[Carvedilol]], [[Celecoxib]], [[Ciclosporin]], [[Ciprofloxacin and Dexamethasone]], [[Cisplatin]], [[Clopidogrel]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Denosumab]], [[Desirudin]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diflunisal]], [[Digoxin]], [[Digoxin immune fab]], [[Dobutamine]], [[Enalapril maleate]], [[Enoxaparin]], [[epoetin alfa]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Ethambutol]], [[Etodolac]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Fenoldopam]], [[Fluconazole]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fondaparinux]], [[Furosemide]], [[Glimepiride]], [[Glucagon]], [[Heparin]], [[HPV Vaccine]], [[Hyoscyamine]], [[Ibandronic acid]], [[Infliximab]], [[Insulin glargine]], [[Insulin glulisine]], [[Insulin lispro]], [[Interferon beta-1a]], [[Interferon beta-1b]], [[Ipratropium Bromide And Albuterol]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Labetalol]], [[Levalbuterol]], [[Lepirudin]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Metaxalone]], [[Methylphenidate]], [[Methyltestosterone]], [[Metoclopramide]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Mupirocin]], [[Nabumetone]], [[Nadolol]], [[Nebivolol]], [[Nitrofurantoin]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Ondansetron]], [[Oxytocin]], [[Penbutolol]], [[Pindolol]], [[Prochlorperazine]], [[Propranolol]], [[Progesterone]], [[Protamine]], [[Rituximab]], [[Rivaroxaban]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Solifenacin]], [[Sumatriptan]], [[Tinzaparin]], [[Tocilizumab]], [[Trastuzumab]], [[Triamcinolone]], [[Triamterene]], [[Urokinase]], [[Valganciclovir hydrochloride]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Systemic lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Arthralgia, myalgias, fever, malaise<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Armodafinil]], [[Hydralazine]], [[procainamide]], [[isoniazid]], [[propafenone]], [[Levonorgestrel and Ethinyl estradiol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous or visceral vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[aspirin]], [[Beta-lactam|β-lactam antibiotics]], [[carbamazepine]], [[carbimazole]], [[co-trimoxazole]], [[diltiazem]], [[erythromycin]], [[gold]], [[G-CSF]], [[GM-CSF]], [[Hydralazine]], [[interferons]], [[methotrexate]], [[minocycline]], [[NSAIDs]], [[penicillamine]], [[propylthiouracil]], [[retinoids]], [[sulfasalazine]], [[sulfonamides]], [[thiazides]], [[thrombolytics]], [[Adalimumab]], [[Amiodarone]], [[Cefdinir]], [[Methyldopa]], [[Amoxapine]], [[Moxifloxacin]], [[Fluticasone]], [[Acyclovir]], [[Allopurinol]], [[Amlodipine]], [[Bortezomib]], [[Captopril]], [[Captopril and Hydrochlorothiazide]], [[Chlorothiazide]], [[Chlorthalidone]], [[Clopidogrel]], [[Delavirdine]], [[Enalapril maleate]], [[Filgrastim]], [[Fosinopril]], [[Furosemide]], [[Hydrochlorothiazide]],,[[Imatinib]], [[Isotretinoin]], [[Lisinopril]], [[Lisinopril/Hydrochlorothiazide]], [[Losartan]], [[Lovastatin]], [[Methyclothiazide]], [[Metolazone]], [[Ofloxacin]], [[Pravastatin]], [[Prazosin]], [[Ramipril]], [[Abatacept]], [[Spironolactone]], [[Spironolactone/Hydrochlorothiazide]], [[Ticlopidine]], [[Valsartan]], [[Colchicine]], [[Quinidine]], [[Quinidine gluconate]], [[Dronedarone]], [[Enoxaparin]], [[Thiazide]], [[Fluticasone/salmeterol]], [[Infliximab]], [[Sitagliptin]], [[Enalaprilat]], [[Fluoxetine]], [[Glyburide]], [[Hydrochloride]], [[Hydroflumethiazide]], [[Polythiazide]], [[Valaciclovir]], [[Simvastatin]], [[Losartan and Hydrochlorothiazide]], [[Methylphenidate]], [[Dexlansoprazole]], [[Sumatriptan]], [[Bisoprolol]], [[Rituximab]], [[Aggrenox]], [[Penicillin G]], [[Norfloxacin]], [[Isoniazid]], [[Penicillin G procaine]], [[Famciclovir]], [[Cefuroxime]], [[Rifampin isoniazid]], [[Rifampin]], [[Interferon alfa-2a]], [[Amoxicillin-clavulanate potassium]], [[Interferon alfa-2a]], [[Pegylated interferon alfa-2a]], [[vancomycin]], [[Atovaquone proguanil]], [[Terbinafine]], [[Indinavir]], [[Ciprofloxacin Hydrochloride]], [[Lamivudine zidovudine]], [[Interferon alfa-2b]], [[Gemifloxacin mesylate]], [[Pentamidine Isethionate]], [[Abacavir lamivudine zidovudine]], [[Nitrofurantoin]], [[Zidovudine]], [[Quinine Sulfate]], [[Valproic acid]], [[Divalproex]], [[Niacin/Simvastatin]], [[Ezetimibe/Simvastatin]], [[Felodipine]], [[Fosinopril/Hydrochlorothiazide]], [[Moexipril/Hydrochlorothiazide]], [[Quinapril/Hydrochlorothiazide]], [[Enalapril maleate/Hydrochlorothiazide]], [[Enalapril/Felodipine]], [[Perindopril]] ,[[Fluvastatin]], [[Diltiazem]], [[Metoprolol succinate and hydrochlorothiazide]], [[Nebivolol]], [[Amiodarone]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Amlodipine Besylate]], [[Divalproex]], [[Pioglitazone/Glimepiride]], [[Aspirin/Dipyridamole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Serum sickness<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, arthralgia, fever<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Heterologous]] [[antibodies]], [[infliximab]], [[Cefdinir]], [[Bupropion]], [[Levothyroxine]], [[Tetracycline hydrochloride]], [[Antivenom]], [[Glatiramer acetate]], [[Antivenin]],,[[Measles]], [[Ticlopidine]], [[Clopidogrel]], [[Novobiocin]], [[Epinephrine]], [[Omalizumab]], [[Rituximab]], [[Immunosuppressive drug]], [[Digoxin]], [[Levothyroxine]], [[Ciprofloxacin]], [[Cefprozil]], [[Cefaclor]], [[Oxacillin]], [[Amoxicillin]], [[Ofloxacin]], [[Penicillin G benzathine]], [[Ampicillin]], [[Ceftibuten]], [[Cefpodoxime]], [[Terbinafine]], [[Gemifloxacin]], [[Metronidazole]], [[Cefadroxil]], [[Doxycycline]], [[Levofloxacin]], [[Minocycline]], [[Moxifloxacin]], [[Sulfadiazine]], [[Lincomycin]], [[Sulfamethoxazole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Drug reaction with eosinophilia and systemic symptoms (DRESS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[anticonvulsant]]s, [[Armodafinil]], [[atazanavir]], [[Carbamazepine]], [[minocycline]], [[sulfonamide]]s, [[spironolactone]]<br />
|}<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Allergology]]<br />
[[Category:Immunology]]<br />
[[Category:Emergency medicine]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Drug_allergy_causes&diff=1058942Drug allergy causes2015-01-23T14:53:33Z<p>Deepika Beereddy: /* Causes in Alphabetical Order */</p>
<hr />
<div>__NOTOC__<br />
{{Drug allergy}}<br />
{{CMG}}; {{AE}} {{CP}}, {{JM}}<br />
<br />
==Overview==<br />
The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.<br />
<br />
==Causes==<br />
===Common Causes===<br />
When a medication causes an allergic reaction, it is called an [[allergen]]. The following is a short list of the most common drug allergens<br />
*Antibiotics<br />
**[[Penicillin]]<br />
**[[Sulfonamide (medicine)|Sulfa drugs]]<br />
**[[Tetracycline]]<br />
*Analgesics<br />
**[[Codeine]]<br />
**[[Non-steroidal anti-inflammatory drug]]s (NSAIDs)<br />
*Anticonvulsives<br />
**[[Phenytoin|Dilantin]]<br />
**[[Carbamazepine|Tegretol]]<br />
<br />
===Causes by Organ System===<br />
<br />
{|style="width:75%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Effect'''<br />
|bgcolor="Beige"| [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Adapalene]], [[Adenosine]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Allopurinol]], [[Alteplase]], [[Amifostine]], [[Amiloride]], [[Aminocaproic acid]], [[Amiodarone]], [[Amlodipine]], [[Amlodipine besylate and Valsartan]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Antithrombin III]], [[Argatroban]], [[Aripiprazole]], [[Armodafinil]], [[Atazanavir]], [[Atenolol]], [[Atomoxetine]], [[Atorvastatin calcium]], [[Barbiturates]], [[Benazepril]], [[Bendamustine]], [[Benoxaprofen]], [[Betaxolol]], [[Bevacizumab]], [[Bisoprolol]], [[Botulinum toxin]], [[Brentuximab vedotin]], [[Brimonidine]], [[Brinzolamide]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Bumetanide]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[Cabergoline]], [[Captopril]], [[Carbamazepine]], [[Carbidopa and Levodopa]], [[Carteolol]], [[Carvedilol]], [[Cefdinir]], [[Celecoxib]], [[Cephalosporins]], [[Cetuximab]], [[Chlorambucil]], [[Chlormezanone]], [[Chlorothiazide]], [[Chlorthalidone]], [[Cholestyramine]], [[Ciclosporin]], [[Cilostazol]], [[Ciprofloxacin and Dexamethasone]], [[Citalopram Hydrobromide]], [[Clindamycin]], [[Clonidine]], [[Clopidogrel]], [[Coagulation factor VIIa]], [[Codeine]], [[Colestipol]], [[Conivaptan]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Danazol]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Dasatinib]], [[Denosumab]], [[Desirudin]], [[Desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diazoxide]], [[Diclofenac]], [[Diclofenamide]], [[Dofetilide]], [[Digoxin]], [[Digoxin immune fab]], [[Diltiazem]], [[Donepezil]], [[Dipyridamole]], [[Disopyramide]], [[Dobutamine]], [[Dorzolamide]], [[Doxycycline Hyclate]], [[Dronedarone]], [[Duloxetine]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]], [[Ethynodiol diacetate and ethinyl estradiol]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Eprosartan]], [[Eptifibatide]], [[Erlotinib]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]], [[Ethacrynic acid]], [[Ethambutol]], [[Ethotoin]], [[Etodolac]], [[Etravirine]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Ezetimibe And Simvastatin]], [[Factor IX complex]], [[Felodipine]], [[Fenofibrate]], [[Fenoldopam]], [[Filgrastim]], [[Flecainide]], [[Fluconazole]], [[Fluphenazine]], [[Fluticasone]], [[Fluticasone and Salmeterol]], [[Fluvastatin]], [[Fondaparinux]], [[Fosamprenavir]], [[Fosinopril]], [[Glimepiride]], [[Glyburide and Metformin]], [[Gold]], [[HPV Vaccine]], [[Hydrocodone bitartrate and Homatropine methylbromide]], [[Ibandronic acid]], [[Ibritumomab tiuxetan]], [[Ibuprofen]], [[Imiquimod]], [[Interferon beta-1b]], [[Ipilimumab]], [[Insulin]], [[Insulin glulisine]], [[Interferon beta-1a]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isoniazid]], [[Isotretinoin]], [[Ketorolac tromethamine]] [[Lamotrigine]], [[Leflunomide]], [[Lenalidomide]], [[levetiracetam]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Mesalamine]], [[Metformin]], [[Methimazole]], [[Methotrexate]], [[Methyldopa]], [[Methylphenidate]], [[Metronidazole]], [[Mirabegron]], [[Moxifloxacin]], [[Mupirocin]], [[Mycophenolate]], [[Nafarelin]], [[Naproxen sodium]], [[Nebivolol]], [[Nevirapine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[NSAIDs]], [[Nystatin]], [[Ofloxacin]], [[Oxycodone]], [[Oxytocin]], [[Pantoprazole]], [[Paroxetine]], [[Pemetrexed]], [[Penicillamine]], [[Pentosan polysulfate]], [[Phenacetin]], [[Phenobarbitol]], [[Phenylbutazone]], [[Piroxicam]], [[Prochlorperazine]], [[Progesterone]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Phenytoin]], [[Pioglitazone]], [[Potassium chloride]], [[Primidone]], [[Procainamide]], [[Quinidine]], [[Rifabutin]], [[Risedronate]], [[Rosiglitazone]], [[Rosuvastatin]], [[Sorafenib]], [[Streptomycin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfasalazine]], [[Sulfonamide]], [[Sulfonylurea]], [[Sumatriptan]], [[Suramin]], [[Tacrolimus]], [[Tamoxifen]], [[Terbinafine]], [[Tetracycline]], [[Thiabendazole]], [[Thioacetazone]], [[Tolterodine]], [[Tretinoin]], [[Triamcinolone]], [[Valsartan]], [[Vancomycin]], [[Vandetanib]], [[Varenicline]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]], [[Zonisamide]]<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
===Causes in Alphabetical Order===<br />
{{col-begin|width=80%}}<br />
{{col-break|width=33%}}<br />
<br />
* [[Abatacept]]<br />
* [[Abciximab]]<br />
* [[Acebutolol]]<br />
* [[Acetylcysteine]]<br />
* [[Acyclovir]]<br />
* [[Acetazolamide]]<br />
* [[Adalimumab]]<br />
* [[Adapalene]]<br />
* [[Adenosine]]<br />
* [[Albuterol]]<br />
* [[Alendronate]]<br />
* [[Aliskiren]]<br />
* [[Allopurinol]]<br />
* [[Alteplase]],<br />
* [[Amifostine]]<br />
* [[Amiloride]]<br />
* [[Aminocaproic acid]]<br />
* [[Amiodarone]]<br />
* [[Amlodipine]]<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Anastrozole]]<br />
* [[Antihemophilic factor]]<br />
* [[Anti-inhibitor coagulant complex]]<br />
* [[Antithrombin III]]<br />
* [[Argatroban]]<br />
* [[Aripiprazole]]<br />
* [[Armodafinil]]<br />
* [[Atazanavir]]<br />
* [[Atenolol]]<br />
* [[Atomoxetine]]<br />
* [[Atorvastatin calcium]]<br />
* [[Barbiturates]]<br />
* [[Benoxaprofen]]<br />
* [[Benazepril]]<br />
* [[Bendamustine]]<br />
* [[Betaxolol]]<br />
* [[Bevacizumab]]<br />
* [[Bisoprolol]]<br />
* [[Bivalirudin]]<br />
* [[Bortezomib]]<br />
* [[Brentuximab vedotin]]<br />
* [[Brimonidine]]<br />
* [[Brinzolamide]]<br />
* [[Budesonide And Formoterol Fumarate Dihydrate]]<br />
* [[Bumetanide]]<br />
* [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]]<br />
* [[Cabergoline]]<br />
* [[Candesartan]]<br />
* [[Capecitabine]]<br />
* [[Captopril]]<br />
* [[Carbamazepine]]<br />
* [[Carbidopa and Levodopa]]<br />
* [[Carteolol]]<br />
* [[Carvedilol]]<br />
* [[Cefdinir]]<br />
* [[Celecoxib]]<br />
* [[Cephalosporins]]<br />
* [[Cetuximab]]<br />
* [[Chlorambucil]]<br />
* [[Chlormezanone]]<br />
* [[Chlorothiazide]]<br />
* [[Chlorthalidone]]<br />
* [[Cholestyramine]]<br />
* [[Ciclosporin]]<br />
* [[Cilostazol]]<br />
* [[Ciprofloxacin and Dexamethasone]]<br />
* [[Citalopram Hydrobromide]]<br />
* [[Clindamycin]]<br />
* [[Clonidine]]<br />
* [[Clopidogrel]]<br />
* [[Coagulation factor VIIa]]<br />
* [[Codeine]]<br />
* [[Colestipol]]<br />
* [[Conivaptan]]<br />
* [[Crotamiton]]<br />
* [[Cyclobenzaprine]]<br />
* [[Cyclophosphamide]]<br />
* [[Dabigatran]]<br />
* [[Dalteparin]]<br />
* [[Danazol]]<br />
* [[Daptomycin]]<br />
* [[Darbepoetin Alfa]]<br />
* [[Darifenacin]]<br />
* [[Darunavir]]<br />
* [[Dasatinib]]<br />
* [[Denosumab]]<br />
* [[Desirudin]]<br />
* [[Desvenlafaxine]]<br />
* [[Dexamethasone]]<br />
* [[Dexlansoprazole]]<br />
* [[Dexmethylphenidate]]<br />
* [[Diazoxide]]<br />
* [[Diclofenac]]<br />
* [[Diclofenamide]]<br />
* [[Digoxin]]<br />
* [[Digoxin immune fab]]<br />
* [[Diltiazem]]<br />
* [[Dipyridamole]]<br />
* [[Disopyramide]]<br />
* [[Dobutamine]]<br />
* [[Dofetilide]]<br />
* [[Donepezil]]<br />
* [[Dorzolamide]]<br />
* [[Doxazosin]]<br />
* [[Doxycycline Hyclate]]<br />
* [[Dronedarone]]<br />
* [[Metronidazole]]<br />
* [[Duloxetine]]<br />
* [[Dutasteride]]<br />
* [[Dutasteride and Tamsulosin hydrochloride]]<br />
* [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]]<br />
* [[Enalapril maleate]]<br />
* [[Enoxaparin]]<br />
* [[Epoetin alfa]]<br />
* [[Eprosartan]]<br />
* [[Eptifibatide]]<br />
* [[Erlotinib]] <br />
* [[Erythropoietin]]<br />
* [[Esmolol]]<br />
* [[Esomeprazole]]<br />
* [[Eszopiclone]]<br />
* [[Etanercept]]<br />
* [[Ethacrynic acid]]<br />
* [[Ethambutol]]<br />
* [[Ethotoin]] <br />
* [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]]<br />
* [[Etravirine]]<br />
* [[Etodolac]]<br />
* [[Everolimus]]<br />
* [[Exenatide]] <br />
* [[Ezetimibe And Simvastatin]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Factor IX complex]]<br />
* [[Felodipine]]<br />
* [[Fenofibrate]]<br />
* [[Fenoldopam]]<br />
* [[Filgrastim]]<br />
* [[Flecainide]]<br />
* [[Fluconazole]]<br />
* [[Fluorometholone]]<br />
* [[Fluoxetine]]<br />
* [[Fluphenazine]]<br />
* [[Fluticasone]]<br />
* [[Fluticasone and Salmeterol]]<br />
* [[Fluvastatin]]<br />
* [[Fondaparinux]]<br />
* [[Fosamprenavir]]<br />
* [[Fosinopril]]<br />
* [[Glimepiride]]<br />
* [[Glyburide]]<br />
* [[Glipizide]]<br />
* [[Glucagon]]<br />
* [[Glyburide and Metformin]]<br />
* [[Gold]]<br />
* [[HPV Vaccine]]<br />
* [[Hydrocodone bitartrate and Homatropine methylbromide]]<br />
* [[Ibandronic acid]]<br />
* [[Ibritumomab tiuxetan]]<br />
* [[Ibuprofen]]<br />
* [[Imiquimod]]<br />
* [[Ipilimumab]]<br />
* [[Ipratropium Bromide And Albuterol]]<br />
* [[Insulin]]<br />
* [[Insulin glulisine]]<br />
* [[Interferon beta-1a]]<br />
* [[Interferon beta-1b]] <br />
* [[Irbesartan]]<br />
* [[Isoniazid]] <br />
* [[Isotretinoin]]<br />
* [[Ketorolac tromethamine]]<br />
* [[Lamotrigine]] <br />
* [[Leflunomide]]<br />
* [[Lenalidomide]]<br />
* [[Levetiracetam]] <br />
* [[Levonorgestrel and Ethinyl estradiol]]<br />
* [[Linagliptin]]<br />
* [[Linagliptin and Metformin hydrochloride]]<br />
* [[Lisinopril and Hydrochlorothiazide]]<br />
* [[Losartan and Hydrochlorothiazide]]<br />
* [[Medroxyprogesterone]]<br />
* [[Mefenamic acid]]<br />
* [[Meloxicam]]<br />
* [[Mesalamine]]<br />
* [[Metformin]]<br />
* [[Methotrexate]]<br />
* [[Methyldopa]] <br />
* [[Methylphenidate]]<br />
* [[Mirabegron]]<br />
* [[Moxifloxacin]]<br />
* [[Mupirocin]]<br />
* [[Mycophenolate]]<br />
* [[Nafarelin]]<br />
* [[Naproxen sodium]]<br />
* [[Nebivolol]] <br />
* [[Nevirapine]] <br />
* [[Nitrofurantoin]]<br />
* [[Norgestimate and Ethinyl estradiol]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[NSAIDs]]<br />
* [[Nystatin]]<br />
* [[Ofloxacin]]<br />
* [[Olmesartan]]<br />
* [[Oxycodone]]<br />
* [[Oxytocin]]<br />
* [[Pantoprazole]]<br />
* [[Paroxetine]]<br />
* [[Pemetrexed]]<br />
* [[Penicillamine]]<br />
* [[Pentosan polysulfate]]<br />
* [[Phenacetin]] <br />
* [[Phenobarbitol]] <br />
* [[Phenylbutazone]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Phenytoin]]<br />
* [[Pimecrolimus]] <br />
* [[Pioglitazone]]<br />
* [[Piroxicam]]<br />
* [[Potassium chloride]]<br />
* [[Primidone]] <br />
* [[Procainamide]] <br />
* [[Prochlorperazine]]<br />
* [[Progesterone]]<br />
* [[Quinidine]]<br />
* [[Rifabutin]]<br />
* [[Risedronate]]<br />
* [[Rosiglitazone]]<br />
* [[Rosuvastatin]] <br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
* [[Sorafenib]]<br />
* [[Streptomycin]]<br />
* [[Sulfacetamide sodium And Prednisolone acetate]] <br />
* [[Sulfasalazine]] <br />
* [[Sulfonamide]]<br />
* [[Sulfonylurea]]<br />
* [[Sumatriptan]]<br />
* [[Suramin]]<br />
* [[Tacrolimus]]<br />
* [[Tamoxifen]]<br />
* [[Terbinafine]] <br />
* [[Tetracycline]] <br />
* [[Thiabendazole]] <br />
* [[Thioacetazone]]<br />
* [[Tolterodine]]<br />
* [[Tretinoin]]<br />
* [[Triamcinolone]]<br />
* [[Valsartan]]<br />
* [[Vancomycin]] <br />
* [[Vandetanib]]<br />
* [[Venlafaxine]] <br />
* [[Varenicline]]<br />
* [[Zaleplon]]<br />
* [[Zanamivir]]<br />
* [[Zidovudine]]<br />
* [[Zolpidem]]<br />
* [[Zonisamide]]<br />
{{col-end}}<br />
<br />
===Causes by Specific Allergic Reactions<ref>{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy | journal = The Journal of Allergy and Clinical Immunology | date = 2010-02 | pmid = 20176256 }}</ref><ref>{{cite book | last = Lee | first = Anne | title = Adverse drug reactions | publisher = Pharmaceutical Press | location = London Chicago | year = 2006 | isbn = 0853696012 }}</ref>===<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Cutaneous reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Exanthems<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Delayed-type hypersensitivity <BR> ▸ Evolve over days after drug initiation <BR> ▸ Diffuse macules and papules <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[Amlodipine]], [[Amphotericin]], [[Barbiturates]], [[Captopril]], [[carbamazepine]], [[cephalosporins]], [[chloramphenicol]], [[Digoxin]], [[Erythromycin]], [[Furosemide]], [[gentamicin]], [[Glipizide]], [[gold salts]], [[Lithium]], [[Nalidixic acid]], [[Nitrofurantoin]], [[Penicillins]], [[Phenothiazines]], [[Phenylbutazone]], [[Phenytoin]], [[Sulfonamides]], [[Thiazides]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Urticaria/ angioedema<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Often IgE mediated <BR> ▸ Onset within minutes of drug initiation<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[ACE inhibitors]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Alteplase]], [[Aminosalicylic acid]], [[Amlodipine]], [[Amlodipine and Benazepril]], [[Anastrozole]], [[Anti-inhibitor coagulant complex]], [[Anticonvulsants]], [[Antihemophilic factor]], [[Antithrombin III]], [[Aripiprazole]], [[Armodafinil]], [[Aspirin]], [[Atomoxetine]], [[Atropine]], [[Beclometasone dipropionate]], [[Benazepril]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Captopril]], [[Carbidopa and Levodopa]], [[Carvedilol]], [[Celecoxib]], [[cephalosporins]], [[Cetuximab]], [[Cholestyramine]], [[Ciclosporin]], [[Cisplatin]], [[Clomifene]], [[Clonidine]], [[Clopidogrel]], [[Colestipol]], [[Cyclobenzaprine]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Darunavir]], [[Dasatinib]], [[Denosumab]], [[desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Dextran]], [[Diflunisal]], [[Digoxin immune fab]], [[Dofetilide]], [[Donepezil]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Erythropoietin]], [[Esomeprazole]], [[Eszopiclone]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Febuxostat]], [[Felodipine]], [[Fesoterodine]], [[Filgrastim]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fosinopril]], [[Frovatriptan]], [[Gemfibrozil]], [[Gentamicin]], [[Glimepiride]], [[Glipizide]], [[Glyburide]], [[Heparin]], [[Hydralazine]], [[Hydroxychloroquine]], [[Hyoscyamine]], [[Ibuprofen]], [[Indomethacin]], [[Interferon beta-1a]], [[Ipratropium bromide]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isotretinoin]], [[Isradipine]], [[Lamotrigine]], [[Levalbuterol]], [[Levonorgestrel and Ethinyl estradiol]], [[Levothyroxine]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Liraglutide]], [[Lisinopril]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Minocycline hydrochloride]], [[Moxifloxacin ophthalmic]], [[Mupirocin]], [[Losartan]], [[Meloxicam]], [[Metaxalone]], [[Methimazole]], [[Methocarbamol]], [[Methylphenidate]], [[Metoclopramide]], [[Metolazone]], [[Modafinil]], [[Moexipril hydrochloride]], [[Monoclonal antibodies]], [[Moxifloxacin]], [[Nabumetone]], [[Nafarelin]], [[Naltrexone]], [[Naproxen and esomeprazole magnesium]], [[Nisoldipine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Opioids]], [[Orphenadrine]], [[Oxcarbazepine]], [[Oxycodone]], [[Pantoprazole]], [[Pegfilgrastim]], [[Penicillins]], [[Pentamidine Isethionate]], [[Pentoxifylline]], [[Perindopril]], [[Phentermine]], [[Pramipexole]], [[Prochlorperazine]], [[Promethazine]], [[Rifaximin]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Sertraline]], [[Pitavastatin]], [[Procainamide]], [[Rizatriptan]], [[Quinidine sulfate]], [[Quinine]], [[Ramipril]], [[Ranolazine]], [[Repaglinide]], [[Risedronate]], [[Rosuvastatin]], [[Sitagliptin]], [[Sulfonamides]], [[Sumatriptan]], [[Tenofovir]], [[Tetracyclines]], [[Thalidomide]], [[Thiouracil]], [[Ticlopidine]], [[Tizanidine]], [[Tocilizumab]], [[Tolterodine]], [[Tubocurarine]], [[Ustekinumab]], [[Valacyclovir]], [[Valsartan]], [[Vancomycin]], [[Vardenafil]], [[Varenicline]], [[Zaleplon]], [[Zolmitriptan]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Fixed drug eruption<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hyperpigmented plaques that recur at same skin or mucosal site<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[ACE inhibitors]], [[adalimumab]], [[allopurinol]], [[amlodipine]], [[aspirin]], [[barbiturates]], [[benzodiazepines]], [[carbamazepine]], [[cephalosporins]], [[clindamycin]], [[co-trimoxazole]], [[dextromethorphan]], [[diltiazem]], [[fluconazole]], [[lamotrigine]], [[lansoprazole]], [[metronidazole]], [[NSAIDs]], [[paclitaxel]], [[paracetamol]], [[penicillin]], [[phenolphthalein]], [[omeprazole]], [[quinine]], [[salicylates]], [[sulfonamides]], [[terbinafine]], [[tetracyclines]], [[trimethoprim]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pustules<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Acute generalized eczematous pustulosis or acneiform rash<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[antibiotics]], [[calcium-channel blockers]], [[corticosteroids]], [[sirolimus]],[[Fluticasone]],[[Erlotinib]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Bullous<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Flaccid or tense blisters <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Argatroban]], [[Bendamustine]], [[Captopril]], [[Carbidopa and Levodopa]], [[Dasatinib]], [[Erlotinib]], [[Penicillamine]], [[Furosemide]], [[Risedronate]], [[Vancomycin]],[[Abciximab]],[[Warfarin]], [[Topiramate]],[[Linezolid]],[[Mirtazapine]],[[Dapsone]], [[Allopurinol]],[[Captopril ]],[[Captopril and Hydrochlorothiazide]],[[Clopidogrel]],[[Erlotinib]],[[Fosinopril]], [[Ibuprofen]], [[Imatinib]],[[Indapamide]],[[Risedronate]],[[Zolpidem]],[[Dasatinib]],[[Minoxidil]],[[Labetalol]],[[Phenytoin]],[[Dalteparin]],[[Bendamustine]],[[Tinzaparin]],[[Tamoxifen]],[[ clarithromycin]],[[Atorvastatin calcium]],[[Caduet]],[[Ticarcillin/Clavulanate]],[[Terbinafine]],[[Quinine]],[[Nevirapine]],[[Topiramate]],[[Perindopril]],[[Moexipril/Hydrochlorothiazide]], [[Naproxen sodium]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Cutaneous lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Erythematous/scaly plaques in photodistribution<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Hydrochlorothiazide]], [[calcium-channel blockers]], [[ACEIs]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Stevens-Johnson syndrome (SJS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Purpuric macules on face and trunk with &lt;10% epidermal detachment, fever, stomatitis, ocular involvement<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Antibiotics]], [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Beta-lactam|Β-lactam antibiotics]], [[Brinzolamide]], [[Carbamazepine]], [[Carvedilol]], [[Celecoxib]], [[Chlorpropamide]], [[Co-trimoxazole]], [[Darunavir]], [[Diflunisal]], [[Dorzolamide]], [[Duloxetine]], [[efavirenz, emtricitabine, and tenofovir disoproxil fumarate]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Fenofibrate]], [[Glimepiride]], [[Gold]], [[H2 Antagonist]]s, [[Histamine]], [[Hydroxychloroquine]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]],[[Lisinopril and Hydrochlorothiazide]], [[Macrolides]], [[Mefenamic acid]], [[Meloxicam]], [[Metolazone]], [[Mefloquine]], [[Methotrexate]], [[Mexiletine]], [[Minocycline hydrochloride]], [[Minoxidil]], [[Modafinil]], [[Naproxen and esomeprazole magnesium]], [[Piroxicam]], [[Moxifloxacin]], [[Nitrofurantoin]], [[NSAIDS]], [[Ofloxacin]], [[Olmesartan medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Phenothiazines]], [[Phenytoin]], [[Rifampicin]], [[Rivaroxaban]], [[Simvastatin]], [[Sitagliptin]], [[Spironolactone]], [[sulfacetamide sodium and prednisolone acetate]], [[Sulfonamides]], [[Tadalafil]], [[Tetracyclines]], [[Thalidomide]], [[Thiazides]], [[Ticlopidine]], [[Varenicline]], [[Zidovudine]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Toxic epidermal necrolysis (TEN)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Similar to SJS but >30% epidermal detachment<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Allopurinol]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Brinzolamide]], [[Carbamazepine]], [[Celecoxib]], [[Diflunisal]], [[Dorzolamide]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Finasteride]], [[Gold]], [[Griseofulvin]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]], [[Lisinopril and Hydrochlorothiazide]], [[Mefenamic acid]], [[Meloxicam]], [[Methotrexate]], [[Metolazone]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Naproxen and esomeprazole magnesium]], [[Nitrofurantoin]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Penicillins]], [[Phenytoin]], [[Piroxicam]], [[Salicylates]], [[Sitagliptin]], [[Spironolactone]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[tetracyclines]], [[Thalidomide]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Organ-specific reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pulmonary<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Pulmonary fibrosis, hypersensitivity pneumonitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Nitrofurantoin]], [[bleomycin]], [[Cabergoline]], [[Cetuximab]], [[Desvenlafaxine]], [[Dronedarone]], [[Erlotinib]], [[Hydrochlorothiazide]], [[Methyclothiazide]], [[Methotrexate]], [[Amiodarone]], [[Moxifloxacin]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hepatic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hepatitis, cholestasis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Aminosalicylic acid|Para-aminosalicylic acid]], [[Brinzolamide]], [[Dorzolamide]], [[Ofloxacin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[phenothiazines]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Renal<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Interstitial nephritis, membranous glomerulonephritis <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |[[Ofloxacin]], [[Penicillin]], [[sulfonamides]], [[gold]], [[penicillamine]], [[allopurinol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hematologic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hemolytic anemia, thrombocytopenia, granulocytopenia<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |<br />
▸ Hemolytic anemia — [[5-Azacytidine]], [[Acetophenazine]], [[Aclarubicin]], [[Actinomycin D]], [[Albendazole]], [[Alemtuzumab]], [[Aminopyrine]], [[Amitriptyline]], [[Amodiaquine]], [[Anakinra]], [[Antipyrine]], [[Azathioprine]], [[Bevacizumab]], [[Bortezomib]], [[Captopril]], [[Carbimazole]], [[Caspofungin]], [[Chloramphenicol]], [[Chlorpromazine]], [[Ciclosporin]], [[Cidofovir]], [[Cilazapril]], [[Clofarabine]], [[Clozapine]], [[Deferiprone]], [[Desipramine]], [[Docetaxel]], [[Dothiepin]], [[Doxorubicin]], [[Eflornithine]], [[Ethosuximide]], [[Erlotinib]], [[Ethotoin]], [[Flucytosine]], [[Fludarabine]], [[Fondaparinux]], [[Ganciclovir]], [[Gemcitabine]], [[Glimepiride]], [[Glyburide]], [[Glyburide and Metformin]], [[Gold salts]], [[Hydroxycarbamide]], [[Hypersplenism]], [[Ibritumomab tiuxetan]], [[Idarubicin]], [[Imatinib mesylate]], [[Interferon alpha]], [[Interferon beta]], [[Irinotecan]], [[Isoniazid]], [[Levomepromazine]], [[Lisinopril and Hydrochlorothiazide]], [[Mercaptopurine]], [[Methimazole]], [[Mirtazapine]], [[Mitoxantrone]], [[Nortriptyline]], [[Ofloxacin]], [[Paclitaxel]], [[Penicillamine]], [[Pentamidine]], [[Pentostatin]], [[Perazine]], [[Phenylbutazone]], [[Phenytoin]], [[Pipothiazine]], [[Procainamide]], [[Propylthiouracil]], [[Pyrimethamine]], [[Quinidine]], [[Remoxipride]], [[Riluzole]], [[Stiripentol]], [[Sulfasalazine]], [[Sulphonamides]], [[Ticlopidine]], [[Topotecan]], [[Trastuzumab]], [[Trimetrexate]], [[Valganciclovir]], [[Zidovudine]], [[Zileuton]]<br />
<br />
▸ Thrombocytopenia — [[Abciximab]], [[Aldesleukin]], [[Amobarbital]], [[Amrinone]], [[Armodafinil]], [[Capreomycin]], [[Carboplatin]], [[Cefotaxime]], [[Cefotetan]], [[Cefoxitin]], [[Ceftizoxime]], [[Chloramphenicol]], [[Chlorpropamide]], [[Ciclosporin]], [[Cinoxacin]], [[Claforan]], [[Diabinese]], [[Digoxin]], [[Disopyramide]], [[Enoxaparin]], [[Eptifibatide]], [[Erlotinib]], [[Estrogens]], [[Ethanol]], [[Exna]], [[Fondaparinux]], [[Glyburide]], [[Heparin]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Paraplatin]], [[Phenylbutazone]], [[Procainamide]], [[Proleukin]], [[Rifabutin]], [[Secobarbital]], [[Sulfonamides]], [[Thiazides]], [[Tuinal]]<br />
<br />
▸ Granulocytopenia — [[Acetazolamide]], [[Aripiprazole]], [[Benzthiazide]], [[Bortezomib]], [[Brinzolamide]], [[Bumetanide]], [[Capecitabine]], [[Captopril]], [[Carbamazepine]], [[Ceftazidime]], [[Celecoxib]], [[Chlorpropamide]], [[Dapsone]], [[Diabinese]], [[Disopyramide]], [[Dorzolamide]], [[Enalapril maleate]], [[Exna]], [[Fosinopril]], [[Fortaz]], [[Glyburide]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Penicillin]], [[quinine]], [[Rifabutin]], [[salicylate]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Multiorgan reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Anaphylaxis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, angioedema, bronchospasm, gastrointestinal symptoms, hypotension<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Albuterol]], [[Aliskiren]], [[Alteplase]], [[Amlodipine and Benazepril]], [[Aminocaproic acid]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Aripiprazole]], [[Armodafinil]], [[Atomoxetine]], [[Beclometasone dipropionate]], [[Beta-lactam|β-lactam antibiotics]], [[Betaxolol]], [[Bisoprolol]], [[Bivalirudin]], [[Bortezomib]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[monoclonal antibodies]], [[adalimumab]], [[Benazepril]], [[Bendamustine]], [[Captopril]], [[Carteolol]], [[Carvedilol]], [[Celecoxib]], [[Ciclosporin]], [[Ciprofloxacin and Dexamethasone]], [[Cisplatin]], [[Clopidogrel]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Denosumab]], [[Desirudin]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diflunisal]], [[Digoxin]], [[Digoxin immune fab]], [[Dobutamine]], [[Enalapril maleate]], [[Enoxaparin]], [[epoetin alfa]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Ethambutol]], [[Etodolac]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Fenoldopam]], [[Fluconazole]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fondaparinux]], [[Furosemide]], [[Glimepiride]], [[Glucagon]], [[Heparin]], [[HPV Vaccine]], [[Hyoscyamine]], [[Ibandronic acid]], [[Infliximab]], [[Insulin glargine]], [[Insulin glulisine]], [[Insulin lispro]], [[Interferon beta-1a]], [[Interferon beta-1b]], [[Ipratropium Bromide And Albuterol]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Labetalol]], [[Levalbuterol]], [[Lepirudin]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Metaxalone]], [[Methylphenidate]], [[Methyltestosterone]], [[Metoclopramide]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Mupirocin]], [[Nabumetone]], [[Nadolol]], [[Nebivolol]], [[Nitrofurantoin]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Ondansetron]], [[Oxytocin]], [[Penbutolol]], [[Pindolol]], [[Prochlorperazine]], [[Propranolol]], [[Progesterone]], [[Protamine]], [[Rituximab]], [[Rivaroxaban]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Solifenacin]], [[Sumatriptan]], [[Tinzaparin]], [[Tocilizumab]], [[Trastuzumab]], [[Triamcinolone]], [[Triamterene]], [[Urokinase]], [[Valganciclovir hydrochloride]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Systemic lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Arthralgia, myalgias, fever, malaise<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Armodafinil]], [[Hydralazine]], [[procainamide]], [[isoniazid]], [[propafenone]], [[Levonorgestrel and Ethinyl estradiol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous or visceral vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[aspirin]], [[Beta-lactam|β-lactam antibiotics]], [[carbamazepine]], [[carbimazole]], [[co-trimoxazole]], [[diltiazem]], [[erythromycin]], [[gold]], [[G-CSF]], [[GM-CSF]], [[Hydralazine]], [[interferons]], [[methotrexate]], [[minocycline]], [[NSAIDs]], [[penicillamine]], [[propylthiouracil]], [[retinoids]], [[sulfasalazine]], [[sulfonamides]], [[thiazides]], [[thrombolytics]], [[Adalimumab]], [[Amiodarone]], [[Cefdinir]], [[Methyldopa]], [[Amoxapine]], [[Moxifloxacin]], [[Fluticasone]], [[Acyclovir]], [[Allopurinol]], [[Amlodipine]], [[Bortezomib]], [[Captopril]], [[Captopril and Hydrochlorothiazide]], [[Chlorothiazide]], [[Chlorthalidone]], [[Clopidogrel]], [[Delavirdine]], [[Enalapril maleate]], [[Filgrastim]], [[Fosinopril]], [[Furosemide]], [[Hydrochlorothiazide]],,[[Imatinib]], [[Isotretinoin]], [[Lisinopril]], [[Lisinopril/Hydrochlorothiazide]], [[Losartan]], [[Lovastatin]], [[Methyclothiazide]], [[Metolazone]], [[Ofloxacin]], [[Pravastatin]], [[Prazosin]], [[Ramipril]], [[Abatacept]], [[Spironolactone]], [[Spironolactone/Hydrochlorothiazide]], [[Ticlopidine]], [[Valsartan]], [[Colchicine]], [[Quinidine]], [[Quinidine gluconate]], [[Dronedarone]], [[Enoxaparin]], [[Thiazide]], [[Fluticasone/salmeterol]], [[Infliximab]], [[Sitagliptin]], [[Enalaprilat]], [[Fluoxetine]], [[Glyburide]], [[Hydrochloride]], [[Hydroflumethiazide]], [[Polythiazide]], [[Valaciclovir]], [[Simvastatin]], [[Losartan and Hydrochlorothiazide]], [[Methylphenidate]], [[Dexlansoprazole]], [[Sumatriptan]], [[Bisoprolol]], [[Rituximab]], [[Aggrenox]], [[Penicillin G]], [[Norfloxacin]], [[Isoniazid]], [[Penicillin G procaine]], [[Famciclovir]], [[Cefuroxime]], [[Rifampin isoniazid]], [[Rifampin]], [[Interferon alfa-2a]], [[Amoxicillin-clavulanate potassium]], [[Interferon alfa-2a]], [[Pegylated interferon alfa-2a]], [[vancomycin]], [[Atovaquone proguanil]], [[Terbinafine]], [[Indinavir]], [[Ciprofloxacin Hydrochloride]], [[Lamivudine zidovudine]], [[Interferon alfa-2b]], [[Gemifloxacin mesylate]], [[Pentamidine Isethionate]], [[Abacavir lamivudine zidovudine]], [[Nitrofurantoin]], [[Zidovudine]], [[Quinine Sulfate]], [[Valproic acid]], [[Divalproex]], [[Niacin/Simvastatin]], [[Ezetimibe/Simvastatin]], [[Felodipine]], [[Fosinopril/Hydrochlorothiazide]], [[Moexipril/Hydrochlorothiazide]], [[Quinapril/Hydrochlorothiazide]], [[Enalapril maleate/Hydrochlorothiazide]], [[Enalapril/Felodipine]], [[Perindopril]] ,[[Fluvastatin]], [[Diltiazem]], [[Metoprolol succinate and hydrochlorothiazide]], [[Nebivolol]], [[Amiodarone]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Amlodipine Besylate]], [[Divalproex]], [[Pioglitazone/Glimepiride]], [[Aspirin/Dipyridamole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Serum sickness<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, arthralgia, fever<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Heterologous]] [[antibodies]], [[infliximab]], [[Cefdinir]], [[Bupropion]], [[Levothyroxine]], [[Tetracycline hydrochloride]], [[Antivenom]], [[Glatiramer acetate]], [[Antivenin]],,[[Measles]], [[Ticlopidine]], [[Clopidogrel]], [[Novobiocin]], [[Epinephrine]], [[Omalizumab]], [[Rituximab]], [[Immunosuppressive drug]], [[Digoxin]], [[Levothyroxine]], [[Ciprofloxacin]], [[Cefprozil]], [[Cefaclor]], [[Oxacillin]], [[Amoxicillin]], [[Ofloxacin]], [[Penicillin G benzathine]], [[Ampicillin]], [[Ceftibuten]], [[Cefpodoxime]], [[Terbinafine]], [[Gemifloxacin]], [[Metronidazole]], [[Cefadroxil]], [[Doxycycline]], [[Levofloxacin]], [[Minocycline]], [[Moxifloxacin]], [[Sulfadiazine]], [[Lincomycin]], [[Sulfamethoxazole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Drug reaction with eosinophilia and systemic symptoms (DRESS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[anticonvulsant]]s, [[Armodafinil]], [[atazanavir]], [[Carbamazepine]], [[minocycline]], [[sulfonamide]]s, [[spironolactone]]<br />
|}<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Allergology]]<br />
[[Category:Immunology]]<br />
[[Category:Emergency medicine]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Drug_allergy_causes&diff=1058939Drug allergy causes2015-01-23T14:52:29Z<p>Deepika Beereddy: /* Causes by Organ System */</p>
<hr />
<div>__NOTOC__<br />
{{Drug allergy}}<br />
{{CMG}}; {{AE}} {{CP}}, {{JM}}<br />
<br />
==Overview==<br />
The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.<br />
<br />
==Causes==<br />
===Common Causes===<br />
When a medication causes an allergic reaction, it is called an [[allergen]]. The following is a short list of the most common drug allergens<br />
*Antibiotics<br />
**[[Penicillin]]<br />
**[[Sulfonamide (medicine)|Sulfa drugs]]<br />
**[[Tetracycline]]<br />
*Analgesics<br />
**[[Codeine]]<br />
**[[Non-steroidal anti-inflammatory drug]]s (NSAIDs)<br />
*Anticonvulsives<br />
**[[Phenytoin|Dilantin]]<br />
**[[Carbamazepine|Tegretol]]<br />
<br />
===Causes by Organ System===<br />
<br />
{|style="width:75%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Effect'''<br />
|bgcolor="Beige"| [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Adapalene]], [[Adenosine]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Allopurinol]], [[Alteplase]], [[Amifostine]], [[Amiloride]], [[Aminocaproic acid]], [[Amiodarone]], [[Amlodipine]], [[Amlodipine besylate and Valsartan]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Antithrombin III]], [[Argatroban]], [[Aripiprazole]], [[Armodafinil]], [[Atazanavir]], [[Atenolol]], [[Atomoxetine]], [[Atorvastatin calcium]], [[Barbiturates]], [[Benazepril]], [[Bendamustine]], [[Benoxaprofen]], [[Betaxolol]], [[Bevacizumab]], [[Bisoprolol]], [[Botulinum toxin]], [[Brentuximab vedotin]], [[Brimonidine]], [[Brinzolamide]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Bumetanide]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[Cabergoline]], [[Captopril]], [[Carbamazepine]], [[Carbidopa and Levodopa]], [[Carteolol]], [[Carvedilol]], [[Cefdinir]], [[Celecoxib]], [[Cephalosporins]], [[Cetuximab]], [[Chlorambucil]], [[Chlormezanone]], [[Chlorothiazide]], [[Chlorthalidone]], [[Cholestyramine]], [[Ciclosporin]], [[Cilostazol]], [[Ciprofloxacin and Dexamethasone]], [[Citalopram Hydrobromide]], [[Clindamycin]], [[Clonidine]], [[Clopidogrel]], [[Coagulation factor VIIa]], [[Codeine]], [[Colestipol]], [[Conivaptan]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Danazol]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Dasatinib]], [[Denosumab]], [[Desirudin]], [[Desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diazoxide]], [[Diclofenac]], [[Diclofenamide]], [[Dofetilide]], [[Digoxin]], [[Digoxin immune fab]], [[Diltiazem]], [[Donepezil]], [[Dipyridamole]], [[Disopyramide]], [[Dobutamine]], [[Dorzolamide]], [[Doxycycline Hyclate]], [[Dronedarone]], [[Duloxetine]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]], [[Ethynodiol diacetate and ethinyl estradiol]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Eprosartan]], [[Eptifibatide]], [[Erlotinib]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]], [[Ethacrynic acid]], [[Ethambutol]], [[Ethotoin]], [[Etodolac]], [[Etravirine]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Ezetimibe And Simvastatin]], [[Factor IX complex]], [[Felodipine]], [[Fenofibrate]], [[Fenoldopam]], [[Filgrastim]], [[Flecainide]], [[Fluconazole]], [[Fluphenazine]], [[Fluticasone]], [[Fluticasone and Salmeterol]], [[Fluvastatin]], [[Fondaparinux]], [[Fosamprenavir]], [[Fosinopril]], [[Glimepiride]], [[Glyburide and Metformin]], [[Gold]], [[HPV Vaccine]], [[Hydrocodone bitartrate and Homatropine methylbromide]], [[Ibandronic acid]], [[Ibritumomab tiuxetan]], [[Ibuprofen]], [[Imiquimod]], [[Interferon beta-1b]], [[Ipilimumab]], [[Insulin]], [[Insulin glulisine]], [[Interferon beta-1a]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isoniazid]], [[Isotretinoin]], [[Ketorolac tromethamine]] [[Lamotrigine]], [[Leflunomide]], [[Lenalidomide]], [[levetiracetam]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Mesalamine]], [[Metformin]], [[Methimazole]], [[Methotrexate]], [[Methyldopa]], [[Methylphenidate]], [[Metronidazole]], [[Mirabegron]], [[Moxifloxacin]], [[Mupirocin]], [[Mycophenolate]], [[Nafarelin]], [[Naproxen sodium]], [[Nebivolol]], [[Nevirapine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[NSAIDs]], [[Nystatin]], [[Ofloxacin]], [[Oxycodone]], [[Oxytocin]], [[Pantoprazole]], [[Paroxetine]], [[Pemetrexed]], [[Penicillamine]], [[Pentosan polysulfate]], [[Phenacetin]], [[Phenobarbitol]], [[Phenylbutazone]], [[Piroxicam]], [[Prochlorperazine]], [[Progesterone]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Phenytoin]], [[Pioglitazone]], [[Potassium chloride]], [[Primidone]], [[Procainamide]], [[Quinidine]], [[Rifabutin]], [[Risedronate]], [[Rosiglitazone]], [[Rosuvastatin]], [[Sorafenib]], [[Streptomycin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[Sulfasalazine]], [[Sulfonamide]], [[Sulfonylurea]], [[Sumatriptan]], [[Suramin]], [[Tacrolimus]], [[Tamoxifen]], [[Terbinafine]], [[Tetracycline]], [[Thiabendazole]], [[Thioacetazone]], [[Tolterodine]], [[Tretinoin]], [[Triamcinolone]], [[Valsartan]], [[Vancomycin]], [[Vandetanib]], [[Varenicline]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]], [[Zonisamide]]<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
===Causes in Alphabetical Order===<br />
{{col-begin|width=80%}}<br />
{{col-break|width=33%}}<br />
<br />
* [[Abatacept]]<br />
* [[Abciximab]]<br />
* [[Acebutolol]]<br />
* [[Acetylcysteine]]<br />
* [[Acyclovir]]<br />
* [[Acetazolamide]]<br />
* [[Adalimumab]]<br />
* [[Adapalene]]<br />
* [[Adenosine]]<br />
* [[Albuterol]]<br />
* [[Alendronate]]<br />
* [[Aliskiren]]<br />
* [[Allopurinol]]<br />
* [[Alteplase]],<br />
* [[Amifostine]]<br />
* [[Amiloride]]<br />
* [[Aminocaproic acid]]<br />
* [[Amiodarone]]<br />
* [[Amlodipine]]<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Anastrozole]]<br />
* [[Antihemophilic factor]]<br />
* [[Anti-inhibitor coagulant complex]]<br />
* [[Antithrombin III]]<br />
* [[Argatroban]]<br />
* [[Aripiprazole]]<br />
* [[Armodafinil]]<br />
* [[Atazanavir]]<br />
* [[Atenolol]]<br />
* [[Atomoxetine]]<br />
* [[Atorvastatin calcium]]<br />
* [[Barbiturates]]<br />
* [[Benoxaprofen]]<br />
* [[Benazepril]]<br />
* [[Bendamustine]]<br />
* [[Betaxolol]]<br />
* [[Bevacizumab]]<br />
* [[Bisoprolol]]<br />
* [[Bivalirudin]]<br />
* [[Bortezomib]]<br />
* [[Brentuximab vedotin]]<br />
* [[Brimonidine]]<br />
* [[Brinzolamide]]<br />
* [[Budesonide And Formoterol Fumarate Dihydrate]]<br />
* [[Bumetanide]]<br />
* [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]]<br />
* [[Cabergoline]]<br />
* [[Candesartan]]<br />
* [[Capecitabine]]<br />
* [[Captopril]]<br />
* [[Carbamazepine]]<br />
* [[Carbidopa and Levodopa]]<br />
* [[Carteolol]]<br />
* [[Carvedilol]]<br />
* [[Cefdinir]]<br />
* [[Celecoxib]]<br />
* [[Cephalosporins]]<br />
* [[Cetuximab]]<br />
* [[Chlorambucil]]<br />
* [[Chlormezanone]]<br />
* [[Chlorothiazide]]<br />
* [[Chlorthalidone]]<br />
* [[Cholestyramine]]<br />
* [[Ciclosporin]]<br />
* [[Cilostazol]]<br />
* [[Ciprofloxacin and Dexamethasone]]<br />
* [[Citalopram Hydrobromide]]<br />
* [[Clindamycin]]<br />
* [[Clonidine]]<br />
* [[Clopidogrel]]<br />
* [[Coagulation factor VIIa]]<br />
* [[Codeine]]<br />
* [[Colestipol]]<br />
* [[Conivaptan]]<br />
* [[Crotamiton]]<br />
* [[Cyclobenzaprine]]<br />
* [[Cyclophosphamide]]<br />
* [[Dabigatran]]<br />
* [[Dalteparin]]<br />
* [[Danazol]]<br />
* [[Daptomycin]]<br />
* [[Darbepoetin Alfa]]<br />
* [[Darifenacin]]<br />
* [[Darunavir]]<br />
* [[Dasatinib]]<br />
* [[Denosumab]]<br />
* [[Desirudin]]<br />
* [[Desvenlafaxine]]<br />
* [[Dexamethasone]]<br />
* [[Dexlansoprazole]]<br />
* [[Dexmethylphenidate]]<br />
* [[Diazoxide]]<br />
* [[Diclofenac]]<br />
* [[Diclofenamide]]<br />
* [[Digoxin]]<br />
* [[Digoxin immune fab]]<br />
* [[Diltiazem]]<br />
* [[Dipyridamole]]<br />
* [[Disopyramide]]<br />
* [[Dobutamine]]<br />
* [[Dofetilide]]<br />
* [[Donepezil]]<br />
* [[Dorzolamide]]<br />
* [[Doxazosin]]<br />
* [[Doxycycline Hyclate]]<br />
* [[Dronedarone]]<br />
* [[Metronidazole]]<br />
* [[Duloxetine]]<br />
* [[Dutasteride]]<br />
* [[Dutasteride and Tamsulosin hydrochloride]]<br />
* [[Efavirenz, Emtricitabine, and Tenofovir disoproxil fumarate]]<br />
* [[Enalapril maleate]]<br />
* [[Enoxaparin]]<br />
* [[Epoetin alfa]]<br />
* [[Eprosartan]]<br />
* [[Eptifibatide]]<br />
* [[Erlotinib]] <br />
* [[Erythropoietin]]<br />
* [[Esmolol]]<br />
* [[Esomeprazole]]<br />
* [[Eszopiclone]]<br />
* [[Etanercept]]<br />
* [[Ethacrynic acid]]<br />
* [[Ethambutol]]<br />
* [[Ethotoin]] <br />
* [[Etonogestrel and Ethinyl Estradiol Vaginal Ring]]<br />
* [[Etravirine]]<br />
* [[Etodolac]]<br />
* [[Everolimus]]<br />
* [[Exenatide]] <br />
* [[Ezetimibe And Simvastatin]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Factor IX complex]]<br />
* [[Felodipine]]<br />
* [[Fenofibrate]]<br />
* [[Fenoldopam]]<br />
* [[Filgrastim]]<br />
* [[Flecainide]]<br />
* [[Fluconazole]]<br />
* [[Fluorometholone]]<br />
* [[Fluoxetine]]<br />
* [[Fluphenazine]]<br />
* [[Fluticasone]]<br />
* [[Fluticasone and Salmeterol]]<br />
* [[Fluvastatin]]<br />
* [[Fondaparinux]]<br />
* [[Fosamprenavir]]<br />
* [[Fosinopril]]<br />
* [[Glimepiride]]<br />
* [[Glyburide]]<br />
* [[Glipizide]]<br />
* [[Glucagon]]<br />
* [[Glyburide and Metformin]]<br />
* [[Gold]]<br />
* [[HPV Vaccine]]<br />
* [[Hydrocodone bitartrate and Homatropine methylbromide]]<br />
* [[Ibandronic acid]]<br />
* [[Ibritumomab tiuxetan]]<br />
* [[Ibuprofen]]<br />
* [[Imiquimod]]<br />
* [[Ipilimumab]]<br />
* [[Ipratropium Bromide And Albuterol]]<br />
* [[Insulin]]<br />
* [[Insulin glulisine]]<br />
* [[Interferon beta-1a]]<br />
* [[Interferon beta-1b]] <br />
* [[Irbesartan]]<br />
* [[Isoniazid]] <br />
* [[Isotretinoin]]<br />
* [[Ketorolac tromethamine]]<br />
* [[Lamotrigine]] <br />
* [[Leflunomide]]<br />
* [[Lenalidomide]]<br />
* [[Levetiracetam]] <br />
* [[Levonorgestrel and Ethinyl estradiol]]<br />
* [[Linagliptin]]<br />
* [[Linagliptin and Metformin hydrochloride]]<br />
* [[Lisinopril and Hydrochlorothiazide]]<br />
* [[Losartan and Hydrochlorothiazide]]<br />
* [[Medroxyprogesterone]]<br />
* [[Mefenamic acid]]<br />
* [[Meloxicam]]<br />
* [[Mesalamine]]<br />
* [[Metformin]]<br />
* [[Methotrexate]]<br />
* [[Methyldopa]] <br />
* [[Methylphenidate]]<br />
* [[Moxifloxacin]]<br />
* [[Mupirocin]]<br />
* [[Mycophenolate]]<br />
* [[Nafarelin]]<br />
* [[Naproxen sodium]]<br />
* [[Nebivolol]] <br />
* [[Nevirapine]] <br />
* [[Nitrofurantoin]]<br />
* [[Norgestimate and Ethinyl estradiol]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[NSAIDs]]<br />
* [[Nystatin]]<br />
* [[Ofloxacin]]<br />
* [[Olmesartan]]<br />
* [[Oxycodone]]<br />
* [[Oxytocin]]<br />
* [[Pantoprazole]]<br />
* [[Paroxetine]]<br />
* [[Pemetrexed]]<br />
* [[Penicillamine]]<br />
* [[Pentosan polysulfate]]<br />
* [[Phenacetin]] <br />
* [[Phenobarbitol]] <br />
* [[Phenylbutazone]]<br />
<br />
{{col-break|width=33%}}<br />
<br />
* [[Phenytoin]]<br />
* [[Pimecrolimus]] <br />
* [[Pioglitazone]]<br />
* [[Piroxicam]]<br />
* [[Potassium chloride]]<br />
* [[Primidone]] <br />
* [[Procainamide]] <br />
* [[Prochlorperazine]]<br />
* [[Progesterone]]<br />
* [[Quinidine]]<br />
* [[Rifabutin]]<br />
* [[Risedronate]]<br />
* [[Rosiglitazone]]<br />
* [[Rosuvastatin]] <br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
* [[Sorafenib]]<br />
* [[Streptomycin]]<br />
* [[Sulfacetamide sodium And Prednisolone acetate]] <br />
* [[Sulfasalazine]] <br />
* [[Sulfonamide]]<br />
* [[Sulfonylurea]]<br />
* [[Sumatriptan]]<br />
* [[Suramin]]<br />
* [[Tacrolimus]]<br />
* [[Tamoxifen]]<br />
* [[Terbinafine]] <br />
* [[Tetracycline]] <br />
* [[Thiabendazole]] <br />
* [[Thioacetazone]]<br />
* [[Tolterodine]]<br />
* [[Tretinoin]]<br />
* [[Triamcinolone]]<br />
* [[Valsartan]]<br />
* [[Vancomycin]] <br />
* [[Vandetanib]]<br />
* [[Venlafaxine]] <br />
* [[Varenicline]]<br />
* [[Zaleplon]]<br />
* [[Zanamivir]]<br />
* [[Zidovudine]]<br />
* [[Zolpidem]]<br />
* [[Zonisamide]]<br />
{{col-end}}<br />
<br />
===Causes by Specific Allergic Reactions<ref>{{Cite journal | doi = 10.1016/j.jaci.2009.10.028 | issn = 1097-6825 | volume = 125 | issue = 2 Suppl 2 | pages = –126-137 | last = Khan | first = David A. | coauthors = Roland Solensky | title = Drug allergy | journal = The Journal of Allergy and Clinical Immunology | date = 2010-02 | pmid = 20176256 }}</ref><ref>{{cite book | last = Lee | first = Anne | title = Adverse drug reactions | publisher = Pharmaceutical Press | location = London Chicago | year = 2006 | isbn = 0853696012 }}</ref>===<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Cutaneous reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Exanthems<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Delayed-type hypersensitivity <BR> ▸ Evolve over days after drug initiation <BR> ▸ Diffuse macules and papules <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[Amlodipine]], [[Amphotericin]], [[Barbiturates]], [[Captopril]], [[carbamazepine]], [[cephalosporins]], [[chloramphenicol]], [[Digoxin]], [[Erythromycin]], [[Furosemide]], [[gentamicin]], [[Glipizide]], [[gold salts]], [[Lithium]], [[Nalidixic acid]], [[Nitrofurantoin]], [[Penicillins]], [[Phenothiazines]], [[Phenylbutazone]], [[Phenytoin]], [[Sulfonamides]], [[Thiazides]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Urticaria/ angioedema<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Often IgE mediated <BR> ▸ Onset within minutes of drug initiation<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[ACE inhibitors]], [[Acetylcysteine]], [[Acyclovir]], [[Adalimumab]], [[Albuterol]], [[Alendronate]], [[Aliskiren]], [[Alteplase]], [[Aminosalicylic acid]], [[Amlodipine]], [[Amlodipine and Benazepril]], [[Anastrozole]], [[Anti-inhibitor coagulant complex]], [[Anticonvulsants]], [[Antihemophilic factor]], [[Antithrombin III]], [[Aripiprazole]], [[Armodafinil]], [[Aspirin]], [[Atomoxetine]], [[Atropine]], [[Beclometasone dipropionate]], [[Benazepril]], [[Budesonide And Formoterol Fumarate Dihydrate]], [[Captopril]], [[Carbidopa and Levodopa]], [[Carvedilol]], [[Celecoxib]], [[cephalosporins]], [[Cetuximab]], [[Cholestyramine]], [[Ciclosporin]], [[Cisplatin]], [[Clomifene]], [[Clonidine]], [[Clopidogrel]], [[Colestipol]], [[Cyclobenzaprine]], [[Darbepoetin Alfa]], [[Darifenacin]], [[Darunavir]], [[Dasatinib]], [[Denosumab]], [[desvenlafaxine]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Dextran]], [[Diflunisal]], [[Digoxin immune fab]], [[Dofetilide]], [[Donepezil]], [[Dutasteride]], [[Dutasteride and Tamsulosin hydrochloride]], [[Enalapril maleate]], [[Enoxaparin]], [[Epoetin alfa]], [[Erythropoietin]], [[Esomeprazole]], [[Eszopiclone]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Febuxostat]], [[Felodipine]], [[Fesoterodine]], [[Filgrastim]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fosinopril]], [[Frovatriptan]], [[Gemfibrozil]], [[Gentamicin]], [[Glimepiride]], [[Glipizide]], [[Glyburide]], [[Heparin]], [[Hydralazine]], [[Hydroxychloroquine]], [[Hyoscyamine]], [[Ibuprofen]], [[Indomethacin]], [[Interferon beta-1a]], [[Ipratropium bromide]], [[Ipratropium Bromide And Albuterol]], [[Irbesartan]], [[Isotretinoin]], [[Isradipine]], [[Lamotrigine]], [[Levalbuterol]], [[Levonorgestrel and Ethinyl estradiol]], [[Levothyroxine]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Liraglutide]], [[Lisinopril]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Minocycline hydrochloride]], [[Moxifloxacin ophthalmic]], [[Mupirocin]], [[Losartan]], [[Meloxicam]], [[Metaxalone]], [[Methimazole]], [[Methocarbamol]], [[Methylphenidate]], [[Metoclopramide]], [[Metolazone]], [[Modafinil]], [[Moexipril hydrochloride]], [[Monoclonal antibodies]], [[Moxifloxacin]], [[Nabumetone]], [[Nafarelin]], [[Naltrexone]], [[Naproxen and esomeprazole magnesium]], [[Nisoldipine]], [[Nitrofurantoin]], [[Norgestimate and Ethinyl estradiol]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Opioids]], [[Orphenadrine]], [[Oxcarbazepine]], [[Oxycodone]], [[Pantoprazole]], [[Pegfilgrastim]], [[Penicillins]], [[Pentamidine Isethionate]], [[Pentoxifylline]], [[Perindopril]], [[Phentermine]], [[Pramipexole]], [[Prochlorperazine]], [[Promethazine]], [[Rifaximin]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Sertraline]], [[Pitavastatin]], [[Procainamide]], [[Rizatriptan]], [[Quinidine sulfate]], [[Quinine]], [[Ramipril]], [[Ranolazine]], [[Repaglinide]], [[Risedronate]], [[Rosuvastatin]], [[Sitagliptin]], [[Sulfonamides]], [[Sumatriptan]], [[Tenofovir]], [[Tetracyclines]], [[Thalidomide]], [[Thiouracil]], [[Ticlopidine]], [[Tizanidine]], [[Tocilizumab]], [[Tolterodine]], [[Tubocurarine]], [[Ustekinumab]], [[Valacyclovir]], [[Valsartan]], [[Vancomycin]], [[Vardenafil]], [[Varenicline]], [[Zaleplon]], [[Zolmitriptan]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Fixed drug eruption<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hyperpigmented plaques that recur at same skin or mucosal site<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[ACE inhibitors]], [[adalimumab]], [[allopurinol]], [[amlodipine]], [[aspirin]], [[barbiturates]], [[benzodiazepines]], [[carbamazepine]], [[cephalosporins]], [[clindamycin]], [[co-trimoxazole]], [[dextromethorphan]], [[diltiazem]], [[fluconazole]], [[lamotrigine]], [[lansoprazole]], [[metronidazole]], [[NSAIDs]], [[paclitaxel]], [[paracetamol]], [[penicillin]], [[phenolphthalein]], [[omeprazole]], [[quinine]], [[salicylates]], [[sulfonamides]], [[terbinafine]], [[tetracyclines]], [[trimethoprim]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pustules<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Acute generalized eczematous pustulosis or acneiform rash<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[antibiotics]], [[calcium-channel blockers]], [[corticosteroids]], [[sirolimus]],[[Fluticasone]],[[Erlotinib]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Bullous<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Flaccid or tense blisters <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Argatroban]], [[Bendamustine]], [[Captopril]], [[Carbidopa and Levodopa]], [[Dasatinib]], [[Erlotinib]], [[Penicillamine]], [[Furosemide]], [[Risedronate]], [[Vancomycin]],[[Abciximab]],[[Warfarin]], [[Topiramate]],[[Linezolid]],[[Mirtazapine]],[[Dapsone]], [[Allopurinol]],[[Captopril ]],[[Captopril and Hydrochlorothiazide]],[[Clopidogrel]],[[Erlotinib]],[[Fosinopril]], [[Ibuprofen]], [[Imatinib]],[[Indapamide]],[[Risedronate]],[[Zolpidem]],[[Dasatinib]],[[Minoxidil]],[[Labetalol]],[[Phenytoin]],[[Dalteparin]],[[Bendamustine]],[[Tinzaparin]],[[Tamoxifen]],[[ clarithromycin]],[[Atorvastatin calcium]],[[Caduet]],[[Ticarcillin/Clavulanate]],[[Terbinafine]],[[Quinine]],[[Nevirapine]],[[Topiramate]],[[Perindopril]],[[Moexipril/Hydrochlorothiazide]], [[Naproxen sodium]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Cutaneous lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Erythematous/scaly plaques in photodistribution<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Hydrochlorothiazide]], [[calcium-channel blockers]], [[ACEIs]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Stevens-Johnson syndrome (SJS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Purpuric macules on face and trunk with &lt;10% epidermal detachment, fever, stomatitis, ocular involvement<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Antibiotics]], [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Beta-lactam|Β-lactam antibiotics]], [[Brinzolamide]], [[Carbamazepine]], [[Carvedilol]], [[Celecoxib]], [[Chlorpropamide]], [[Co-trimoxazole]], [[Darunavir]], [[Diflunisal]], [[Dorzolamide]], [[Duloxetine]], [[efavirenz, emtricitabine, and tenofovir disoproxil fumarate]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Fenofibrate]], [[Glimepiride]], [[Gold]], [[H2 Antagonist]]s, [[Histamine]], [[Hydroxychloroquine]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]],[[Lisinopril and Hydrochlorothiazide]], [[Macrolides]], [[Mefenamic acid]], [[Meloxicam]], [[Metolazone]], [[Mefloquine]], [[Methotrexate]], [[Mexiletine]], [[Minocycline hydrochloride]], [[Minoxidil]], [[Modafinil]], [[Naproxen and esomeprazole magnesium]], [[Piroxicam]], [[Moxifloxacin]], [[Nitrofurantoin]], [[NSAIDS]], [[Ofloxacin]], [[Olmesartan medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Phenothiazines]], [[Phenytoin]], [[Rifampicin]], [[Rivaroxaban]], [[Simvastatin]], [[Sitagliptin]], [[Spironolactone]], [[sulfacetamide sodium and prednisolone acetate]], [[Sulfonamides]], [[Tadalafil]], [[Tetracyclines]], [[Thalidomide]], [[Thiazides]], [[Ticlopidine]], [[Varenicline]], [[Zidovudine]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Toxic epidermal necrolysis (TEN)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Similar to SJS but >30% epidermal detachment<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Acyclovir]], [[Alendronate]], [[Allopurinol]], [[Armodafinil]], [[Atazanavir]], [[Barbiturates]], [[Bendamustine]], [[Brinzolamide]], [[Carbamazepine]], [[Celecoxib]], [[Diflunisal]], [[Dorzolamide]], [[Erlotinib]], [[Escitalopram]], [[Etodolac]], [[Finasteride]], [[Gold]], [[Griseofulvin]], [[Indapamide]], [[Indomethacin]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Lamotrigine]], [[Leflunomide]], [[levetiracetam]], [[Lisinopril and Hydrochlorothiazide]], [[Mefenamic acid]], [[Meloxicam]], [[Methotrexate]], [[Metolazone]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Naproxen and esomeprazole magnesium]], [[Nitrofurantoin]], [[NSAIDs]], [[Ofloxacin]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Oxcarbazepine]], [[Penicillins]], [[Phenytoin]], [[Piroxicam]], [[Salicylates]], [[Sitagliptin]], [[Spironolactone]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[tetracyclines]], [[Thalidomide]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Organ-specific reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Pulmonary<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Pulmonary fibrosis, hypersensitivity pneumonitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Nitrofurantoin]], [[bleomycin]], [[Cabergoline]], [[Cetuximab]], [[Desvenlafaxine]], [[Dronedarone]], [[Erlotinib]], [[Hydrochlorothiazide]], [[Methyclothiazide]], [[Methotrexate]], [[Amiodarone]], [[Moxifloxacin]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hepatic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hepatitis, cholestasis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Acetazolamide]], [[Aminosalicylic acid|Para-aminosalicylic acid]], [[Brinzolamide]], [[Dorzolamide]], [[Ofloxacin]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]], [[phenothiazines]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Renal<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Interstitial nephritis, membranous glomerulonephritis <br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |[[Ofloxacin]], [[Penicillin]], [[sulfonamides]], [[gold]], [[penicillamine]], [[allopurinol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Hematologic<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Hemolytic anemia, thrombocytopenia, granulocytopenia<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top |<br />
▸ Hemolytic anemia — [[5-Azacytidine]], [[Acetophenazine]], [[Aclarubicin]], [[Actinomycin D]], [[Albendazole]], [[Alemtuzumab]], [[Aminopyrine]], [[Amitriptyline]], [[Amodiaquine]], [[Anakinra]], [[Antipyrine]], [[Azathioprine]], [[Bevacizumab]], [[Bortezomib]], [[Captopril]], [[Carbimazole]], [[Caspofungin]], [[Chloramphenicol]], [[Chlorpromazine]], [[Ciclosporin]], [[Cidofovir]], [[Cilazapril]], [[Clofarabine]], [[Clozapine]], [[Deferiprone]], [[Desipramine]], [[Docetaxel]], [[Dothiepin]], [[Doxorubicin]], [[Eflornithine]], [[Ethosuximide]], [[Erlotinib]], [[Ethotoin]], [[Flucytosine]], [[Fludarabine]], [[Fondaparinux]], [[Ganciclovir]], [[Gemcitabine]], [[Glimepiride]], [[Glyburide]], [[Glyburide and Metformin]], [[Gold salts]], [[Hydroxycarbamide]], [[Hypersplenism]], [[Ibritumomab tiuxetan]], [[Idarubicin]], [[Imatinib mesylate]], [[Interferon alpha]], [[Interferon beta]], [[Irinotecan]], [[Isoniazid]], [[Levomepromazine]], [[Lisinopril and Hydrochlorothiazide]], [[Mercaptopurine]], [[Methimazole]], [[Mirtazapine]], [[Mitoxantrone]], [[Nortriptyline]], [[Ofloxacin]], [[Paclitaxel]], [[Penicillamine]], [[Pentamidine]], [[Pentostatin]], [[Perazine]], [[Phenylbutazone]], [[Phenytoin]], [[Pipothiazine]], [[Procainamide]], [[Propylthiouracil]], [[Pyrimethamine]], [[Quinidine]], [[Remoxipride]], [[Riluzole]], [[Stiripentol]], [[Sulfasalazine]], [[Sulphonamides]], [[Ticlopidine]], [[Topotecan]], [[Trastuzumab]], [[Trimetrexate]], [[Valganciclovir]], [[Zidovudine]], [[Zileuton]]<br />
<br />
▸ Thrombocytopenia — [[Abciximab]], [[Aldesleukin]], [[Amobarbital]], [[Amrinone]], [[Armodafinil]], [[Capreomycin]], [[Carboplatin]], [[Cefotaxime]], [[Cefotetan]], [[Cefoxitin]], [[Ceftizoxime]], [[Chloramphenicol]], [[Chlorpropamide]], [[Ciclosporin]], [[Cinoxacin]], [[Claforan]], [[Diabinese]], [[Digoxin]], [[Disopyramide]], [[Enoxaparin]], [[Eptifibatide]], [[Erlotinib]], [[Estrogens]], [[Ethanol]], [[Exna]], [[Fondaparinux]], [[Glyburide]], [[Heparin]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Paraplatin]], [[Phenylbutazone]], [[Procainamide]], [[Proleukin]], [[Rifabutin]], [[Secobarbital]], [[Sulfonamides]], [[Thiazides]], [[Tuinal]]<br />
<br />
▸ Granulocytopenia — [[Acetazolamide]], [[Aripiprazole]], [[Benzthiazide]], [[Bortezomib]], [[Brinzolamide]], [[Bumetanide]], [[Capecitabine]], [[Captopril]], [[Carbamazepine]], [[Ceftazidime]], [[Celecoxib]], [[Chlorpropamide]], [[Dapsone]], [[Diabinese]], [[Disopyramide]], [[Dorzolamide]], [[Enalapril maleate]], [[Exna]], [[Fosinopril]], [[Fortaz]], [[Glyburide]], [[Lisinopril and Hydrochlorothiazide]], [[Ofloxacin]], [[Penicillin]], [[quinine]], [[Rifabutin]], [[salicylate]], [[Sulfacetamide sodium And Prednisolone acetate]], [[sulfonamides]]<br />
|}<br />
<br />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 80%;" align=center<br />
! style="background: #4479BA; padding: 5px 5px; width: 20%;" | {{fontcolor|#FFFFFF|Multiorgan reactions}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 30%;" | {{fontcolor|#FFFFFF|Clinical features}}<br />
! style="background: #4479BA; padding: 5px 5px; width: 50%;" | {{fontcolor|#FFFFFF|Implicated medications}}<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Anaphylaxis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, angioedema, bronchospasm, gastrointestinal symptoms, hypotension<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Abatacept]], [[Abciximab]], [[Acebutolol]], [[Acetazolamide]], [[Acetylcysteine]], [[Albuterol]], [[Aliskiren]], [[Alteplase]], [[Amlodipine and Benazepril]], [[Aminocaproic acid]], [[Anastrozole]], [[Antihemophilic factor]], [[Anti-inhibitor coagulant complex]], [[Aripiprazole]], [[Armodafinil]], [[Atomoxetine]], [[Beclometasone dipropionate]], [[Beta-lactam|β-lactam antibiotics]], [[Betaxolol]], [[Bisoprolol]], [[Bivalirudin]], [[Bortezomib]], [[Buprenorphine Hydrochloride, Naloxone Hydrochloride]], [[monoclonal antibodies]], [[adalimumab]], [[Benazepril]], [[Bendamustine]], [[Captopril]], [[Carteolol]], [[Carvedilol]], [[Celecoxib]], [[Ciclosporin]], [[Ciprofloxacin and Dexamethasone]], [[Cisplatin]], [[Clopidogrel]], [[Cyclobenzaprine]], [[Cyclophosphamide]], [[Dabigatran]], [[Dalteparin]], [[Daptomycin]], [[Darbepoetin Alfa]], [[Denosumab]], [[Desirudin]], [[Dexamethasone]], [[Dexlansoprazole]], [[Dexmethylphenidate]], [[Diflunisal]], [[Digoxin]], [[Digoxin immune fab]], [[Dobutamine]], [[Enalapril maleate]], [[Enoxaparin]], [[epoetin alfa]], [[Erythropoietin]], [[Esmolol]], [[Esomeprazole]], [[Eszopiclone]], [[Etanercept]], [[Ethambutol]], [[Etodolac]], [[Everolimus]], [[Exenatide]], [[Ezetimibe]], [[Factor IX complex]], [[Fenoldopam]], [[Fluconazole]], [[Fluoxetine]], [[Fluphenazine]], [[Fluticasone]], [[Fondaparinux]], [[Furosemide]], [[Glimepiride]], [[Glucagon]], [[Heparin]], [[HPV Vaccine]], [[Hyoscyamine]], [[Ibandronic acid]], [[Infliximab]], [[Insulin glargine]], [[Insulin glulisine]], [[Insulin lispro]], [[Interferon beta-1a]], [[Interferon beta-1b]], [[Ipratropium Bromide And Albuterol]], [[Isotretinoin]], [[Ketorolac tromethamine]], [[Labetalol]], [[Levalbuterol]], [[Lepirudin]], [[Levonorgestrel and Ethinyl estradiol]], [[Linagliptin]], [[Linagliptin and Metformin hydrochloride]], [[Lisinopril and Hydrochlorothiazide]], [[Loperamide]], [[Losartan and Hydrochlorothiazide]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Metaxalone]], [[Methylphenidate]], [[Methyltestosterone]], [[Metoclopramide]], [[Minocycline hydrochloride]], [[Modafinil]], [[Moxifloxacin]], [[Mupirocin]], [[Nabumetone]], [[Nadolol]], [[Nebivolol]], [[Nitrofurantoin]], [[Ofloxacin]], [[Olmesartan]], [[Omalizumab]], [[Ondansetron]], [[Oxytocin]], [[Penbutolol]], [[Pindolol]], [[Prochlorperazine]], [[Propranolol]], [[Progesterone]], [[Protamine]], [[Rituximab]], [[Rivaroxaban]], [[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]], [[Solifenacin]], [[Sumatriptan]], [[Tinzaparin]], [[Tocilizumab]], [[Trastuzumab]], [[Triamcinolone]], [[Triamterene]], [[Urokinase]], [[Valganciclovir hydrochloride]], [[Zaleplon]], [[Zanamivir]], [[Zidovudine]], [[Zolpidem]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Systemic lupus erythematosus<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Arthralgia, myalgias, fever, malaise<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Armodafinil]], [[Hydralazine]], [[procainamide]], [[isoniazid]], [[propafenone]], [[Levonorgestrel and Ethinyl estradiol]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous or visceral vasculitis<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[aspirin]], [[Beta-lactam|β-lactam antibiotics]], [[carbamazepine]], [[carbimazole]], [[co-trimoxazole]], [[diltiazem]], [[erythromycin]], [[gold]], [[G-CSF]], [[GM-CSF]], [[Hydralazine]], [[interferons]], [[methotrexate]], [[minocycline]], [[NSAIDs]], [[penicillamine]], [[propylthiouracil]], [[retinoids]], [[sulfasalazine]], [[sulfonamides]], [[thiazides]], [[thrombolytics]], [[Adalimumab]], [[Amiodarone]], [[Cefdinir]], [[Methyldopa]], [[Amoxapine]], [[Moxifloxacin]], [[Fluticasone]], [[Acyclovir]], [[Allopurinol]], [[Amlodipine]], [[Bortezomib]], [[Captopril]], [[Captopril and Hydrochlorothiazide]], [[Chlorothiazide]], [[Chlorthalidone]], [[Clopidogrel]], [[Delavirdine]], [[Enalapril maleate]], [[Filgrastim]], [[Fosinopril]], [[Furosemide]], [[Hydrochlorothiazide]],,[[Imatinib]], [[Isotretinoin]], [[Lisinopril]], [[Lisinopril/Hydrochlorothiazide]], [[Losartan]], [[Lovastatin]], [[Methyclothiazide]], [[Metolazone]], [[Ofloxacin]], [[Pravastatin]], [[Prazosin]], [[Ramipril]], [[Abatacept]], [[Spironolactone]], [[Spironolactone/Hydrochlorothiazide]], [[Ticlopidine]], [[Valsartan]], [[Colchicine]], [[Quinidine]], [[Quinidine gluconate]], [[Dronedarone]], [[Enoxaparin]], [[Thiazide]], [[Fluticasone/salmeterol]], [[Infliximab]], [[Sitagliptin]], [[Enalaprilat]], [[Fluoxetine]], [[Glyburide]], [[Hydrochloride]], [[Hydroflumethiazide]], [[Polythiazide]], [[Valaciclovir]], [[Simvastatin]], [[Losartan and Hydrochlorothiazide]], [[Methylphenidate]], [[Dexlansoprazole]], [[Sumatriptan]], [[Bisoprolol]], [[Rituximab]], [[Aggrenox]], [[Penicillin G]], [[Norfloxacin]], [[Isoniazid]], [[Penicillin G procaine]], [[Famciclovir]], [[Cefuroxime]], [[Rifampin isoniazid]], [[Rifampin]], [[Interferon alfa-2a]], [[Amoxicillin-clavulanate potassium]], [[Interferon alfa-2a]], [[Pegylated interferon alfa-2a]], [[vancomycin]], [[Atovaquone proguanil]], [[Terbinafine]], [[Indinavir]], [[Ciprofloxacin Hydrochloride]], [[Lamivudine zidovudine]], [[Interferon alfa-2b]], [[Gemifloxacin mesylate]], [[Pentamidine Isethionate]], [[Abacavir lamivudine zidovudine]], [[Nitrofurantoin]], [[Zidovudine]], [[Quinine Sulfate]], [[Valproic acid]], [[Divalproex]], [[Niacin/Simvastatin]], [[Ezetimibe/Simvastatin]], [[Felodipine]], [[Fosinopril/Hydrochlorothiazide]], [[Moexipril/Hydrochlorothiazide]], [[Quinapril/Hydrochlorothiazide]], [[Enalapril maleate/Hydrochlorothiazide]], [[Enalapril/Felodipine]], [[Perindopril]] ,[[Fluvastatin]], [[Diltiazem]], [[Metoprolol succinate and hydrochlorothiazide]], [[Nebivolol]], [[Amiodarone]], [[Olmesartan Medoxomil-Hydrochlorothiazide]], [[Amlodipine Besylate]], [[Divalproex]], [[Pioglitazone/Glimepiride]], [[Aspirin/Dipyridamole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Serum sickness<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Urticaria, arthralgia, fever<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Heterologous]] [[antibodies]], [[infliximab]], [[Cefdinir]], [[Bupropion]], [[Levothyroxine]], [[Tetracycline hydrochloride]], [[Antivenom]], [[Glatiramer acetate]], [[Antivenin]],,[[Measles]], [[Ticlopidine]], [[Clopidogrel]], [[Novobiocin]], [[Epinephrine]], [[Omalizumab]], [[Rituximab]], [[Immunosuppressive drug]], [[Digoxin]], [[Levothyroxine]], [[Ciprofloxacin]], [[Cefprozil]], [[Cefaclor]], [[Oxacillin]], [[Amoxicillin]], [[Ofloxacin]], [[Penicillin G benzathine]], [[Ampicillin]], [[Ceftibuten]], [[Cefpodoxime]], [[Terbinafine]], [[Gemifloxacin]], [[Metronidazole]], [[Cefadroxil]], [[Doxycycline]], [[Levofloxacin]], [[Minocycline]], [[Moxifloxacin]], [[Sulfadiazine]], [[Lincomycin]], [[Sulfamethoxazole]]<br />
|-<br />
| style="background: #DCDCDC; padding: 5px 5px; font-weight: bold;" valign=top | Drug reaction with eosinophilia and systemic symptoms (DRESS)<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | ▸ Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy<br />
| style="background: #F5F5F5; padding: 5px 5px;" valign=top | [[Allopurinol]], [[anticonvulsant]]s, [[Armodafinil]], [[atazanavir]], [[Carbamazepine]], [[minocycline]], [[sulfonamide]]s, [[spironolactone]]<br />
|}<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Allergology]]<br />
[[Category:Immunology]]<br />
[[Category:Emergency medicine]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Headache_causes&diff=1058934Headache causes2015-01-23T14:48:15Z<p>Deepika Beereddy: /* Causes by Organ SystemSailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Bla...</p>
<hr />
<div>__NOTOC__<br />
{{Headache}}<br />
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'''Editor-In-Chief:''' [[User:Bobby Schwartz|Robert G. Schwartz, M.D.]] [mailto:RGSHEAL@aol.com], [http://www.piedmontpmr.com Piedmont Physical Medicine and Rehabilitation, P.A.]; '''Associate Editor-In-Chief''': {{CZ}}<br />
==Overview==<br />
The vast majority of headaches are benign and self-limiting. Common causes are [[tension headache|tension]],[[Neck pain]], [[migraine]], eye strain, [[dehydration|dehydration]], low blood sugar, and [[sinusitis]]. Much rarer are headaches due to life-threatening conditions such as [[meningitis]], [[encephalitis]], [[cerebral aneurysm]]s, [[hypertensive emergency|extremely high blood pressure]], and [[brain tumor]]s. When the headache occurs in conjunction with a [[head injury]] the cause is usually quite evident. A large percentage of headaches among females are caused by ever-fluctuating [[estrogen]] during [[menstruation|menstrual]] years. This can occur prior to, during or even midcycle menstruation.<br />
<br />
==Causes==<br />
===Common Causes===<br />
* [[Tension headache]]<br />
* [[Neck pain]]<br />
* [[Migraine]]<br />
* Eye strain<br />
* [[Dehydration]]<br />
* [[Low blood sugar]]<br />
* [[Sinusitis]].<br />
<br />
===Causes by Organ System<ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016</ref><ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X</ref>===<br />
<br />
{|style="width:80%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiac'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | • [[Hypotension]] • [[Hypertension]] • [[Malignant hypertension]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / Poisoning'''<br />
|bgcolor="Beige"| • [[Amnesic shellfish poisoning]] • [[Anadenanthera peregrina]] • [[Antimony]] • [[Arsenic poisoning]] • [[Artemisia afra]] • [[Carbon monoxide]] • [[Copper]] • [[Cyanide]] • [[Heavy metal ingestion]] • [[Hemlock]] • [[Hydrogen sulfide]] • [[Lead poisoning]] • [[Manganese]] • [[Marine toxins]] • [[Monocrotophos]] • [[Nicotine poisoning]] • [[Radiation poisoning]] • [[Soil contamination]] • [[Thallium]] • [[Toxic headache]] • [[Water intoxication]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| • [[Linear immunoglobulin A dermatosis]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Side Effect'''<br />
|bgcolor="Beige"| • [[Acamprosate]] • [[Acetaminophen]] • [[Acyclovir]] • [[Alatrofloxacin Injection]] • [[Albendazole]] • [[Alosetron]] • [[Amantadine]] • [[Ambrisentan]] • [[Aminophylline]] • [[Amiodarone]] • [[Amlodipine]] • [[Amobarbital sodium]] • [[Amoxicillin]] • [[Amphotericin B]] • [[Anagrelide]] • [[Aprepitant]] * [[Armodafinil]] • [[Atorvastatin]] • [[Atropine]] • [[Benazepril]] • [[Bepridil]] • [[Bexarotene]] • [[Bisoprolol]] • [[Bosentan]] * [[Botulinum toxin]] • [[Bromocriptine]] • [[Butabarbital]] • [[Butorphanol]] • [[Cabergoline]] • [[Caffeine]] • [[Candesartan]] • [[Capecitabine]] • [[Carbamazepine]] • [[Carbidopa and Levodopa]] • [[Carbimazole]] •[[Carisoprodol]] • [[Carmustine]] • [[Carteolol]] • [[Carvedilol]] • [[Caspofungin]] • [[Cilansetron]] • [[Cilostazol]] • [[Cimetidine]] • [[Clomethiazole]] • [[Combined oral contraceptive pill]] • [[Cortisone]] • [[Cycloserine]] • [[Cyclosporin]] • [[Cefaclor]] • [[Cefamandole Nafate Injection]] • [[Cefotetan]] • [[Cefdinir]] * [[Cetirizine hydrochloride]] • [[Cefoperazone Sodium Injection]] • [[Calcitriol]] • [[Chelation therapy]] • [[Chlorothiazide]] • [[Chlorthalidone]] • [[Clomifene]] • [[Cilostazol]] • [[Cimetidine]] • [[Clopidogrel]] • [[Clozapine]] • [[Conjugated estrogens]] * [[Cycloserine]] • [[Cyclosporine Injection]] • [[Deferasirox]] • [[Desmopressin]] * [[Dexamethasone]] • [[Dextroamphetamine|Dexamfetamine]] • [[Digoxin]] • [[Diltiazem]] • [[Dimercaprol]] • [[Dinoprostone]] • [[Dipivefrine]] • [[Dipyridamole]] • [[Disopyramide]] • [[Docosanol]] • [[Dolasetron]] • [[Dofetilide]] • [[Drospirenone and Ethinyl estradiol]] • [[Doxazosin]] • [[Eculizumab]] • [[Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate]] • [[Efavirenz]] * [[Enalapril]] * [[Estradiol valerate and estradiol valerate/dienogest]] • [[Ethynodiol diacetate and ethinyl estradiol]] • [[Epinephrine]] • [[Eplerenone]] • [[Epoprostenol]] • [[Ergotamine]] • [[Etanercept Injection]] • [[Ethacrynic Acid]] • [[Ethanol]] • [[Ethosuximide]] • [[Etodolac]] • [[Exemestane]] * [[Ezetimibe]] • [[Felodipine]] • [[Fenofibrate]] • [[Fenoldopam]] • [[Fesoterodine]] • [[Flu vaccine]] • [[Fluorouracil]] • [[Fluoxetine]] • [[Fluvastatin]] • [[Epinephrine]] • [[Fosinopril]] • [[Furosemide]] • [[Ganciclovir]] • [[Gemeprost]] • [[Glimepiride]] • [[Glipizide]] • [[Glyburide and Metformin]] * [[Glyceryl trinitrate]] • [[Granisetron]] • [[Griseofulvin]] • [[Gyromitrin]] • [[Hydroxocobalamin]] * [[Ibuprofen]] • [[Imiquimod]] • [[Indomethacin]] • [[Insulin lispro]] • [[Influenza vaccine]] • [[Imatinib mesylate]] • [[Interferon beta- 1b]] * [[Interferon gamma]] * [[Interleukin 2]] * [[Isotretinoin]] • [[Isosorbide dinitrate]] • [[Isosorbide mononitrate]] * [[Ivacaftor]] * [[Ketorolac tromethamine]] *[[Lacosamide]] * [[lamivudine]] * [[Lansoprazole]] • Lerisetron • [[Levofloxacin]] * [[Levonorgestrel]] * [[Levosimendan]] * [[Lisinopril and Hydrochlorothiazide]] • [[Lofepramine]] • [[Lomotil]] • [[Loratadine]] • [[Lorcaserin]] • [[Lisuride]] * [[Mebendazole]] * [[Medroxyprogesterone]] • [[Mefloquine]] [[Memantine]] [[Meropenem]] • [[Metaxalone]] * [[Metformin]] • [[Methimazole]] • [[Metronidazole]] * [[Methotrexate]] * [[Methylphenidate]] • [[Methyprylon]] * [[Mifepristone]] * [[Milnacipran hydrochloride]], [[Mirabegron]], [[Misoprostol]] • [[Modafinil]]• [[Monosodium glutamate]] • [[Moricizine]] * [[Nafarelin]] * [[Naproxen sodium]] * [[Natalizumab]] * [[Niacin/simvastatin]] • [[Nicorandil]] • [[Nifedipine]] • [[Nitrendipine]] • [[Nitroglycerine]] • [[Non-steroidal anti-inflammatory drugs]] • [[Norethindrone acetate and Ethinyl estradiol]] * [[Norgestimate and Ethinyl estradiol]] * [[Norgestrel and Ethinyl estradiol]] * [[Ofloxacin]] • [[Oxtriphylline]] • [[Oxytocin injection]] • [[Omalizumab]] • [[Ondansetron]] • [[Palonosetron]] * [[permethrin]] * [[Pantoprazole]] * [[Paroxetine]] • Pemirolast • [[Pergolide]] • [[Pirfenidone]], [[Pimecrolimus]] • [[Piribedil]] * [[Piroxicam]] * [[Praziquantel]] * [[Progesterone]] *[[Prednisone]] • [[Propylthiouracil]] * [[Potassium iodide]] • [[Quinidine]] • [[Quinine]] • [[Rabeprazole]] * [[Rasagiline]] • Reproterol • [[Ribavirin]] * [[Roflumilast]] • [[Ropinirole]] • [[Ruxolitinib]] * [[Salbutamol]] •[[Saxagliptin]], [[Saxagliptin hydrochloride and Metformin hydrochloride]] • [[Selective serotonin reuptake inhibitor]] • [[Sildenafil]] • [[Sodium nitrite]] • Sulprostone * [[Sumatriptan]] * [[Spironolactone]] *[[Sunitinib]] *[[Tacrolimus]] • [[Tamsulosin]] • [[Tadalafil]] * [[Temozolomide]] • [[Tigecycline]] * [[Tocilizumab]] * [[Trabectedin]] * [[Tretinoin]] • [[Trimeprazine]] • [[Trimethobenzamide]] • Tribavirin • [[Trimethadione]] • [[Tropisetron]] • [[Tolbutamide]] *[[Valacyclovir]] • [[Vardenafil]] * [[Varenicline]] • [[Venlafaxine]] • [[Vitamin A]] * [[Von Willebrand factor]]• [[Voriconazole]] * [[Vytorin]] • [[Zafirlukast]] * [[Zaleplon]] * [[Zidovudine]] • [[Zileuton]] • [[Zomepirac]] • [[Zopiclone]] •<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| • [[Angina tonsillaris]] • [[Nasal polyp]] • [[Otitis externa]] • [[Otitis media]] • [[Pharyngitis]] • [[Rhinolith]] • [[Peritonsillar abscess]] • [[Strep throat]] • [[Sinusitis]] • [[Trochleitis]] • [[Tonsillitis]] • [[Upper respiratory tract infection]] • <br />
|- <br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| • [[Acromegaly]] • [[Addison's disease]] • [[Conn syndrome]] • [[Diabetes mellitus|Diabetes mellitus]] • [[Hypoglycemia]] • [[Hyperaldosteronism]] • [[Hyperparathyroidism]] • [[Hyperpituitarism]] • [[Insulinoma]] • [[Menopause]] • [[Pituitary tumour]] (growth hormone secreting) • [[Polycystic Ovarian Syndrome]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental Conditions'''<br />
|bgcolor="Beige"| • [[Airsickness]] • [[Altitude sickness]] • [[Brain freeze]] • [[Diesel particulate matter]] • [[Heat stroke]] • Ice cream headache • [[Multiple chemical sensitivity]] • [[Second-hand smoke]] •<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| • [[Crohn's disease]] • [[Inflammatory Bowel Disease]] •<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| • No underlying causes • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| • [[Anemia]] • [[Blood transfusion]] • [[Leukemia]] • [[Multiple myeloma]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| [[Acute Disseminated Encephalomyelitis]] • [[Acute viral nasopharyngitis (common cold)]] • [[Adenoiditis]] • [[AIDS]] • [[Alkhurma virus]] • [[Anaplasmosis]] • [[Aseptic meningitis]] • [[Aspergillus clavatus]] • [[Astrovirus]] • [[Blastomycosis]] • [[Bolivian hemorrhagic fever]] • [[Byssinosis]] • [[Brucellosis]] • [[Bruxism]] • [[Boutonneuse fever]] • [[Campylobacteriosis]] • [[California encephalitis virus]] • [[Chagas disease]] • [[Chikungunya]] • [[Cladosporium]] • [[Cotton fever]] • [[Coxsackie B]] • [[Cryptococcosis]] • [[Cysticercosis]] • [[Dengue fever]] • Dental infection • [[Ebola]] • [[Encephalitis]] • [[Fever]] • [[Feverfew]] • [[Freshers' Flu]] • [[Giardia lamblia]] • [[Glioblastoma multiforme]] • [[Gradenigo's syndrome]] • [[Group A streptococcal infection]] • [[Haemophilus influenzae serotype B infection]] • [[Hangover]] • [[Hantavirus]] • [[Hay fever]] • [[Harvest mite]] • [[Henipavirus]] • [[Herpes zoster]] • [[Hepatitis]] • [[Herpesviridae]] • [[HIV]] • [[Japanese encephalitis]][ • [[Hymenolepis infection]] • [[Influenza]] • Intracranial abscess / granuloma • [[Lábrea fever]] • [[Legionellosis]] • [[Leptospirosis]] • [[Listeriosis]] • [[Lyme disease]] • [[Malaria]] • [[Marburg virus]] • [[Mansonelliasis]] • [[Meningococcemia]] • [[Meningoencephalitis]] • [[Metabolic acidosis]] • [[Metal fume fever]] • [[Mononucleosis]] • [[Micropolyspora faeni]] • [[Monkeypox virus]] • [[Mucormycosis]] • [[Mumps]] • [[Mycoplasma pneumoniae]] • [[Naegleria fowleri]] • [[Naegleria infection]] • [[Neisseria meningitidis]] • [[Nipah virus encephalitis]] • [[Nocardiosis]] • [[Norovirus]] • [[Oropouche fever]] • [[Pityriasis rosea]] • [[Psittacosis]] • [[Q fever]] • [[Ramsay Hunt syndromes]] • [[Rat-bite fever]] • [[Relapsing fever]] • [[Rhinovirus]] • [[Rickettsial infections]] • [[Rift valley fever]] • [[Ross River Fever]] • [[Rocky Mountain spotted fever]] • [[Rubella]] • [[Saccharopolyspora rectivirgula]] • [[Snakebite]] • [[Scarlet fever]] • [[Scrumpox]] • [[Shingles]] • [[Siraitia grosvenorii]] • [[Sitophilus granarius]] • [[Sodoku]] • [[St. Louis encephalitis]] • [[Staphylococcal enteritis]] • [[Streptobacillus]] • [[Syphilis]] • [[Thermoactinomyces sacchari]] • [[Thermoactinomyces vulgaris]] • [[Trench fever]] • [[Trichinosis]] • [[Tuberculous meningitis]] • [[Tularemia]] • [[Typhoid fever]] • [[Viral Gastroenteritis]] • [[Viral Hepatitis C]] • [[West Nile Virus]] • [[Yellow fever]] • [[Yersinia Pestis Infection]] • [[Zika fever]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| • [[Cervical spondylosis]] • [[Temporomandibular joint disorder]] •<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| • [[Acoustic neuroma]] • [[Apoplexy]] • [[Arachnoid cyst]] • [[Arcuate foramen]] • [[Acute disseminated encephalomyelitis]] • [[Arnold nerve cough syndrome]] • [[Epilepsy]] • [[Idiopathic intracranial hypertension]] • [[Multiple sclerosis]] • [[Pituitary apoplexy]] • [[Posterior cervical sympathetic syndrome]] • [[Posterior leucoencephalopathy syndrome]] • [[Raised intracranial pressure]] • [[Spinal autonomic dysreflexia]] • [[West syndrome]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| • [[Thiamine (Vitamin B1) deficiency]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetrics & Gynecology'''<br />
|bgcolor="Beige"| • [[Eclampsia]] • [[Pre-eclampsia]] • [[Pregnancy]] • [[Premenstrual syndrome]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| • [[Acoustic neuroma]] • [[Adrenal carcinoma]] • [[Adrenal tumor]] • [[Astrocytoma]] • [[Atypical Teratoid Rhabdoid Tumor]] • [[Brain tumor]] • [[Brain Stem Gliomas]] • [[Carcinoid tumours and carcinoid syndrome]] • [[Craniopharyngioma]] • [[Ependymoma]] • [[Gliomatosis cerebri]] • [[Medulloblastoma]] • [[Meningioma]] • [[Oligoastrocytoma]] • [[Phaeochromocytoma]] • [[Polycythaemia rubra vera]] • [[Subdural hygroma]] • [[Tongue cancer]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| • [[Acute posterior multifocal placoid pigment epitheliopathy]] • [[Aneisokonia]] • [[Asthenopia]] • [[Computer vision syndrome]] • [[Ocular Neurosis]] • [[Oculogyric crisis]] • [[Progressive lenses]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| • [[Acute alcohol intoxication]] • [[Alcohol withdrawal]] • [[Alcoholism]] • [[Rebound headache|Medication overuse]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| • [[Anxiety disorder]] • Functional disorders • Primary affective disorder • [[Chronic stress]] • [[Clinical depression]] • [[Workplace stress]] • [[Gulf War syndrome]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| • [[Acute bronchitis]] • [[Bird breeder's lung]] • [[Bird fancier's lung]] • [[Cheese worker's lung]] • [[Chemical worker's lung]] • [[Cough]] • [[Community-acquired pneumonia]] • [[Grain handler's lung]] • [[Hot tub lung]] • [[Humidifier lung]] • [[Hypersensitivity pneumonitis]] • [[Lower respiratory tract infection]] • [[Malt worker's lung]] • [[Nylon worker's lung]] • [[Obesity hypoventilation syndrome]] • [[Paprika splitter's lung]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| • [[Diabetic nephropathy]] • [[Hypercalcemia]] • [[Hyponatremia]] •<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Auto Immune / Allergy'''<br />
|bgcolor="Beige"| • [[Antiphospholipid syndrome]] • [[Polymyalgia rheumatica]] • [[Systemic lupus erythematosus]] • [[Takayasu arteritis]] • [[Temporal arteritis]] • [[Wegener's granulomatosis]] • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| • [[Spinal cord injury|Cervical spine trauma]] • Dental trauma •<br />
|-<br />
|bgcolor="LightSteelBlue" | '''Vascular Diseases & Malformations'''<br />
|bgcolor="Beige" | • [[Arteriovenous malformation]] • [[Berry aneurysm]] • [[Carotid artery dissection]] • [[Cavernous angioma]] • [[Cavernous Sinus Thrombosis]] • [[Cerebral venous sinus thrombosis]] • Cerebellar infarction • [[Cerebral aneurysm]] • [[Cerebral arteriovenous malformation]] • [[Cerebrovascular accident]] • [[Cerebrovascular disease]] • [[Epidural hematoma]] • Intracranial haemorrhage • [[Migraine]] • Posterior communicating artery aneurysm • [[Subarachnoid haemorrhage]] • [[Superior vena cava syndrome]] • [[Vascular headache]] • Vertebral artery dissection • Vertebro-basilar artery syndrome • <br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| • [[Agastache rugosa]] • [[Bearberry]] • [[Cluster headache]] • [[Colloid cyst of third ventricle]] • [[Hepatic failure]] • [[Intracranial space-occupying lesion]] • [[Paroxysmal hemicrania, chronic]] • [[Parry-Romberg syndrome]] • [[Reversible posterior leukoencephalopathy syndrome]] • [[Spontaneous intracranial hypotension]] • [[Standing (position)]] • [[Thunderclap headache]] • <br />
|-<br />
|}<br />
<br />
===Causes by alphabetical order===<br />
*[[Amoxicillin]]<br />
*[[Aprepitant]]<br />
*[[Cimetidine]]<br />
*[[Cycloserine]]<br />
*[[Desmopressin]]<br />
*[[Eculizumab]]<br />
*[[Efavirenz]]<br />
*[[Exemestane]]<br />
*[[Hydroxocobalamin]]<br />
*[[Interferon gamma]]<br />
*[[Ivacaftor]]<br />
*[[Levonorgestrel]]<br />
*[[Loratadine]]<br />
*[[Mebendazole]]<br />
*[[Mifepristone]]<br />
*[[Milnacipran hydrochloride]]<br />
*[[Natalizumab]]<br />
*[[Papaverine]]<br />
*[[Pirfenidone]]<br />
<br />
*[[Ribavirin]]<br />
*[[Sunitinib]]<br />
*[[Temozolomide]]<br />
*[[Tigecycline]]<br />
*[[Von Willebrand factor]]<br />
*[[Voriconazole]]<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Headaches]]<br />
[[Category:Neurological disorders]]<br />
[[Category:Signs and symptoms]]<br />
[[Category:Neurology]]<br />
[[Category:Emergency medicine]]<br />
[[Category:Primary care]]<br />
[[Category:Needs content]]<br />
[[Category:Needs causes]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Acute_viral_nasopharyngitis_causes&diff=1058931Acute viral nasopharyngitis causes2015-01-23T14:46:38Z<p>Deepika Beereddy: /* Causes by Organ System */</p>
<hr />
<div>__NOTOC__<br />
{{Acute viral nasopharyngitis(common cold)}}<br />
{{CMG}}<br />
<br />
Please help WikiDoc by adding more content here. It's easy! Click [[Help:How_to_Edit_a_Page|here]] to learn about editing.<br />
<br />
==Causes==<br />
===Causes by Organ System===<br />
{|style="width:80%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" |'''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes<br />
|-<br />
|bgcolor="LightSteelBlue"| '''Chemical/Poisoning'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Side Effect'''<br />
|bgcolor="Beige"| [[Cyanocobalamin]], [[Eculizumab]], [[Ivacaftor]], [[Loratadine]], [[Mifepristone]], [[Mirabegron]], [[Rifaximin]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal/Orthopedic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional/Metabolic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ophthalmologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose/Toxicity'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal/Electrolyte'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheumatology/Immunology/Allergy'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|}<br />
<br />
==Causes==<br />
Acute viral nasopharyngitis is commonly caused by viruses, like<br />
*[[Picornaviruses]]<br />
*[[Coronaviruses]]<br />
<br />
====Drug Side Effect====<br />
<br />
* [[Amlodipine besylate and Valsartan]]<br />
* [[Botulinum toxin]]<br />
* [[Cyanocobalamin]]<br />
* [[Eculizumab]]<br />
*[[Ivacaftor]]<br />
* [[Levocetirizine]]<br />
* [[Loratadine]]<br />
* [[Methotrexate]]<br />
* [[Mifepristone]]<br />
* [[Saxagliptin hydrochloride and Metformin hydrochloride]]<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}<br />
[[Category:Needs overview]]<br />
[[Category:Disease]]<br />
[[Category:Needs content]]<br />
[[Category:Viruses]]<br />
[[Category:Viral diseases]]<br />
[[Category:Inflammations|Nasopharyngitis]]<br />
[[Category:Infectious disease]]<br />
[[Category:Pulmonology]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Chronic_hypertension_causes&diff=1058929Chronic hypertension causes2015-01-23T14:46:07Z<p>Deepika Beereddy: /* Causes by Organ System */</p>
<hr />
<div> __NOTOC__<br />
{{Template:Hypertension}}<br />
<br />
{{CMG}}; '''Assistant Editor-In-Chief: '''[[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]]<br />
<br />
==Overview==<br />
Secondary hypertension is only responsible for 5% of cases of chronic hypertension whereas [[primary hypertension]] (also known as [[essential hypertension]] where no identifiable cause is identified) is responsible for 95% of cases.<ref name="pmid12537168">{{cite journal| author=Onusko E| title=Diagnosing secondary hypertension. | journal=Am Fam Physician | year= 2003 | volume= 67 | issue= 1 | pages= 67-74 | pmid=12537168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12537168 }} </ref> Common causes of secondary hypertension include [[obstructive sleep apnea]], [[hyperaldosteronism]], [[kidney disease]]s, excess [[catecholamine]]s, [[coarctation]] of the arota, [[cushing syndrome]] among other diseases.<br />
<br />
<br />
{{Familytree/start}}<br />
{{Familytree | | | A01 | | A01= '''[[Chronic hypertension]]'''}}<br />
{{Familytree | |,|-|^|-|.| }}<br />
{{Familytree | B01 | | B02 | B01='''[[Primary hypertension]]''' <br>(also known as [[essential hypertension]]) <br> (95% of the cases)| B02= '''[[Secondary hypertension]]'''<br> <br> (5% of the cases)}}<br />
{{Familytree/end}}<br />
<br />
<br />
==Primary Hypertension==<br />
When a full evaluation yields no clear etiology for the elevated blood pressure, the latter is identified as primary hypertension. Primary or essential hypertension is considered a chronic disease requiring lifelong treatment and follow-up. If an underlying disease is identifiable as the cause, secondary hypertension is diagnosed. Secondary hypertension is a potentially curable condition in most cases.<ref name="pmid17462751">{{cite journal| author=Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA et al.| title=Secondary hypertension: current diagnosis and treatment. | journal=Int J Cardiol | year= 2008 | volume= 124 | issue= 1 | pages= 6-21 | pmid=17462751 | doi=10.1016/j.ijcard.2007.01.119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17462751 }} </ref> In comparison, the prevalence of primary hypertension is significantly higher than secondary hypertension, where only 5-10% of patients have a secondary etiology<ref name="pmid12537168">{{cite journal| author=Onusko E| title=Diagnosing secondary hypertension. | journal=Am Fam Physician | year= 2003 | volume= 67 | issue= 1 | pages= 67-74 | pmid=12537168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12537168 }} </ref> Classically, the common age range for the presentation of primary hypertension is 30 to 55 years<ref name="pmid11509166">{{cite journal| author=Dosh SA| title=The diagnosis of essential and secondary hypertension in adults. | journal=J Fam Pract | year= 2001 | volume= 50 | issue= 8 | pages= 707-12 | pmid=11509166 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11509166 }} </ref>, but age alone should never warrant a diagnosis of primary hypertension without a proper work-up.<br />
<br />
==Secondary Hypertension==<br />
===When to Suspect Secondary Hypertension===<br />
It is not cost effective to evaluate all hypertensive patients for secondary hypertension. <ref name="pmid17462751">{{cite journal| author=Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA et al.| title=Secondary hypertension: current diagnosis and treatment. | journal=Int J Cardiol | year= 2008 | volume= 124 | issue= 1 | pages= 6-21 | pmid=17462751 | doi=10.1016/j.ijcard.2007.01.119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17462751 }} </ref> There are certain clinical scenarios, though, that should prompt further evaluation.<br />
<br />
====Early Onset Hypertension Under Age 30====<br />
Primary hypertension generally first occurs between 30 and 55 years. Onset of hypertension before puberty and before age 30 in the absence of risk factors should raise suspicion for secondary hypertension. <br />
<br />
====Abrupt Onset of Hypertension in A Normotensive Patient====<br />
<br />
====Rapidly Progressive Hypertension or a Hypertensive Emergency or Urgency====<br />
<br />
====Refractory Hypertension====<br />
<br />
<div class="mw-collapsible mw-collapsed"><br />
<br />
===Evaluation of Secondary Hypertension===<br />
<br />
<div class="mw-collapsible-content"><br />
<br />
{{Familytree/start}}<br />
{{Familytree|boxstyle=text-align: center; font-size: 90%; padding: 0px; width: 50%;| | | | | | A01 | | | | | | | | | |A01=<div style="padding: 15px;">'''''Evaluation of secondary hypertension'''''</div>}}<br />
{{Familytree|boxstyle=text-align: left; font-size: 90%; padding: 0px; width: 50%; border-top: 0px;| | | | | | A01 | | | | | | | | | |A01=<div style="padding: 15px;"><br />
'''Investigation should be limited for patients with clues suggestive of potentially correctable causes.'''<br />
<br />
❑ Presence of clues for renovascular hypertension (most common potentially correctable cause)?<ref name="pmid16549646">{{cite journal| author=Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL et al.| title=ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. | journal=Circulation | year= 2006 | volume= 113 | issue= 11 | pages= e463-654 | pmid=16549646 | doi=10.1161/CIRCULATIONAHA.106.174526 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16549646 }} </ref><ref name="pmid21963765">{{cite journal| author=Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK et al.| title=2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2011 | volume= 58 | issue= 19 | pages= 2020-45 | pmid=21963765 | doi=10.1016/j.jacc.2011.08.023 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21963765 }} </ref><br />
<br />
: ❑ Onset of hypertension before the age of 30 years<br />
: ❑ Onset of severe hypertension (SBP ≥180 mm Hg and/or DBP ≥120 mm Hg) after the age of 55 years<br />
: ❑ New azotemia or worsening renal function after administration of an ACE inhibitor or ARB agent<br />
: ❑ Unexplained atrophic kidney or size discrepancy between kidneys of greater than 1.5 cm<br />
: ❑ Sudden, unexplained pulmonary edema<br />
: ❑ Accelerated hypertension (sudden and persistent worsening of previously controlled hypertension)<br />
: ❑ Resistant hypertension (failure to achieve goal blood pressure in patients who are adhering to full doses of an appropriate 3-drug regimen that includes a diuretic)<br />
: ❑ Malignant hypertension (hypertension with coexistent evidence of acute end-organ damage, i.e., acute renal failure, acutely decompensated congestive heart failure, new visual or neurological disturbance, and/or advanced [grade III to IV] retinopathy)<br />
: ❑ Unexplained renal failure in the absence of proteinuria or an abnormal urine sediment<br />
: ❑ Multivessel coronary artery disease<br />
: ❑ Unexplained congestive heart failure<br />
: ❑ Refractory angina<br />
</div>}}<br />
{{Familytree|boxstyle=text-align: left; font-size: 90%; padding: 0px;| | |,|-|-|-|^|-|-|-|.| | | | | |}}<br />
{{Familytree|boxstyle=text-align: center; font-size: 90%; padding: 0px;| | A01 | | | | | | A02 |A01=<div style="padding: 10px; font-weight: bold;">YES</div>|A02=<div style="padding: 10px; font-weight: bold;">NO</div>}}<br />
{{Familytree|boxstyle=text-align: left; font-size: 90%; padding: 0px; border-top: 0px; vertical-align: top; width: 25%;| | A01 | | | | | | A02 |A01=<div style="padding: 10px;"><br />
❑ Perform noninvasive diagnostic studies<br />
: ❑ Duplex ultrasonography<br />
: ❑ Gadolinium-enhanced magnetic resonance angiography<br />
: ❑ Computed tomographic angiography (in individuals with normal renal function)<br />
❑ Consider catheter angiography when noninvasive studies are inconclusive</div><br />
|A02=<div style="padding: 10px; font-size: 85%;"><br />
Look for findings suggestive of other identifiable causes<br />
<br />
❑ Pheochromocytoma<br />
: ❑ Paroxysmal pounding headache<br />
: ❑ Palpitations<br />
: ❑ Profound perspiration<br />
: ❑ Pallor<br />
: ❑ Hand tremor<br />
<br />
❑ Hyperaldosteronism<br />
: ❑ Unexplained hypokalemia with urinary potassium wasting<br />
<br />
❑ Obstructive sleep apnea<br />
: ❑ Daytime somnolence<br />
: ❑ Snoring<br />
: ❑ Obesity<br />
<br />
❑ Hyperparathyroidism<br />
: ❑ Hypercalcemia<br />
<br />
❑ Hypothyroidism<br />
: ❑ Elevated TSH<br />
: ❑ Puffy face<br />
<br />
❑ Aortic coarctation<br />
: ❑ Diminished or delayed femoral pulses and low or unobtainable blood pressures in the legs</div>}}<br />
{{Family tree/end}}<br />
<br />
</div></div><br />
<br />
===Common Causes of Secondary Hypertension===<br />
Common causes of secondary hypertension are often memorized by the mnemonic ABCDE:<br />
<br />
{| border="1" style="border-collapse:collapse; text-align:left; font-size:130%;" cellpadding="5" align="center" width="600px"<br />
|-<br />
|bgcolor="#67e1ff"|'''Letter'''<br />
|bgcolor="#67e1ff"|'''Causes of Secondary Hypertension'''<br />
|-<br />
|bgcolor="#f3f3f3"| A<br />
|Accuracy, Apnea, Aldosteronism<br />
|- <br />
|bgcolor="#f3f3f3"| B<br />
|Bruit, Bad Kidneys<br />
|- <br />
|bgcolor="#f3f3f3"| C<br />
|Catecholamines, Coarctation, Cushing’s Syndrome<br />
|- <br />
|bgcolor="#f3f3f3"| D<br />
|Drugs, Diet<br />
|-<br />
|bgcolor="#f3f3f3"| E<br />
|Erythropoitin, Endocrine Disorders<br />
|}<br />
<br />
=====Accuracy=====<br />
An accurate assessment and re-assessment of blood pressures is an essential first step when a patient presents with high blood pressure. The accuracy of home BP measurements should be confirmed by calibrating the patient's measurement technique with that obtained in the doctor's office.<br />
<br />
=====Apnea=====<br />
[[Obstructive sleep apnea]] (OSA) is a respiratory disease characterized by repetitive narrowing or collapse of the upper airway during sleep<ref name="pmid18250206">{{cite journal| author=Eckert DJ, Malhotra A| title=Pathophysiology of adult obstructive sleep apnea. | journal=Proc Am Thorac Soc | year= 2008 | volume= 5 | issue= 2 | pages= 144-53 | pmid=18250206 | doi=10.1513/pats.200707-114MG | pmc=PMC2628457 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18250206 }} </ref> leading to [[apnea]], [[hypopnea]], and a nocturnal decrease in oxygen tension.<ref name="pmid8872797">{{cite journal| author=Silverberg DS, Oksenberg A| title=Essential and secondary hypertension and sleep-disordered breathing: a unifying hypothesis. | journal=J Hum Hypertens | year= 1996 | volume= 10 | issue= 6 | pages= 353-63 | pmid=8872797 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8872797 }} </ref> Symptoms and signs that might suggest OSA include daytime [[somnolence]], [[obesity]], [[snoring]], and [[morning headache]].<ref name="pmid10593319">{{cite journal| author=Victor LD| title=Obstructive sleep apnea. | journal=Am Fam Physician | year= 1999 | volume= 60 | issue= 8 | pages= 2279-86 | pmid=10593319 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10593319 }} </ref> Patients with sleep apnea also tend to have drug resistant hypertension and may retain sodium. Diagnosis is made by polysomnography. Treatment relies on maintaining airway patency at night and includes, among others, the use of continuous positive airway pressure (CPAP).<br />
<br />
=====Aldosterone=====<br />
Primary (hyporeninemic) and secondary (hyperreninemic) [[hyperaldosteronism]] result in excess sodium and water retention with slight [[hypernatremia]] along with excretion of [[potassium]] resulting in [[hypokalemia]] in one half of patients.<ref name="pmid9854120">{{cite journal| author=Ganguly A| title=Primary aldosteronism. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 25 | pages= 1828-34 | pmid=9854120 | doi=10.1056/NEJM199812173392507 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9854120 }} </ref> Common symptoms of hyperaldosteronism include drug resistant hypertension, [[fatigue]], [[headache]], intermittent [[paralysis]], [[muscle weakness]], and [[numbness]]. The most common cause of [[primary hyperaldosteronism]] is an aldosterone-producing [[adenoma]] (an "[[aldosteronoma]]"), i.e. [[Conn’s Syndrome]]. [[Secondary hyperaldosteronism]] is due to an overactive [[RAAS]], as seen in renin-secreting tumors, [[renal artery stenosis]], [[pheochromocytoma]], and other syndromes. The diagnosis is made by measuring the ratio of plasma aldosterone to plasma renin activity.<ref name="pmid7923898">{{cite journal| author=Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC| title=High incidence of primary aldosteronism in 199 patients referred with hypertension. | journal=Clin Exp Pharmacol Physiol | year= 1994 | volume= 21 | issue= 4 | pages= 315-8 | pmid=7923898 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7923898 }} </ref> It is elevated in [[primary hyperaldosteronism]] and decreased/normal with elevated [[renin]] in [[secondary hyperaldosteronism]]. It should be noted that obesity can also cause [[aldosterone]] levels to be elevated. Treatment depends upon the underlying etiology: surgery to resect an adenoma causing [[primary hyperaldosteronism]] and [[spironolactone]], an aldosterone antagonist to treat [[secondary hyperaldosteronism]].<br />
<br />
===== Bruit=====<br />
[[Renovascular hypertension]] is due to decreased blood supply to the [[kidneys]] secondary to renal artery stenosis and it is the most common correctable cause of secondary hypertension. [[Atherosclerosis]] of the renal artery ([[renal artery stenosis]]) in older patients above 50 years of age<ref name="pmid12196346">{{cite journal| author=Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC et al.| title=Distinct renal injury in early atherosclerosis and renovascular disease. | journal=Circulation | year= 2002 | volume= 106 | issue= 9 | pages= 1165-71 | pmid=12196346 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12196346 }} </ref> and [[fibromuscular dysplasia]] in younger patients are the most common etiologies. <br />
<br />
According to the 2013 ACC/AHA Guidelines for the Management of PAD<ref name="pmid23457117">{{cite journal| author=Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH et al.| title=Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=Circulation | year= 2013 | volume= 127 | issue= 13 | pages= 1425-43 | pmid=23457117 | doi=10.1161/CIR.0b013e31828b82aa | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23457117 }} </ref>, diagnostic work-up for renal artery stenosis is indicated in the following conditions:<br />
<br />
====Class I Recommendations<ref name="pmid23457117">{{cite journal| author=Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH et al.| title=Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=Circulation | year= 2013 | volume= 127 | issue= 13 | pages= 1425-43 | pmid=23457117 | doi=10.1161/CIR.0b013e31828b82aa | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23457117 }} </ref>====<br />
*Hypertension of any stage before the age of 30<br />
*Stage II hypertension (severe hypertension systolic blood pressure > 180 mm Hg or diastolic blood pressure > 120 mm Hg) in patients older than 55 years. If only mild hypertension is present, then renal artery stenosis is the underlying cause in only 1% of patients <ref name="pmid3872106">{{cite journal| author=Lewin A, Blaufox MD, Castle H, Entwisle G, Langford H| title=Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program. | journal=Arch Intern Med | year= 1985 | volume= 145 | issue= 3 | pages= 424-7 | pmid=3872106 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3872106 }} </ref>, but if the blood pressure is markedly elevated, then the risk of renal artery stenosis goes up 10 to 50 fold.<br />
*Accelerated condition of previously controlled hypertension<br />
*[[Resistant hypertension]]<br />
*[[Malignant hypertension]]<br />
*New [[azotemia]] (50% rise in [[creatinine]] that is sustained) within one week after administration of an [[Angiotensin Converting Enzyme]] ([[ACE]])inhibitor or [[ARB]]<br />
*Unexplained atrophic kidney or asymmetric kidneys that differ by > 1.5 cm. If the kidney is < 9 cm in size, there is a 75% chance that renal artery stenosis is present.<br />
*Severe hypertension, impaired renal function, and recurrent flash [[pulmonary edema]]<br />
<br />
====Class IIa Recommendations<ref name="pmid23457117">{{cite journal| author=Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH et al.| title=Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=Circulation | year= 2013 | volume= 127 | issue= 13 | pages= 1425-43 | pmid=23457117 | doi=10.1161/CIR.0b013e31828b82aa | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23457117 }} </ref>====<br />
*Unexplained renal failure including patients starting renal replacement therapy<br />
<br />
====Class IIb Recommendations<ref name="pmid23457117">{{cite journal| author=Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH et al.| title=Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=Circulation | year= 2013 | volume= 127 | issue= 13 | pages= 1425-43 | pmid=23457117 | doi=10.1161/CIR.0b013e31828b82aa | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23457117 }} </ref>====<br />
*Presence of multi vessel [[CAD]] and no clinical clues of ARAS or PAD<br />
*Unexplained [[CHF]] or [[refractory angina]]<br />
<br />
====Other Indications====<br />
* Severe hypertension in the presence of polyvascular disease ([[coronary artery disease]] or [[peripheral arterial disease]])<br />
* A unilateral systolic-diastolic [[abdominal bruit]]. Although a bruit is infrequent in documented renal artery stenosis (the sensitivity is only 40% percent) if it is auscultated, it is associated with a very high specificity of 99%.<ref name="pmid7563536">{{cite journal| author=Turnbull JM| title=The rational clinical examination. Is listening for abdominal bruits useful in the evaluation of hypertension? | journal=JAMA | year= 1995 | volume= 274 | issue= 16 | pages= 1299-301 | pmid=7563536 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7563536 }} </ref><br />
*The association of race with renal artery stenosis is not clear. Reports that it is observed more often in white patients may be due to reporting bias.<ref name="pmid2022411">{{cite journal| author=Svetkey LP, Kadir S, Dunnick NR, Smith SR, Dunham CB, Lambert M et al.| title=Similar prevalence of renovascular hypertension in selected blacks and whites. | journal=Hypertension | year= 1991 | volume= 17 | issue= 5 | pages= 678-83 | pmid=2022411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2022411 }} </ref><br />
<br />
Definitive diagnosis is made by magnetic resonance angiography (MRA) and renal arteriography.<ref name="pmid11416635">{{cite journal| author=Wofford MR, King DS, Wyatt SB, Jones DW| title=Secondary Hypertension: Detection and Management for the Primary Care Provider. | journal=J Clin Hypertens (Greenwich) | year= 2000 | volume= 2 | issue= 2 | pages= 124-131 | pmid=11416635 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11416635 }} </ref> Other diagnostic methods include duplex ultrasound scanning<ref name="pmid22595689">{{cite journal| author=AbuRahma AF, Srivastava M, Mousa AY, Dearing DD, Hass SM, Campbell JR et al.| title=Critical analysis of renal duplex ultrasound parameters in detecting significant renal artery stenosis. | journal=J Vasc Surg | year= 2012 | volume= 56 | issue= 4 | pages= 1052-9, 1060.e1; discussion 1059-60 | pmid=22595689 | doi=10.1016/j.jvs.2012.03.036 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22595689 }} </ref>, and captopril-augmented radio-isotopic renogram<ref name="pmid10482969">{{cite journal| author=Aitchison F, Page A| title=Diagnostic imaging of renal artery stenosis. | journal=J Hum Hypertens | year= 1999 | volume= 13 | issue= 9 | pages= 595-603 | pmid=10482969 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10482969 }} </ref>. Treatment is based upon the underlying etiology.<br />
<br />
===== Bad Kidney (Chronic Renal Failure)=====<br />
Renal parenchymal disease blunts the kidney’s physiological ability to maintain appropriate [[blood pressure]]. Notably, [[hypertension]] is both a cause and a consequence of renal parenchymal disease; the two are closely associated and may potentiate each other.<ref name="pmid11866231">{{cite journal| author=Soergel M, Schaefer F| title=Effect of hypertension on the progression of chronic renal failure in children. | journal=Am J Hypertens | year= 2002 | volume= 15 | issue= 2 Pt 2 | pages= 53S-56S | pmid=11866231 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11866231 }} </ref> The diagnosis is made by demonstration of a decreased [[GFR]]. The mechanisms by which renal parenchymal disease leads to the development of hypertension are numerous and include activation of the local [[RAAS]], release of vasoconstrictor [[cytokines]], and inappropriate [[natriuresis]] for any given [[blood pressure]].<br />
<br />
=====Catecholamines=====<br />
Catecholamine excess occurs in several non-disease states, such as acute [[stress]], the administration of medications with sympathomimetic activity, and illicit drug use such as [[cocaine]] and these conditions can be ruled out by thorough history taking. [[Pheochromocytoma]], a tumor of the adrenal gland leading to excess secretion of [[epinephrine]], should be considered in young patients with the triad of intermittent hypertensive episodes causing [[headache]], [[sweating]], and [[tachycardia]]. However, [[pheochromocytoma]] in older adults or a presentation with sustained hypertension is not uncommon. Diagnostic studies to evaluate pheochromocytoma include measurement of plasma free [[metanephrines]] and urinary fractionated metanephrines. The diagnostic value of plasma and urinary catecholamines is of limited value given the very short half-life of catecholamines. Treatment is usually by surgical resection of the secreting tumor with appropriate adrenergic blockade.<ref name="pmid11903030">{{cite journal| author=Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P et al.| title=Biochemical diagnosis of pheochromocytoma: which test is best? | journal=JAMA | year= 2002 | volume= 287 | issue= 11 | pages= 1427-34 | pmid=11903030 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11903030 }} </ref><br />
<br />
=====Coarctation=====<br />
[[Coarctation of the aorta]] is a [[congenital heart defect]], caused by a narrowing in a segment of the ascending or [[descending aorta]]. The diagnosis is often made in a neonate or an infant as a result of a weak femoral pulse or asymmetric brisk brachial pulses. [[Hypertension]] occurs as a result of a reduction in the effective circulation at the level of the [[kidneys]] which respond by increasing plasma volume which in turn causes hypertension in the upper extremities. Diagnosis is by [[CT angiography]], but can also be made in neonates and infants by ultrasound of the heart and the great vessels. Definitive treatment is by surgical correction and or stenting.<br />
<br />
=====Cushing’s Syndrome=====<br />
[[Cushing's syndrome]] is an endocrine disorder caused by prolonged exposure to high endogenous or exogenous [[cortisol]] levels. Hypertension in [[Cushing’s syndrome]] has been classically attributed to the [[mineralocorticoid]] effects of cortisol. It manifests as an absent fall of nocturnal [[blood pressure]] physiologically seen in normotensive subjects with associated disturbance in the adrenocorticotropic hormone-glucocorticoid system.<ref name="pmid3397172">{{cite journal| author=Imai Y, Abe K, Sasaki S, Minami N, Nihei M, Munakata M et al.| title=Altered circadian blood pressure rhythm in patients with Cushing's syndrome. | journal=Hypertension | year= 1988 | volume= 12 | issue= 1 | pages= 11-9 | pmid=3397172 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3397172 }} </ref> Symptoms of Cushing's syndrome include rapid [[obesity|weight gain]], particularly of the trunk and face with sparing of the limbs ([[central obesity]]), a round face often referred to as a "[[moon face]]" along with central obesity, excess [[sweating]], [[proximal muscle weakness]], [[ecchymoses]], [[insomnia]], reduced [[libido]], [[impotence]], [[amenorrhoea]], [[infertility]] and psychological disturbances, ranging from [[Euphoria (emotion)|euphoria]] to [[psychosis]]. [[clinical depression|Depression]] and [[anxiety]].<ref>{{cite book |title=The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences |last=Yudofsky |first=Stuart C. |coauthors=Robert E. Hales |edition=5th |year=2007 |publisher=American Psychiatric Pub, Inc. |isbn=1585622397 }}</ref> Although an ideal diagnostic test is not considered yet available, clinicians often assess the 24-hour urinary [[cortisol]] excretion<ref name="pmid3958132">{{cite journal| author=Contreras LN, Hane S, Tyrrell JB| title=Urinary cortisol in the assessment of pituitary-adrenal function: utility of 24-hour and spot determinations. | journal=J Clin Endocrinol Metab | year= 1986 | volume= 62 | issue= 5 | pages= 965-9 | pmid=3958132 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3958132 }} </ref>, a low-dose [[dexamethasone suppression test]]<ref name="pmid14315650">{{cite journal| author=NUGENT CA, NICHOLS T, TYLER FH| title=Diagnosis of Cushing’s Syndrome; Single Dose Dexamethasone Suppression Test. | journal=Arch Intern Med | year= 1965 | volume= 116 | issue= | pages= 172-6 | pmid=14315650 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14315650 }} </ref>, late evening serum or salivary cortisol<ref name="pmid9709931">{{cite journal| author=Raff H, Raff JL, Findling JW| title=Late-night salivary cortisol as a screening test for Cushing's syndrome. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 8 | pages= 2681-6 | pmid=9709931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9709931 }} </ref>, and a [[CRH]] a following a [[dexamethasone suppression test]] to establish the diagnosis.<ref name="pmid8386285">{{cite journal| author=Yanovski JA, Cutler GB, Chrousos GP, Nieman LK| title=Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. | journal=JAMA | year= 1993 | volume= 269 | issue= 17 | pages= 2232-8 | pmid=8386285 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8386285 }} </ref><br />
<br />
=====Drugs=====<br />
An extensive list of drugs can be associated with hypertension. The most common agents include immunosuppressive agents, non-steroidal anti-inflammatory drugs, [[oral contraceptive pills]], some weight loss agents, stimulants, monoamine oxidase inhibitors, triptans, ergotamines, and sympathomimetics.<ref name="pmid12537168">{{cite journal| author=Onusko E| title=Diagnosing secondary hypertension. | journal=Am Fam Physician | year= 2003 | volume= 67 | issue= 1 | pages= 67-74 | pmid=12537168 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12537168 }} </ref><br />
<br />
=====Diet=====<br />
In addition to the association of [[obesity]] with hypertension, the 2001 study “Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet” concluded that a high sodium diet above the recommended 100 mmol per day (2.4 g of sodium or 6 g of sodium chloride salt) is associated with hypertension. As a result, reduction of sodium levels below 100 mmol per day and following the DASH diet (rich in vegetables, fruits, with low-fat dairy products) can significantly lower BP.<ref name="pmid11136953">{{cite journal| author=Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D et al.| title=Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 1 | pages= 3-10 | pmid=11136953 | doi=10.1056/NEJM200101043440101 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11136953 }} </ref> Ingestion of excessive amounts of [[liquorice]] can lead to elevation in the [[blood pressure]].<br />
<br />
=====Erythropoietin=====<br />
Elevated erythropoietin is typically seen in [[COPD]] patients who have functional anemia due to chronic [[hypoxia]] and in hematologic disorders such as polycythemia. The pathogenesis of erythropoietin-induced hypertension includes increased hematocrit and blood viscosity, altered sensitivity to vasopressors, dysregulated vasodilatory factors, and vascular cell growth causing arterial remodeling and changes in arterial smooth musculature.<ref name="pmid10213636">{{cite journal| author=Vaziri ND| title=Mechanism of erythropoietin-induced hypertension. | journal=Am J Kidney Dis | year= 1999 | volume= 33 | issue= 5 | pages= 821-8 | pmid=10213636 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10213636 }} </ref> Diagnosis and treatment are etiology-dependent.<br />
<br />
=====Endocrine=====<br />
In addition to the more common endocrine causes of hypertension such as hyperaldosteronism, [[Cushing’s syndrome]], and [[pheochromocytoma]], several other endocrine changes can cause hypertension. Both hypothyroidism and hyperthyroidism can cause hypertension by volume retention and by increased cardiac output, respectively. Also, [[hyperparathyroidism]] and hypovitaminosis D can cause hypertension due to poorly understood mechanisms, where [[parathyroidectomy]] seems to significantly decrease blood pressure in patients with parathyroid disease and elevated BP.<ref name="pmid22145139">{{cite journal| author=Chopra S, Cherian D, Jacob JJ| title=The thyroid hormone, parathyroid hormone and vitamin D associated hypertension. | journal=Indian J Endocrinol Metab | year= 2011 | volume= 15 Suppl 4 | issue= | pages= S354-60 | pmid=22145139 | doi=10.4103/2230-8210.86979 | pmc=PMC3230087 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22145139 }} </ref> [[Acromegaly]] can also be a cause of hypertension.<br />
<br />
==Causes by Organ System==<br />
<br />
{|style="width:80%; height:100px" border="1"<br />
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''<br />
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | [[Aortic regurgitation]], [[aortic dissection]], acute severe vascular damage, [[adams Nance syndrome ]], [[aneurysm]], [[aortic coarctation ]], [[aortic stenosis]], [[arterial occlusive disease, progressive - -- heart defects -- bone fragility -- brachysyndactyly ]], [[arteriosclerosis]], [[atheroma]], [[avasthey syndrome ]], [[carotid paraganglioma ]],Congenital [[mitral stenosis ]], [[eisenmenger's Syndrome ]], [[fibromuscular dysplasia of arteries ]], [[grange syndrome ]], hemangiomatosis (familial pulmonary capillary disease), [[hypertensive heart disease ]], [[pulmonary artery agenesis ]], [[vasculitis ]], [[patent ductus arteriosus]], [[third degree AV block]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Chemical / poisoning'''<br />
|bgcolor="Beige"| [[Acetaldehyde ]], [[aristolochic acid]] poisoning , [[arizona Bark Scorpion poisoning ]], [[black widow spider envenomation ]], [[cadmium poisoning]], [[cocaine]], [[ecstasy]] abuse , [[ginseng ]], [[heavy metal poisoning]], Indian [[tobacco]] poisoning, [[jimsonweed poisoning ]], [[lead poisoning]] , [[lockwood-Feingold syndrome ]], [[mustard tree poisoning ]], [[nicotine]] addiction , [[pseudoephedrine]] poisoning , [[silicosis ]], [[toxic mushrooms -- Psychedelic ]], [[lobelia]] poisoning<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dermatologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Drug Side Effect'''<br />
|bgcolor="Beige"| [[almotriptan]], [[amitriptyline]], [[Asenapine maleate]], [[Atropine]], [[Betamethasone valerate]], [[Betamethasone dipropionate]], [[Butorphanol]], [[Cidofovir]], [[cocaine]], [[combined oral contraceptive pill]], [[cyclosporine]], [[caspofungin acetate]] [[desipramine]], [[Desmopressin]], [[dihydroergotamine]], [[diflunisal]], [[doxepin]], [[Drospirenone and Ethinyl estradiol]], [[Eculizumab]], [[Eletriptan]], [[ephedrine]], [[ergotamine]], [[Erythropoietin]], [[etodolac]], [[febuxostat]], [[formoterol]], [[frovatriptan]], [[glucocorticoid resistance ]], [[Hydroxocobalamin]], [[Indomethacin]],[[imipramine]], [[isometheptene]], [[Ketorolac tromethamine]], [[Leuprolide]], [[Levalbuterol]], [[Medroxyprogesterone]], [[Mefenamic acid]], [[Meloxicam]], [[Meloxicam]], [[Meropenem]], [[Methylphenidate]], [[Methylprednisolone]], [[Metoclopramide]], [[Mifepristone]], [[Milnacipran hydrochloride]], [[Mirabegron]], [[monoamine oxidase inhibitor]]s, [[Nabilone]], [[nasal decongestants]], [[Naproxen and esomeprazole magnesium]], [[Norethindrone acetate and Ethinyl estradiol]], [[Norgestimate and Ethinyl estradiol]], [[Norgestrel and Ethinyl estradiol]], [[nortriptyline]], [[NSAIDs]], [[Oxcarbazepine]], [[Pentamidine Isethionate]], [[phencyclidine]], [[phenylpropanolamine]], [[Pilocarpine]], [[Piroxicam]], [[Pralidozxime]],[[protriptyline]], [[pseudoephedrine]], [[prednisolone]], [[Prednisone]], [[Rasagiline]], [[Repaglinide and Metformin hydrochloride]], [[rizatriptan]], [[sedative dependence]], [[serotonin toxicity]], [[Sertraline]], [[Sorafenib]], [[steroid abuse]], [[Sulindac]], [[sumatriptan]], [[Sunitinib]], [[Thalidomide]], [[Tocilizumab]], [[Travoprost]], [[Triamcinolone]], [[Valganciclovir hydrochloride]], [[zolmitriptan]], [[Zolmitriptan]], [[Zonisamide]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Ear Nose Throat'''<br />
|bgcolor="Beige"| [[Nephrosis -- deafness -- urinary tract -- digital malformation ]], [[Fitzsimmons-Walson-Mellor syndrome ]]<br />
<br />
|- <br />
|-bgcolor="LightSteelBlue"<br />
| '''Endocrine'''<br />
|bgcolor="Beige"| [[Carcinoid Syndrome]], [[acromegaly ]], [[adrenal incidentaloma ]], [[alcohol-induced pseudo-Cushing syndrome ]], [[apparent mineralocorticoid excess ]], [[congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency]], [[congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency]], [[Conn's syndrome]], [[cushing's disease]], [[cushing's syndrome ]], [[diabetes]], Familial [[cushing syndrome ]], [[graves disease ]], [[hyperadrenalism ]], [[hyperparathyroidism ]], [[hyperpituitarism ]], [[hyperthyroidism]], [[hypothyroidism]], isolated secretion of corticosterone, isolated secretion of deoxycorticosterone, [[mineralocorticoid excess]], [[multiple endocrine neoplasia type 1]], [[myxoedema]], [[pheochromocytoma]], [[primary aldosteronism]], primary cortisol resistance, [[pseudohyperaldosteronism ]], [[pseudohypoaldosteronism ]], [[Schroeder syndrome 1 ]], [[hyperthyroidism]], [[hypoglycemia]], isolated secretion of 18-hydroxy-deoxycorticosterone, [[renin-secreting tumors]], [[dexamethasone sensitive hypertension]]<br />
|- <br />
|-bgcolor="LightSteelBlue"<br />
| '''Environmental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Gastroenterologic'''<br />
|bgcolor="Beige"| [[Hepatorenal tyrosinemia ]], [[pancreatitis]], [[retroperitoneal Fibrosis]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Genetic'''<br />
|bgcolor="Beige"| [[Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency]], [[congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency]], [[cockayne syndrome ]], [[down Syndrome ]], [[Fabry's Disease ]], isolated secretion of 18-hydroxy-deoxycorticosterone, [[Pierre Robin's sequence ]], [[Senior-Loken Syndrome]], [[Turner Syndrome ]], [[Vater-like syndrome, with pulmonary hypertension, abnormal ears and growth deficiency ]], [[Von Hippel-Lindau Disease ]], [[Werner syndrome ]], [[Williams Syndrome ]], [[Gaucher disease type 3 ]], [[mucopolysaccharidosis]] type I [[Hurler syndrome ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Hematologic'''<br />
|bgcolor="Beige"| [[Anemia]], Atypical [[Hemolytic uremic syndrome]], Catastrophic [[antiphospholipid syndrome ]], Essential mixed [[cryoglobulinemia ]], [[Faye-Petersen-Ward-Carey syndrome ]], [[hemolytic uremic syndrome ]], [[hypereosinophilic syndrome ]], [[Liddle's syndrome]], Multicentric reticulohistiocytosis , [[polycythemia ]], [[thromboembolism ]], [[thrombotic thrombocytopenic purpura]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Iatrogenic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Infectious Disease'''<br />
|bgcolor="Beige"| [[Poliomyelitis]], [[meningitis]], [[post streptococcal glomerulonephritis ]], [[renal tuberculosis]], [[nipah virus encephalitis ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Musculoskeletal / Ortho'''<br />
|bgcolor="Beige"| [[Acrodynia ]], [[Allain Babin Demarquez syndrome ]], [[familial osteodysplasia - Anderson type]], [[Paget's disease of bone ]], [[Grange syndrome ]], [[Faye-Petersen-Ward-Carey syndrome ]], [[oculo skeletal renal syndrome ]], [[Thieffry and Sorrell Dejerine syndrome ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Neurologic'''<br />
|bgcolor="Beige"| [[Guillain-Barre Syndrome]], [[autonomic dysreflexia syndrome ]], [[Binswanger's Disease ]], Brain stem [[encephalitis]], [[central sleep apnea ]], [[choroideremia -- hypopituitarism ]], [[disequilibrium syndrome ]], [[dysautonomia ]], [[hereditary sensory and autonomic neuropathy 3 ]], [[increased intracranial pressure]], [[neurofibromatosis syndrome Type II]] , [[neurogenic hypertension ]], [[nipah virus encephalitis ]], [[obstructive sleep apnea ]], [[Sneddon Syndrome ]], [[upper spinal cord lesions]], [[Wolfram's disease]], [[meningitis]], [[polyradiculitis]], [[quadriplegia]], [[Adams Nance syndrome ]], [[glycine encephalopathy]] - classical neonatal form, [[pituitary Cancer ]], [[Fitzsimmons-Walson-Mellor syndrome ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Nutritional / Metabolic'''<br />
|bgcolor="Beige"| [[Abdominal obesity metabolic syndrome ]], [[acute intermittent porphyria ]], [[congenital hepatic porphyria ]], [[Gaucher disease]] type 3, [[glycine encephalopathy]] - classical neonatal form, [[glycine synthase deficiency ]], [[gouty nephropathy]], [[liquorice]], [[metabolic syndrome]], [[tyrosinemia ]], [[Von Gierke disease]] IB, [[increased salt intake]], [[mucopolysaccharidosis]] type I [[Hurler syndrome]], [[Fabry's Disease ]], [[vitamin D -- adverse effects]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Obstetric/Gynecologic'''<br />
|bgcolor="Beige"| [[Eclampsia ]], [[Fowler-Christmas-Chapple syndrome ]], [[gestational hypertension]], [[HELLP syndrome ]], [[ovarian dysgenesis]], [[PCOS]], [[pregnancy toxemia /hypertension ]], twin-twin transfusion syndrome<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Oncologic'''<br />
|bgcolor="Beige"| [[Endothelin]] producing tumor, [[adrenal Cancer ]], familial [[adrenal adenoma ]], [[renal Cancer ]], [[neuroblastoma ]]<br />
[[pituitary Cancer ]], [[renin-secreting tumors]], [[rhabdoid tumor ]], [[Wilms' tumor ]], [[adrenal incidentaloma ]], familial [[renal cell carcinoma ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Opthalmologic'''<br />
|bgcolor="Beige"| Isolated Ectopia lentis, [[oculo skeletal renal syndrome ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Overdose / Toxicity'''<br />
|bgcolor="Beige"| [[Amphetamine]] abuse, [[almotriptan]], [[dihydroergotamine]], [[ergotamine]], [[frovatriptan]], [[isometheptene]], [[rizatriptan]], [[sumatriptan]], [[zolmitriptan]], [[amitriptyline]], [[cyclosporine]], [[desipramine]], [[dexamethasone]] sensitive hypertension, [[doxepin]], [[ephedrine]], [[glucocorticoid resistance ]], [[imipramine]], [[nasal decongestants]], [[nortriptyline]], [[combined oral contraceptive pill]], [[phencyclidine]], [[phenylpropanolamine]], [[protriptyline]], [[serotonin toxicity]], [[steroid abuse]], [[pseudoephedrine]], [[cocaine]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Psychiatric'''<br />
|bgcolor="Beige"| [[Anxiety]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Pulmonary'''<br />
|bgcolor="Beige"| [[Asphyxia ]], [[bronchopulmonary dysplasia]], [[COPD ]], [[Goodpasture syndrome ]], [[pulmonary cystic lymphangiectasis ]], [[pulmonary embolism ]], [[pulmonary fibrosis]] /[[granuloma ]], [[pulmonary veno-occlusive disease ]], pulmonary lymphangiomatosis, [[respiratory acidosis ]], [[respiratory failure ]], [[unilateral pulmonary agenesis ]], [[hyperventilation]], [[obstructive sleep apnea ]], [[Wegener's granulomatosis ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Renal / Electrolyte'''<br />
|bgcolor="Beige"| [[Bartter's Syndrome]], [[dissection of the renal arteries]], [[acid-base imbalance ]], [[acute renal failure ]], [[albuminuria ]], [[analgesic nephropathy syndrome ]], autosomal dominant [[polycystic kidney disease ]], autosomal recessive [[polycystic kidney disease ]], bilateral [[renal artery stenosis ]], [[Bright's Disease ]], [[chronic kidney disease ]], [[chronic pyelonephritis]], congenital [[membranous glomerulonephritis]], [[congenital stenosis of renal artery]], congenital hydronephrosis, [[diffuse mesangial sclerosis]], familial [[renal cell carcinoma ]], [[Fitzsimmons-Walson-Mellor syndrome ]], [[glomerulonephritis ]], [[hereditary nephritis]] (X-linked), [[hypoplastic kidney]], [[IgA nephropathy ]], [[kidney arteriovenous fistula ]], [[Kimmelstiel-Wilson disease]], [[lupus nephritis ]], [[nephrocalcinosis ]], [[nephrosclerosis ]], [[nephrosis -- deafness -- urinary tract -- digital malformation ]], [[nephrotic syndrome ]], [[oculo skeletal renal syndrome ]], [[Pierson syndrome ]], Severe infantile [[polycystic kidneys]] with [[tuberous sclerosis ]], [[post streptococcal glomerulonephritis ]], [[renal artery thrombosis]], [[renal artery stenosis]], [[renal emboli]], [[renal segmental hypoplasia-induced Hypertension ]], [[renal tuberculosis]], [[Salcedo syndrome ]], [[simple kidney cysts ]], [[Thieffry and Sorrell Dejerine syndrome ]], [[urinary tract infections ]], [[urinary tract obstruction]], [[vesicoureteral reflux ]], [[Wegener's granulomatosis ]], [[Gitelman's Syndrome]], [[hepatorenal tyrosinemia ]], Atypical [[hemolytic uremic syndrome]], [[gouty nephropathy]], [[Goodpasture syndrome ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Rheum / Immune / Allergy'''<br />
|bgcolor="Beige"| [[Autoimmune Vasculitis ]], [[systemic lupus erythematosus]], diffuse [[systemic sclerosis ]], [[polyarteritis nodosa ]], [[Takayasu arteritis ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Sexual'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Trauma'''<br />
|bgcolor="Beige"| [[Electrical burns ]], [[head injury]], [[skull fracture ]]<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Urologic'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Dental'''<br />
|bgcolor="Beige"| No underlying causes<br />
|-<br />
|-bgcolor="LightSteelBlue"<br />
| '''Miscellaneous'''<br />
|bgcolor="Beige"| Acquired total [[lipodystrophy ]], following [[kidney transplantation]], [[aging]], [[alcohol|alcohol intake]], [[alcohol withdrawal]], [[amyloidosis ]], bone cement implantation syndrome, [[brachydactyly with hypertension]], [[Carnevale-Canun-Mendoza syndrome ]], [[codeine withdrawal ]], [[collagen disease]], [[essential hypertension]], [[fever]], [[Gram's syndrome ]], [[hypothermia]], [[irradiation]], [[Kashani-Strom-Utley syndrome ]], [[lymphomatoid granulomatosis ]], [[MSBD syndrome ]], [[neuroleptic malignant syndrome ]], [[obesity]], [[physical inactivity ]], [[Selye syndrome ]], [[serotonin syndrome ]], [[shaken baby syndrome ]], [[stress-induced hypertension ]], [[type A personality]], [[Wagener syndrome ]], [[pain]], [[post-exercise]], [[transfusion of large blood volumes]], [[white coat hypertension]]<br />
|-<br />
|}<br />
<br />
==Causes in Alphabetical Order==<br />
<br />
{{MultiCol}}<br />
* [[Abdominal obesity metabolic syndrome ]]<br />
* [[Absence of pulmonary artery ]]<br />
* [[Acetaldehyde ]]<br />
* [[Acid-Base Imbalance ]]<br />
* Acquired total [[Lipodystrophy ]]<br />
* [[Acrodynia ]]<br />
* [[Acromegaly ]]<br />
* [[Acute intermittent porphyria ]]<br />
* [[Acute renal failure ]]<br />
* [[Acute severe vascular damage]]<br />
* [[Adams Nance syndrome ]]<br />
* [[Adrenal Cancer ]]<br />
* [[Adrenal incidentaloma ]]<br />
* After [[Kidney transplantation]]<br />
* [[Kidney tumor]]<br />
* [[Aging]]<br />
* [[Albuminuria ]]<br />
* [[Alcohol]]<br />
* [[Alcohol withdrawal]]<br />
* [[Alcohol-induced pseudo-Cushing syndrome ]]<br />
* [[Allain Babin Demarquez syndrome ]]<br />
* [[Almotriptan]]<br />
* [[Amitriptyline]]<br />
* [[Amphetamine]] abuse<br />
* [[Amyloidosis ]]<br />
* [[Analgesic nephropathy syndrome ]]<br />
* [[Anemia]]<br />
* [[Aneurysm]]<br />
* [[Anxiety]]<br />
* [[Aortic coarctation ]]<br />
* [[Aortic regurgitation]]<br />
* [[Aortic stenosis]]<br />
* [[Valvular diseases|Aortic valve disease]]<br />
* [[Apparent mineralocorticoid excess ]]<br />
* [[Aristolochic Acid poisoning ]]<br />
* [[Arizona Bark Scorpion poisoning ]]<br />
* [[Arterial occlusive disease, progressive - -- heart defects -- bone fragility -- brachysyndactyly ]]<br />
* [[Arteriosclerosis]]<br />
* [[Asphyxia ]]<br />
* [[Atheroma]]<br />
*[[Atropine]]<br />
* Atypical [[Hemolytic uremic syndrome]]<br />
* [[Autoimmune Vasculitis ]]<br />
* [[Autonomic dysreflexia syndrome ]]<br />
* Autosomal dominant [[Polycystic kidney disease ]]<br />
* Autosomal Recessive [[Polycystic Kidney Disease ]]<br />
* [[Avasthey syndrome ]]<br />
* [[Bartter's Syndrome]]<br />
*[[Betamethasone valerate]]<br />
*[[Betamethasone dipropionate]]<br />
* Bilateral [[Renal artery stenosis ]]<br />
* [[Binswanger's Disease ]]<br />
* [[Black widow spider envenomation ]]<br />
* [[Bone cement implantation syndrome ]]<br />
* [[Brachydactyly with hypertension]]<br />
* Brain stem [[Encephalitis]]<br />
* [[Bright's Disease ]]<br />
* [[Bronchopulmonary dysplasia]]<br />
*[[Butorphanol]]<br />
* [[Cadmium poisoning]]<br />
* [[Carcinoid Syndrome]]<br />
* [[Carnevale-Canun-Mendoza syndrome ]]<br />
* [[Carotid paraganglioma ]]<br />
* Catastrophic [[Antiphospholipid Syndrome ]]<br />
* [[Central sleep apnea ]]<br />
* [[Choroideremia -- hypopituitarism ]]<br />
* [[Chronic kidney disease ]]<br />
* [[Chronic pyelonephritis]]<br />
*[[Cidofovir]]<br />
* [[Cocaine]]<br />
* [[Cockayne syndrome ]]<br />
* [[Codeine withdrawal ]]<br />
* [[Collagen disease]]<br />
* [[Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency]]<br />
* [[Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency]]<br />
* [[Congenital hepatic porphyria ]]<br />
* Congenital [[Membranous glomerulonephritis]]<br />
* Congenital [[Mitral stenosis ]]<br />
* [[Congenital stenosis of renal artery]]<br />
* Congenital [[Hydronephrosis ]]<br />
* [[Conn's syndrome]]<br />
* [[COPD ]]<br />
* [[Cushing's disease]]<br />
* [[Cushing's syndrome ]]<br />
* [[Cyclosporine]]<br />
* [[Desipramine]]<br />
*[[Desmopressin]]<br />
* [[Dexamethasone sensitive hypertension]]<br />
* [[Diabetes]]<br />
* Diffuse [[Systemic sclerosis ]]<br />
* [[Diffuse mesangial sclerosis]]<br />
* [[Dihydroergotamine]]<br />
* [[Disequilibrium syndrome ]]<br />
* [[Aortic dissection]]<br />
* [[Dissection of the renal arteries]]<br />
* [[Down Syndrome ]]<br />
* [[Doxepin]]<br />
* [[Dysautonomia ]]<br />
* [[Eclampsia ]]<br />
* [[Ecstasy]] abuse<br />
* [[Eculizumab]]<br />
{{ColBreak}}<br />
* [[Eisenmenger's Syndrome ]]<br />
* [[Electrical burns ]]<br />
* [[Endothelin]] producing tumor<br />
* [[Ephedrine]]<br />
* [[Ergotamine]]<br />
* [[Essential hypertension]]<br />
* Essential mixed [[Cryoglobulinemia ]]<br />
* [[Fabry's Disease ]]<br />
* Familial [[Renal cell carcinoma ]]<br />
* Familial [[Adrenal adenoma ]]<br />
* Familial [[Cushing syndrome ]]<br />
* [[Faye-Petersen-Ward-Carey syndrome ]]<br />
* [[Fever]]<br />
* [[Fibromuscular dysplasia]] of arteries<br />
* [[Fitzsimmons-Walson-Mellor syndrome ]]<br />
* [[Fowler-Christmas-Chapple syndrome ]]<br />
* [[Frovatriptan]]<br />
* [[Gaucher disease]] type 3<br />
* [[Gestational hypertension]]<br />
* [[Ginseng ]]<br />
* [[Gitelman's Syndrome]]<br />
* [[Glomerulonephritis ]]<br />
* [[Glucocorticoid resistance ]]<br />
* [[Glycine encephalopathy]] - classical neonatal form<br />
* [[Glycine synthase deficiency ]]<br />
* [[Goodpasture syndrome ]]<br />
* [[Gouty nephropathy]]<br />
* [[Gram's syndrome ]]<br />
* [[Grange syndrome ]]<br />
* [[Graves Disease ]]<br />
* [[Guillain-Barre Syndrome]]<br />
* [[Head injury]]<br />
* [[Heavy metal poisoning]]<br />
* [[HELLP syndrome ]]<br />
* Familial [[Hemangiomatosis]] - pulmonary capillary<br />
* [[Familial Osteodysplasia - Anderson type]] <br />
* [[Hemolytic uremic syndrome ]]<br />
* [[Hepatorenal tyrosinemia ]]<br />
* [[Hereditary nephritis]] (X-linked)<br />
* [[Hereditary sensory and autonomic neuropathy 3 ]]<br />
*[[Hydroxocobalamin]]<br />
* [[Hyperadrenalism ]]<br />
* [[Hypereosinophilic syndrome ]]<br />
* [[Hyperparathyroidism ]]<br />
* [[Hyperpituitarism ]]<br />
* [[Hypertensive heart disease ]]<br />
* [[Hyperthyroidism]]<br />
* [[Hyperventilation]]<br />
* [[Hypoglycemia]]<br />
* [[Hypoplastic kidney]]<br />
* [[Hypothermia]]<br />
* [[Hypothyroidism]]<br />
* [[IgA nephropathy ]]<br />
* [[Imipramine]]<br />
* [[Increased intracranial pressure]]<br />
* [[Increased salt intake]]<br />
* Indian [[Tobacco]] [[Poisoning ]]<br />
*[[Infliximab]]<br />
* [[Irradiation]]<br />
* [[Isolated secretion of 18-hydroxy-deoxycorticosterone]]<br />
* [[Isolated secretion of corticosterone]]<br />
* [[Isolated secretion of deoxycorticosterone]]<br />
* [[Isolated Ectopia lentis]]<br />
* [[Isometheptene]]<br />
* [[Jimsonweed poisoning ]]<br />
* [[Kashani-Strom-Utley syndrome ]]<br />
* [[Kidney arteriovenous fistula ]]<br />
* [[Renal Cancer ]]<br />
* [[Kimmelstiel-Wilson disease]]<br />
* [[Lead poisoning]]<br />
* [[Liquorice]]<br />
* [[Liddle's syndrome]]<br />
* [[Lobelia]] poisoning<br />
* [[Lockwood-Feingold syndrome ]]<br />
* [[Lupus nephritis ]]<br />
* [[Lymphomatoid granulomatosis ]]<br />
* [[Medroxyprogesterone]]<br />
* [[Meloxicam]]<br />
* [[Meningitis]]<br />
* [[Meropenem]]<br />
* [[Metabolic syndrome]]<br />
* [[Methylphenidate]]<br />
* [[Mifepristone]]<br />
* [Milnacipran hydrochloride]]<br />
* [[Mineralocorticoid excess]]<br />
* [[Monoamine oxidase inhibitor]]s<br />
* [[MSBD syndrome ]]<br />
* [[Mucopolysaccharidosis]] type I [[Hurler syndrome]]<br />
* Multicentric [[Reticulohistiocytosis]]<br />
* [[Multiple endocrine neoplasia type 1]]<br />
* [[Mustard tree poisoning ]]<br />
* [[Myxoedema]]<br />
* [[Nasal decongestants]]<br />
* [[Nephrocalcinosis ]]<br />
* [[Nephrosclerosis ]]<br />
* [[Nephrosis -- deafness -- urinary tract -- digital malformation ]]<br />
* [[Nephrotic syndrome ]]<br />
* [[Neuroblastoma ]]<br />
* [[Neurofibromatosis syndrome Type II]] <br />
* [[Neurogenic hypertension ]]<br />
* [[Neuroleptic malignant Syndrome ]]<br />
* [[Nicotine addiction ]]<br />
* [[Nipah virus encephalitis ]]<br />
* [[Norgestrel and Ethinyl estradiol]]<br />
* [[Nortriptyline]]<br />
* [[NSAIDs]]<br />
* [[Obesity]]<br />
{{ColBreak}}<br />
* [[Obstructive sleep apnea ]]<br />
* [[Oculo skeletal renal syndrome ]]<br />
* [[Oral contraceptive pill]]<br />
* [[Ovarian dysgenesis]]<br />
* [[Paget's disease of bone ]]<br />
* [[Pain]]<br />
* [[Pancreatitis]]<br />
* [[Patent ductus arteriosus]]<br />
* [[PCOS]]<br />
* [[Pheochromocytoma]]<br />
* [[Phencyclidine]]<br />
* [[Phenylpropanolamine]]<br />
* [[Physical inactivity ]]<br />
* [[Pierre Robin's sequence ]]<br />
* [[Pierson syndrome ]]<br />
*[[Pilocarpine]]<br />
* [[Piroxicam]]<br />
* [[Pituitary Cancer ]]<br />
* [[Poliomyelitis]]<br />
* [[Polyarteritis nodosa ]]<br />
* [[Polycystic kidneys, severe infantile, with tuberous sclerosis ]]<br />
* [[Polycythemia ]]<br />
* [[Polyradiculitis]]<br />
* [[Post streptococcal glomerulonephritis ]]<br />
* [[Post-exercise]]<br />
*[[Pralidoxime]]<br />
* [[Pregnancy toxemia /hypertension ]]<br />
* [[Primary aldosteronism]]<br />
* [[Primary cortisol resistance]]<br />
* [[Protriptyline]]<br />
* [[Pseudoephedrine]]<br />
* [[Pseudohyperaldosteronism ]]<br />
* [[Pseudohypoaldosteronism ]]<br />
* [[Pulmonary artery agenesis ]]<br />
* [[Pulmonary cystic lymphangiectasis ]]<br />
* [[Pulmonary embolism ]]<br />
* [[Pulmonary fibrosis /granuloma ]]<br />
* [[Pulmonary veno-occlusive disease ]]<br />
* [[Pulmonary Lymphangiomatosis]]<br />
* [[Quadriplegia]]<br />
* [[Renal artery thrombosis]]<br />
* [[Renal artery stenosis]]<br />
* [[Renal emboli]]<br />
* [[Renal segmental hypoplasia-induced Hypertension ]]<br />
* [[Renal tuberculosis]]<br />
* [[Renin-secreting tumors]]<br />
* [[Respiratory acidosis ]]<br />
* [[Respiratory failure ]]<br />
* [[Retroperitoneal fibrosis]]<br />
* [[Rhabdoid tumor ]]<br />
* [[Rizatriptan]]<br />
* [[Salcedo syndrome ]]<br />
* [[Schroeder syndrome 1 ]]<br />
* [[Scleroderma ]]<br />
* [[Sedative dependence]]<br />
* [[Selye syndrome ]]<br />
* [[Senior-Loken Syndrome]]<br />
* [[Serotonin Syndrome ]]<br />
* [[Serotonin toxicity]]<br />
* [[Shaken Baby Syndrome ]]<br />
* [[Silicosis ]]<br />
* [[Simple kidney cysts ]]<br />
* [[Skull fracture ]]<br />
* [[Sneddon Syndrome ]]<br />
*[[Sorafenib]]<br />
* [[Steroid abuse]]<br />
* [[Stress-induced hypertension ]]<br />
* [[Sumatriptan]]<br />
* [[Sunitinib]]<br />
* [[Systemic lupus erythematosus]]<br />
* [[Takayasu arteritis ]]<br />
* [[Thieffry and Sorrell Dejerine syndrome ]]<br />
* [[Third degree AV block]]<br />
* [[Thromboembolism ]]<br />
* [[Thrombotic thrombocytopenic purpura]]<br />
* [[Toxic mushrooms -- Psychedelic ]]<br />
* [[Transfusion of large blood volumes]]<br />
* [[Turner Syndrome ]]<br />
* [[Twin-Twin Transfusion Syndrome]]<br />
* [[Type A personality]]<br />
* [[Tyrosinemia ]]<br />
* [[Unilateral pulmonary agenesis ]]<br />
* [[Upper spinal cord lesions]]<br />
* [[Urinary tract infections ]]<br />
* [[Urinary tract obstruction]]<br />
* [[Valganciclovir hydrochloride]]<br />
* [[Vasculitis ]]<br />
* [[Vater-like syndrome, with pulmonary hypertension, abnormal ears and growth deficiency ]]<br />
* [[Vesicoureteral reflux ]]<br />
* [[Vitamin D -- adverse effects]]<br />
* [[Von Gierke disease IB ]]<br />
* [[Von Hippel-Lindau Disease ]]<br />
* [[Wagener syndrome ]]<br />
* [[Wegener's granulomatosis ]]<br />
* [[Werner syndrome ]]<br />
* [[White coat hypertension]]<br />
* [[Williams Syndrome ]]<br />
* [[Wilms' tumor ]]<br />
* [[Wolfram's disease]]<br />
* [[Zolmitriptan]]<br />
{{EndMultiCol}}<br />
<br />
==References==<br />
{{reflist|2}}<br />
{{WH}}<br />
{{WS}}<br />
[[Category:Aging-associated diseases]]<br />
[[Category:Cardiology]]<br />
[[Category:Emergency medicine]]<br />
[[Category:Cardiovascular diseases]]<br />
[[Category:Cardiology board review]]<br />
[[Category:Medical conditions related to obesity]]<br />
[[Category:Nephrology]]<br />
[[Category:Up-To-Date]]<br />
[[Category:Up-To-Date cardiology]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058870Mirabegron2015-01-23T04:37:41Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
<br />
* Content<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings='''Increases in Blood Pressure'''<br />
<br />
* Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).<br />
<br />
*In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
*In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
'''Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB'''<br />
<br />
*Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.<br />
<br />
'''Patients Taking Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials='''Clinical Trials Experience'''<br />
<br />
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
*In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
*Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
*The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
*Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
*Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
*Cardiac disorders: palpitations, blood pressure increased<br />
<br />
*Eye Disorders: glaucoma<br />
<br />
*Gastrointestinal disorders: [[dyspepsia]], [[gastritis]], [[abdominal distension]]<br />
<br />
*Infections and Infestations: [[sinusitis]], [[rhinitis]]<br />
<br />
*Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
*Renal and urinary disorders: [[nephrolithiasis]], [[bladder pain]]<br />
<br />
*Reproductive system and breast disorders: [[vulvovaginal pruritus]], vaginal infection<br />
<br />
*Skin and subcutaneous tissue disorders: [[urticaria]], [[leukocytoclastic vasculitis]], [[rash]], [[pruritus]], [[purpura]], lip edema<br />
<br />
*Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
*In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
*In a separate clinical study in Japan, a single case was reported as [[Stevens-Johnson syndrome]] with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=*Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
*The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
*Urologic: [[urinary retention]]<br />
<br />
|drugInteractions=*Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., [[ketoconazole]], [[rifampin]], [[solifenacin]], [[tamsulosin]], and [[oral contraceptives]]). No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
*The following are drug interactions for which monitoring is recommended:<br />
<br />
'''Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
'''Digoxin'''<br />
<br />
*When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and [[digoxin]], the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
'''Warfarin'''<br />
<br />
*The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of [[warfarin]] and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=* There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
'''Risk Summary'''<br />
<br />
*Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
'''Animal Data'''<br />
<br />
*In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
*In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
*The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=*The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=*No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=*No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
*In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).<br />
|useInHepaticImpair=*Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
*In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<!--IV Compatibility--><br />
|IVCompat=* There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=* Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
*Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD='''Urodynamics'''<br />
<br />
*The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO.<br />
<br />
'''Cardiac Electrophysiology'''<br />
<br />
*The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
*For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
*In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
'''Effects on Blood Pressure'''<br />
<br />
*In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
*In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
*In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
'''Effect on Intraocular Pressure (IOP)'''<br />
<br />
*Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
<br />
|PK='''Absorption'''<br />
<br />
*After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
'''Effect of Food'''<br />
<br />
*Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.<br />
'''Distribution'''<br />
<br />
*Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
'''Metabolism'''<br />
<br />
*Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
'''Excretion'''<br />
<br />
*Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
'''Specific Populations'''<br />
<br />
'''Geriatric Patients'''<br />
<br />
*The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).<br />
<br />
'''Pediatric Patients'''<br />
<br />
*The pharmacokinetics of mirabegron in pediatric patients have not been evaluated. <br />
<br />
'''Gender'''<br />
<br />
*The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
'''Race'''<br />
<br />
*The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
'''Renal Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
'''Hepatic Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''Drug Interaction Studies'''<br />
<br />
'''In Vitro Studies'''<br />
<br />
'''Effect of Other Drugs on Mirabegron'''<br />
<br />
*Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
'''Effect of Mirabegron on Other Drugs'''<br />
<br />
*Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
'''In Vivo Studies'''<br />
<br />
*The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
*The effect of [[ketoconazole]], [[rifampicin]], [[solifenacin]], [[tamsulosin]], and [[metformin]] on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
*The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), [[solifenacin]], [[digoxin]], [[warfarin]], [[tamsulosin]], and [[metformin]] is shown in Figure 2.<br />
<br />
*In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent [[CYP3A4]] inhibitor, [[ketoconazole]] increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
*As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to [[metoprolol]] and [[desipramine]]:<br />
<br />
:*Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
:*Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
*Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
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<br />
*Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention.<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
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<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
*For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
* Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
<br />
* Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.<br />
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''<br />
<br />
'''Carcinogenicity'''<br />
<br />
*Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
'''Mutagenesis'''<br />
<br />
*Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
'''Impairment of Fertility'''<br />
<br />
*Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=* Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
*In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
*The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
*Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
*Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 4.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 5.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 6.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 7.png|600px|thumbnail|left]]<br />
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<br />
[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
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|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron pdp 2.jpg|600px|thumbnail|left]]<br />
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<br />
[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
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|fdaPatientInfo=*See FDA-approved patient labeling (Patient Information)<br />
<br />
*Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent [[urinary tract infections]], rapid heart beat, [[rash]], and [[pruritus]]. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
*Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058868Mirabegron2015-01-23T04:34:44Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings='''Increases in Blood Pressure'''<br />
<br />
* Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).<br />
<br />
*In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
*In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
'''Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB'''<br />
<br />
*Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.<br />
<br />
'''Patients Taking Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials='''Clinical Trials Experience'''<br />
<br />
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
*In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
*Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
*The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
*Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
*Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were [[hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
*Cardiac disorders: palpitations, blood pressure increased<br />
<br />
*Eye Disorders: glaucoma<br />
<br />
*Gastrointestinal disorders: [[dyspepsia]], [[gastritis]], [[abdominal distension]]<br />
<br />
*Infections and Infestations: [[sinusitis]], [[rhinitis]]<br />
<br />
*Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
*Renal and urinary disorders: [[nephrolithiasis]], [[bladder pain]]<br />
<br />
*Reproductive system and breast disorders: [[vulvovaginal pruritus]], vaginal infection<br />
<br />
*Skin and subcutaneous tissue disorders: [[urticaria]], [[leukocytoclastic vasculitis]], [[rash]], [[pruritus]], [[purpura]], lip edema<br />
<br />
*Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
*In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
*In a separate clinical study in Japan, a single case was reported as [[Stevens-Johnson syndrome]] with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=*Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
*The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
*Urologic: [[urinary retention]]<br />
<br />
|drugInteractions=*Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., [[ketoconazole]], [[rifampin]], [[solifenacin]], [[tamsulosin]], and [[oral contraceptives]]). No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
*The following are drug interactions for which monitoring is recommended:<br />
<br />
'''Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
'''Digoxin'''<br />
<br />
*When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and [[digoxin]], the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
'''Warfarin'''<br />
<br />
*The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of [[warfarin]] and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=* There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
'''Risk Summary'''<br />
<br />
*Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
'''Animal Data'''<br />
<br />
*In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
*In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
*The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=*The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=*No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=*No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
*In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).<br />
|useInHepaticImpair=*Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
*In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<!--IV Compatibility--><br />
|IVCompat=* There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=* Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
*Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD='''Urodynamics'''<br />
<br />
*The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO.<br />
<br />
'''Cardiac Electrophysiology'''<br />
<br />
*The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
*For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
*In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
'''Effects on Blood Pressure'''<br />
<br />
*In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
*In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
*In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
'''Effect on Intraocular Pressure (IOP)'''<br />
<br />
*Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
<br />
|PK='''Absorption'''<br />
<br />
*After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
'''Effect of Food'''<br />
<br />
*Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.<br />
'''Distribution'''<br />
<br />
*Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
'''Metabolism'''<br />
<br />
*Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
'''Excretion'''<br />
<br />
*Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
'''Specific Populations'''<br />
<br />
'''Geriatric Patients'''<br />
<br />
*The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).<br />
<br />
'''Pediatric Patients'''<br />
<br />
*The pharmacokinetics of mirabegron in pediatric patients have not been evaluated. <br />
<br />
'''Gender'''<br />
<br />
*The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
'''Race'''<br />
<br />
*The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
'''Renal Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
'''Hepatic Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''Drug Interaction Studies'''<br />
<br />
'''In Vitro Studies'''<br />
<br />
'''Effect of Other Drugs on Mirabegron'''<br />
<br />
*Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
'''Effect of Mirabegron on Other Drugs'''<br />
<br />
*Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
'''In Vivo Studies'''<br />
<br />
*The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
*The effect of [[ketoconazole]], [[rifampicin]], [[solifenacin]], [[tamsulosin]], and [[metformin]] on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
*The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), [[solifenacin]], [[digoxin]], [[warfarin]], [[tamsulosin]], and [[metformin]] is shown in Figure 2.<br />
<br />
*In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent [[CYP3A4]] inhibitor, [[ketoconazole]] increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
*As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to [[metoprolol]] and [[desipramine]]:<br />
<br />
:*Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
:*Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
*Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
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<br />
*Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention.<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
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<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
*For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
* Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
<br />
* Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.<br />
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''<br />
<br />
'''Carcinogenicity'''<br />
<br />
*Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
'''Mutagenesis'''<br />
<br />
*Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
'''Impairment of Fertility'''<br />
<br />
*Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=* Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
*In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
*The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
*Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
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<br />
*Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
*Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 4.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 5.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 6.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 7.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
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|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron pdp 2.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
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|fdaPatientInfo=*See FDA-approved patient labeling (Patient Information)<br />
<br />
*Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent [[urinary tract infections]], rapid heart beat, [[rash]], and [[pruritus]]. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
*Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058867Mirabegron2015-01-23T04:32:07Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
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<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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<!--Pediatric Indications and Dosage--><br />
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|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Off-Label Use and Dosage (Pediatric)--><br />
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|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings='''Increases in Blood Pressure'''<br />
<br />
* Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).<br />
<br />
*In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
*In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
'''Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB'''<br />
<br />
*Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.<br />
<br />
'''Patients Taking Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials='''Clinical Trials Experience'''<br />
<br />
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
*In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
*Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
*The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
*Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
*Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were [[hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
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*Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
*Cardiac disorders: palpitations, blood pressure increased<br />
<br />
*Eye Disorders: glaucoma<br />
<br />
*Gastrointestinal disorders: [[dyspepsia]], [[gastritis]], [[abdominal distension]]<br />
<br />
*Infections and Infestations: [[sinusitis]], [[rhinitis]]<br />
<br />
*Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
*Renal and urinary disorders: [[nephrolithiasis]], [[bladder pain]]<br />
<br />
*Reproductive system and breast disorders: [[vulvovaginal pruritus]], vaginal infection<br />
<br />
*Skin and subcutaneous tissue disorders: [[urticaria]], [[leukocytoclastic vasculitis]], [[rash]], [[pruritus]], [[purpura]], lip edema<br />
<br />
*Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
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<br />
*In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
*In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
*In a separate clinical study in Japan, a single case was reported as [[Stevens-Johnson syndrome]] with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=*Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
*The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
*Urologic: [[urinary retention]]<br />
<br />
|drugInteractions=*Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., [[ketoconazole]], [[rifampin]], [[solifenacin]], [[tamsulosin]], and [[oral contraceptives]]). No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
*The following are drug interactions for which monitoring is recommended:<br />
<br />
'''Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
'''Digoxin'''<br />
<br />
*When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and [[digoxin]], the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
'''Warfarin'''<br />
<br />
*The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of [[warfarin]] and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=* There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
'''Risk Summary'''<br />
<br />
*Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
'''Animal Data'''<br />
<br />
*In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
*In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
*The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=*The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=*No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=*No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
*In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).<br />
|useInHepaticImpair=*Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
*In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<!--IV Compatibility--><br />
|IVCompat=* There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=* Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
*Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD='''Urodynamics'''<br />
<br />
*The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO.<br />
<br />
'''Cardiac Electrophysiology'''<br />
<br />
*The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
*For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
*In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
'''Effects on Blood Pressure'''<br />
<br />
*In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
*In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
*In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
'''Effect on Intraocular Pressure (IOP)'''<br />
<br />
*Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
<br />
|PK='''Absorption'''<br />
<br />
*After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
'''Effect of Food'''<br />
<br />
*Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.<br />
'''Distribution'''<br />
<br />
*Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
'''Metabolism'''<br />
<br />
*Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
'''Excretion'''<br />
<br />
*Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
'''Specific Populations'''<br />
<br />
'''Geriatric Patients'''<br />
<br />
*The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).<br />
<br />
'''Pediatric Patients'''<br />
<br />
*The pharmacokinetics of mirabegron in pediatric patients have not been evaluated. <br />
<br />
'''Gender'''<br />
<br />
*The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
'''Race'''<br />
<br />
*The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
'''Renal Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
'''Hepatic Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''Drug Interaction Studies'''<br />
<br />
'''In Vitro Studies'''<br />
<br />
'''Effect of Other Drugs on Mirabegron'''<br />
<br />
*Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
'''Effect of Mirabegron on Other Drugs'''<br />
<br />
*Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
'''In Vivo Studies'''<br />
<br />
*The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
*The effect of [[ketoconazole]], [[rifampicin]], [[solifenacin]], [[tamsulosin]], and [[metformin]] on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
*The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), [[solifenacin]], [[digoxin]], [[warfarin]], [[tamsulosin]], and [[metformin]] is shown in Figure 2.<br />
<br />
*In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent [[CYP3A4]] inhibitor, [[ketoconazole]] increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
*As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to [[metoprolol]] and [[desipramine]]:<br />
<br />
:*Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
:*Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
*Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention.<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Since mirabegron is a moderate [[CYP2D6]] inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as [[thioridazine]], [[flecainide]], and [[propafenone]].<br />
<br />
*For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
* Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
<br />
* Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.<br />
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
'''Carcinogenicity'''<br />
<br />
*Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
'''Mutagenesis'''<br />
<br />
*Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
'''Impairment of Fertility'''<br />
<br />
*Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=* Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
*In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
*The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
*Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
*Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron fig 4.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron fig 5.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron fig 6.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron fig 7.png|600px|thumbnail|left]]<br />
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<br />
[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron pdp 2.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|fdaPatientInfo=*See FDA-approved patient labeling (Patient Information)<br />
<br />
*Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent [[urinary tract infections]], rapid heart beat, [[rash]], and [[pruritus]]. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
*Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058760Mirabegron2015-01-22T22:39:36Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
<br />
* Content<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
<br />
<!--Pediatric Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings='''Increases in Blood Pressure'''<br />
<br />
* Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).<br />
<br />
*In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
*In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
'''Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB'''<br />
<br />
*Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.<br />
<br />
'''Patients Taking Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials='''Clinical Trials Experience'''<br />
<br />
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
*In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
*Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
*The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
*Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
*Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
*Cardiac disorders: palpitations, blood pressure increased<br />
<br />
*Eye Disorders: glaucoma<br />
<br />
*Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension<br />
<br />
*Infections and Infestations: sinusitis, rhinitis<br />
<br />
*Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
*Renal and urinary disorders: nephrolithiasis, bladder pain<br />
<br />
*Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection<br />
<br />
*Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema<br />
<br />
*Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
*In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
*In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=*Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
*The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
*Urologic: urinary retention<br />
|drugInteractions=*Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives). No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
*The following are drug interactions for which monitoring is recommended:<br />
<br />
'''Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.<br />
<br />
'''Digoxin'''<br />
<br />
*When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
'''Warfarin'''<br />
<br />
*The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=* There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
'''Risk Summary'''<br />
<br />
*Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
'''Animal Data'''<br />
<br />
*In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
*In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
*The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=*The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=*No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age [see Clinical Pharmacology (12.3)]. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=*No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
*In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).<br />
|useInHepaticImpair=*Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
*In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<!--IV Compatibility--><br />
|IVCompat=* There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
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|mechAction=* Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=* Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
*Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD='''Urodynamics'''<br />
<br />
*The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2)].<br />
<br />
'''Cardiac Electrophysiology'''<br />
<br />
*The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
*For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
*In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
'''Effects on Blood Pressure'''<br />
<br />
*In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
*In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
*In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
'''Effect on Intraocular Pressure (IOP)'''<br />
<br />
*Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
|PK='''Absorption'''<br />
<br />
*After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
'''Effect of Food'''<br />
<br />
*Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose [see Dosage and Administration (2.1)]. <br />
<br />
'''Distribution'''<br />
<br />
*Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
'''Metabolism'''<br />
<br />
*Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
'''Excretion'''<br />
<br />
*Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
'''Specific Populations'''<br />
<br />
'''Geriatric Patients'''<br />
<br />
*The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).<br />
<br />
'''Pediatric Patients'''<br />
<br />
*The pharmacokinetics of mirabegron in pediatric patients have not been evaluated. <br />
<br />
'''Gender'''<br />
<br />
*The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
'''Race'''<br />
<br />
*The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
'''Renal Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
'''Hepatic Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''Drug Interaction Studies'''<br />
<br />
'''In Vitro Studies'''<br />
<br />
'''Effect of Other Drugs on Mirabegron'''<br />
<br />
*Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
'''Effect of Mirabegron on Other Drugs'''<br />
<br />
*Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
'''In Vivo Studies'''<br />
<br />
*The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
*The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
*The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.<br />
<br />
*In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
*As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:<br />
<br />
:*Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
:*Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
*Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone.<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
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<br />
*Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
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<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.<br />
<br />
*For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
* Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
<br />
* Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.<br />
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
'''Carcinogenicity'''<br />
<br />
*Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
'''Mutagenesis'''<br />
<br />
*Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
'''Impairment of Fertility'''<br />
<br />
*Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=* Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
*In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
*The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
*Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
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<br />
*Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
*Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 4.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
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|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
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|fdaPatientInfo=*See FDA-approved patient labeling (Patient Information)<br />
<br />
*Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
*Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058759Mirabegron2015-01-22T22:37:20Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
<br />
<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
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|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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<!--Pediatric Indications and Dosage--><br />
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|fdaLIADPed=* There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
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|offLabelPedGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings='''Increases in Blood Pressure'''<br />
<br />
* Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg).<br />
<br />
*In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
*In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
'''Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB'''<br />
<br />
*Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.<br />
<br />
'''Patients Taking Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials='''Clinical Trials Experience'''<br />
<br />
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
*In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
*Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
*The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
*Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
*Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
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<br />
*Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
*Cardiac disorders: palpitations, blood pressure increased<br />
<br />
*Eye Disorders: glaucoma<br />
<br />
*Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension<br />
<br />
*Infections and Infestations: sinusitis, rhinitis<br />
<br />
*Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
*Renal and urinary disorders: nephrolithiasis, bladder pain<br />
<br />
*Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection<br />
<br />
*Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema<br />
<br />
*Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
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<br />
*In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
*In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
*In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=*Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
*The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
*Urologic: urinary retention<br />
|drugInteractions=*Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
*The following are drug interactions for which monitoring is recommended:<br />
<br />
'''Drugs Metabolized by CYP2D6'''<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].<br />
<br />
'''Digoxin'''<br />
<br />
*When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology (12.3)].<br />
<br />
'''Warfarin'''<br />
<br />
*The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=* There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
'''Risk Summary'''<br />
<br />
*Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
'''Animal Data'''<br />
<br />
*In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
*In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
*The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
*There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=*There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=*It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=*The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=*No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age [see Clinical Pharmacology (12.3)]. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=*No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=*There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=*Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
*In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2).<br />
|useInHepaticImpair=*Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
*In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).<br />
|useInReproPotential=*There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=*There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<!--IV Compatibility--><br />
|IVCompat=* There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=* Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|mechAction=* Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=* Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
*Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD='''Urodynamics'''<br />
<br />
*The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2)].<br />
<br />
'''Cardiac Electrophysiology'''<br />
<br />
*The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
*For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
*In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
'''Effects on Blood Pressure'''<br />
<br />
*In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
*In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
*In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
'''Effect on Intraocular Pressure (IOP)'''<br />
<br />
*Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
|PK='''Absorption'''<br />
<br />
*After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
'''Effect of Food'''<br />
<br />
*Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose [see Dosage and Administration (2.1)]. <br />
<br />
'''Distribution'''<br />
<br />
*Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
'''Metabolism'''<br />
<br />
*Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
'''Excretion'''<br />
<br />
*Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
'''Specific Populations'''<br />
<br />
'''Geriatric Patients'''<br />
<br />
*The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years).<br />
<br />
'''Pediatric Patients'''<br />
<br />
*The pharmacokinetics of mirabegron in pediatric patients have not been evaluated. <br />
<br />
'''Gender'''<br />
<br />
*The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
'''Race'''<br />
<br />
*The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
'''Renal Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
'''Hepatic Impairment'''<br />
<br />
*Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''Drug Interaction Studies'''<br />
<br />
'''In Vitro Studies'''<br />
<br />
'''Effect of Other Drugs on Mirabegron'''<br />
<br />
*Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
'''Effect of Mirabegron on Other Drugs'''<br />
<br />
*Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
'''In Vivo Studies'''<br />
<br />
*The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
*The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
*The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.<br />
<br />
*In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
*As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:<br />
<br />
:*Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
:*Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
*Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone.<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
*Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.<br />
<br />
*For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.<br />
<br />
* Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated.<br />
<br />
* Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention.<br />
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
'''Carcinogenicity'''<br />
<br />
*Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
'''Mutagenesis'''<br />
<br />
*Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
'''Impairment of Fertility'''<br />
<br />
*Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=* Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
*In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
*The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
*Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
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*Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
*Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
{{clear}}<br />
|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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|fdaPatientInfo=*See FDA-approved patient labeling (Patient Information)<br />
<br />
*Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
*Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
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[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
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<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_pdp_2.jpg&diff=1058758File:Mirabegron pdp 2.jpg2015-01-22T22:24:16Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058757Mirabegron2015-01-22T22:23:14Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
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<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
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<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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|fdaLIADPed======Condition1=====<br />
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:* Dosage<br />
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There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
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|offLabelPedGuideSupport======Condition1=====<br />
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* Developed by: <br />
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* Class of Recommendation: <br />
<br />
* Strength of Evidence: <br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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|offLabelPedNoGuideSupport======Condition1=====<br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Contraindications--><br />
|contraindications=* None.<br />
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<!--Warnings--><br />
|warnings=5.1 Increases in Blood Pressure<br />
<br />
Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology (12.2)].<br />
<br />
In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB<br />
<br />
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB [see Clinical Pharmacology (12.2)].<br />
<br />
5.3 Patients Taking Drugs Metabolized by CYP2D6<br />
<br />
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials=6.1 Clinical Trials Experience<br />
<br />
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
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Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
Cardiac disorders: palpitations, blood pressure increased [see Clinical Pharmacology (12.2)]<br />
<br />
Eye Disorders: glaucoma [see Clinical Pharmacology (12.2)]<br />
<br />
Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension<br />
<br />
Infections and Infestations: sinusitis, rhinitis<br />
<br />
Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
Renal and urinary disorders: nephrolithiasis, bladder pain<br />
<br />
Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection<br />
<br />
Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema<br />
<br />
Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
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In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
Urologic: urinary retention [see Warnings and Precautions (5.2)]<br />
|drugInteractions=Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
The following are drug interactions for which monitoring is recommended:<br />
<br />
7.1 Drugs Metabolized by CYP2D6<br />
<br />
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].<br />
<br />
7.2 Digoxin<br />
<br />
When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology (12.3)].<br />
<br />
7.3 Warfarin<br />
<br />
The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Clinical Pharmacology (12.3)].<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
Risk Summary<br />
<br />
Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
Animal Data<br />
<br />
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br />
|useInPed=The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age [see Clinical Pharmacology (12.3)]. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)].<br />
|useInHepaticImpair=Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose=Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
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|mechAction=Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
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<br />
Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD=Urodynamics<br />
<br />
The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2)].<br />
<br />
Cardiac Electrophysiology<br />
<br />
The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
Effects on Blood Pressure<br />
<br />
In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
Effect on Intraocular Pressure (IOP)<br />
<br />
Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
|PK=Absorption <br />
<br />
After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
Effect of Food<br />
<br />
Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose [see Dosage and Administration (2.1)]. <br />
<br />
Distribution<br />
<br />
Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
Metabolism<br />
<br />
Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
Excretion<br />
<br />
Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
<br />
<br />
Specific Populations<br />
<br />
Geriatric Patients<br />
<br />
The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years) [see Use in Specific Populations (8.5)]. <br />
<br />
Pediatric Patients<br />
<br />
The pharmacokinetics of mirabegron in pediatric patients have not been evaluated [see Use in Specific Populations (8.4)]. <br />
<br />
Gender<br />
<br />
The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
Race<br />
<br />
The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
Renal Impairment<br />
<br />
Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
Hepatic Impairment<br />
<br />
Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
Drug Interaction Studies<br />
<br />
In Vitro Studies<br />
<br />
Effect of Other Drugs on Mirabegron<br />
<br />
Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
Effect of Mirabegron on Other Drugs<br />
<br />
Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
In Vivo Studies<br />
<br />
The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.<br />
<br />
In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:<br />
<br />
Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
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<br />
(1) Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
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<br />
(1) Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].<br />
<br />
(2) For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Drug Interactions (7.2)].<br />
<br />
(3) Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Drug Interactions (7.3)].<br />
<br />
(4) Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
Carcinogenicity<br />
<br />
Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
Mutagenesis<br />
<br />
Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
Impairment of Fertility<br />
<br />
Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
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<br />
Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
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|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
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|fdaPatientInfo=See FDA-approved patient labeling (Patient Information)<br />
<br />
Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
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<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_medication_guide.png&diff=1058756File:Mirabegron medication guide.png2015-01-22T22:22:09Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_label.png&diff=1058755File:Mirabegron label.png2015-01-22T22:21:35Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_pdp.jpg&diff=1058754File:Mirabegron pdp.jpg2015-01-22T22:21:17Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_how_supplied.png&diff=1058753File:Mirabegron how supplied.png2015-01-22T22:21:00Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_8.png&diff=1058752File:Mirabegron fig 8.png2015-01-22T22:20:40Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_7.png&diff=1058751File:Mirabegron fig 7.png2015-01-22T22:20:23Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_2.png&diff=1058750File:Mirabegron fig 2.png2015-01-22T22:20:06Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_1.png&diff=1058749File:Mirabegron fig 1.png2015-01-22T22:19:49Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_6.png&diff=1058748File:Mirabegron fig 6.png2015-01-22T22:18:32Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_5.png&diff=1058747File:Mirabegron fig 5.png2015-01-22T22:18:15Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_4.png&diff=1058746File:Mirabegron fig 4.png2015-01-22T22:17:55Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_fig_3.png&diff=1058745File:Mirabegron fig 3.png2015-01-22T22:16:26Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_t_3.png&diff=1058744File:Mirabegron t 3.png2015-01-22T22:16:09Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_structure.jpg&diff=1058743File:Mirabegron structure.jpg2015-01-22T22:13:55Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_wiki.png&diff=1058742File:Mirabegron wiki.png2015-01-22T22:12:51Z<p>Deepika Beereddy: </p>
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<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058736Mirabegron2015-01-22T22:06:22Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
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<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
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* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
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:*'''Dose Adjustments in Specific Populations'''<br />
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:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
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:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
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<!--Off-Label Use and Dosage (Adult)--><br />
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<!--Guideline-Supported Use (Adult)--><br />
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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<!--Non–Guideline-Supported Use (Adult)--><br />
|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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<!--Pediatric Indications and Dosage--><br />
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<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed======Condition1=====<br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Off-Label Use and Dosage (Pediatric)--><br />
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<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport======Condition1=====<br />
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* Developed by: <br />
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* Class of Recommendation: <br />
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* Strength of Evidence: <br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport======Condition1=====<br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Contraindications--><br />
|contraindications=* None.<br />
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<!--Warnings--><br />
|warnings=5.1 Increases in Blood Pressure<br />
<br />
Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology (12.2)].<br />
<br />
In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB<br />
<br />
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB [see Clinical Pharmacology (12.2)].<br />
<br />
5.3 Patients Taking Drugs Metabolized by CYP2D6<br />
<br />
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
|clinicalTrials=6.1 Clinical Trials Experience<br />
<br />
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
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Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
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Cardiac disorders: palpitations, blood pressure increased [see Clinical Pharmacology (12.2)]<br />
<br />
Eye Disorders: glaucoma [see Clinical Pharmacology (12.2)]<br />
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Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension<br />
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Infections and Infestations: sinusitis, rhinitis<br />
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Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
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Renal and urinary disorders: nephrolithiasis, bladder pain<br />
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Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection<br />
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Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema<br />
<br />
Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
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In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).<br />
|postmarketing=Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
Urologic: urinary retention [see Warnings and Precautions (5.2)]<br />
|drugInteractions=Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended when these drugs are co-administered with mirabegron.<br />
<br />
The following are drug interactions for which monitoring is recommended:<br />
<br />
7.1 Drugs Metabolized by CYP2D6<br />
<br />
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].<br />
<br />
7.2 Digoxin<br />
<br />
When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology (12.3)].<br />
<br />
7.3 Warfarin<br />
<br />
The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Clinical Pharmacology (12.3)].<br />
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|FDAPregCat=C<br />
|useInPregnancyFDA=There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician.<br />
<br />
Risk Summary<br />
<br />
Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.<br />
<br />
Animal Data<br />
<br />
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.<br />
<br />
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.<br />
<br />
The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MHRD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD. <br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. <br />
|useInPed=The safety and effectiveness of Myrbetriq in pediatric patients have not been established.<br />
|useInGeri=No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age [see Clinical Pharmacology (12.3)]. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.<br />
|useInGender=No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or<br />
eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.<br />
<br />
In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)].<br />
|useInHepaticImpair=Myrbetriq has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.<br />
<br />
In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
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*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
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* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
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:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
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:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
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<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
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<!--Overdosage--><br />
|overdose=Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.<br />
|drugBox=[[File:Mirabegron wiki.png|600px|thumbnail|left]]<br />
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|mechAction=Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.<br />
|structure=Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:<br />
<br />
[[File:Mirabegron structure.jpg|600px|thumbnail|left]]<br />
{{clear}}<br />
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Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide.<br />
<br />
Each Myrbetriq extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only).<br />
|PD= Urodynamics<br />
<br />
The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2)].<br />
<br />
Cardiac Electrophysiology<br />
<br />
The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).<br />
<br />
For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).<br />
<br />
In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure).<br />
<br />
Effects on Blood Pressure<br />
<br />
In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.<br />
<br />
In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.<br />
<br />
In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.<br />
<br />
Effect on Intraocular Pressure (IOP)<br />
<br />
Myrbetriq 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of Myrbetriq on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of Myrbetriq 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between Myrbetriq 100 mg and placebo was 0.3 mm Hg.<br />
|PK= Absorption <br />
<br />
After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.<br />
<br />
Effect of Food<br />
<br />
Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose [see Dosage and Administration (2.1)]. <br />
<br />
Distribution<br />
<br />
Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.<br />
<br />
Metabolism<br />
<br />
Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. <br />
<br />
Excretion<br />
<br />
Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg 14C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.<br />
<br />
<br />
<br />
Specific Populations<br />
<br />
Geriatric Patients<br />
<br />
The Cmax and AUC of mirabegron following multiple oral doses in elderly volunteers (≥ 65 years) were similar to those in younger volunteers (18 to 45 years) [see Use in Specific Populations (8.5)]. <br />
<br />
Pediatric Patients<br />
<br />
The pharmacokinetics of mirabegron in pediatric patients have not been evaluated [see Use in Specific Populations (8.4)]. <br />
<br />
Gender<br />
<br />
The Cmax and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% - 30% higher in females compared to males. <br />
<br />
Race<br />
<br />
The pharmacokinetics of mirabegron were comparable between Caucasians and African American Blacks. Cross studies comparison shows that the exposure in Japanese subjects is higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference is smaller.<br />
<br />
Renal Impairment<br />
<br />
Following single dose administration of 100 mg mirabegron in volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in patients with End Stage Renal Disease-ESRD (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis).<br />
<br />
Hepatic Impairment<br />
<br />
Following single dose administration of 100 mg mirabegron in volunteers with mild hepatic impairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher. Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
Drug Interaction Studies<br />
<br />
In Vitro Studies<br />
<br />
Effect of Other Drugs on Mirabegron<br />
<br />
Mirabegron is transported and metabolized through multiple pathways. Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Sulfonylurea hypoglycemic agents glibenclamide (a CYP3A4 substrate), gliclazide (a CYP2C9 and CYP3A4 substrate) and tolbutamide (a CYP2C9 substrate) did not affect the in vitro metabolism of mirabegron.<br />
<br />
Effect of Mirabegron on Other Drugs<br />
<br />
Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is unlikely to inhibit the metabolism of co-administered drugs metabolized by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations. Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport. Mirabegron did not affect the metabolism of glibenclamide or tolbutamide.<br />
<br />
<br />
In Vivo Studies<br />
<br />
The effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs was studied after single and multiple doses of mirabegron. Most drug-drug interactions (DDI) were studied using mirabegron 100 mg extended-release tablets. However, interaction studies of mirabegron with metoprolol and with metformin were studied using mirabegron 160 mg immediate release (IR) tablets.<br />
<br />
The effect of ketoconazole, rifampicin, solifenacin, tamsulosin, and metformin on systemic mirabegron exposure is shown in Figure 1.<br />
<br />
The effect of mirabegron on metoprolol, desipramine, combined oral contraceptive-COC (ethinyl estradiol-EE, levonorgestrel-LNG), solifenacin, digoxin, warfarin, tamsulosin, and metformin is shown in Figure 2.<br />
<br />
In these studies, the largest increase in mirabegron systemic exposure was seen in the ketoconazole DDI study. As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects.<br />
<br />
As a moderate CYP2D6 inhibitor, mirabegron increased the systemic exposure to metoprolol and desipramine:<br />
<br />
Mirabegron increased the C max of metoprolol by 90% and metoprolol AUC by 229% after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet in 12 healthy male subjects administered before and concomitantly with mirabegron. <br />
Mirabegron increased the C max of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron in 28 male and female healthy subjects. <br />
<br />
Caution is advised if Myrbetriq is co-administered with CYP2D6 substrates such as metoprolol and desipramine, and especially narrow therapeutic index drugs, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].<br />
<br />
Figures 1 and 2 show the magnitude of these interactions on the pharmacokinetic parameters and the recommendations for dose adjustment, if any: <br />
<br />
[[File:Mirabegron fig 1.png|600px|thumbnail|left]]<br />
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<br />
(1) Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
<br />
[[File:Mirabegron fig 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
(1) Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].<br />
<br />
(2) For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be prescribed. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Drug Interactions (7.2)].<br />
<br />
(3) Warfarin was administered as a single 25 mg dose of the racemate (a mixture of R-warfarin and S-warfarin). Based on this single dose study, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Drug Interactions (7.3)].<br />
<br />
(4) Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in BOO because of the risk of urinary retention [see Warnings and Precautions (5.2)].<br />
|nonClinToxic=13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
Carcinogenicity<br />
<br />
Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.<br />
<br />
Mutagenesis<br />
<br />
Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.<br />
<br />
Impairment of Fertility<br />
<br />
Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.<br />
|clinicalStudies=Myrbetriq was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).<br />
<br />
In Study 1, patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq 50 mg or Myrbetriq 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq 25 mg or Myrbetriq 50 mg once daily.<br />
<br />
The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.<br />
<br />
Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.<br />
<br />
[[File:Mirabegron t 3.png|600px|thumbnail|left]]<br />
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<br />
Myrbetriq 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq was maintained through the 12-week treatment period.<br />
<br />
Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.<br />
<br />
[[File:Mirabegron fig 3.png|600px|thumbnail|left]]<br />
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[[File:Mirabegron fig 8.png|600px|thumbnail|left]]<br />
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|howSupplied=* Myrbetriq is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:<br />
<br />
[[File:Mirabegron how supplied.png|600px|thumbnail|left]]<br />
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|storage=* Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF). {see USP controlled Room Temperature}<br />
|packLabel=[[File:Mirabegron pdp.jpg|600px|thumbnail|left]]<br />
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[[File:Mirabegron label.png|600px|thumbnail|left]]<br />
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|fdaPatientInfo=See FDA-approved patient labeling (Patient Information)<br />
<br />
Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.<br />
<br />
Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq.<br />
<br />
[[File:Mirabegron medication guide.png|600px|thumbnail|left]]<br />
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
<!--Brand Names--><br />
|brandNames=Myrbetriq<br />
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref><br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_adverse_reactions_t_2.png&diff=1058718File:Mirabegron adverse reactions t 2.png2015-01-22T21:46:19Z<p>Deepika Beereddy: </p>
<hr />
<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=File:Mirabegron_adverse_reactions_t_1.png&diff=1058716File:Mirabegron adverse reactions t 1.png2015-01-22T21:46:02Z<p>Deepika Beereddy: </p>
<hr />
<div></div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058677Mirabegron2015-01-22T21:21:18Z<p>Deepika Beereddy: </p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
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<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
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|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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|offLabelAdultNoGuideSupport=* There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.<br />
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|fdaLIADPed======Condition1=====<br />
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* Dosing Information<br />
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:* Dosage<br />
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=====Condition2=====<br />
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There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.<br />
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|offLabelPedGuideSupport======Condition1=====<br />
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* Developed by: <br />
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* Class of Recommendation: <br />
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* Strength of Evidence: <br />
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* Dosing Information<br />
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:* Dosage<br />
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There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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* Dosing Information<br />
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:* Dosage<br />
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There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
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<!--Contraindications--><br />
|contraindications=* None.<br />
<br />
<!--Warnings--><br />
|warnings=5.1 Increases in Blood Pressure<br />
<br />
Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology (12.2)].<br />
<br />
In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.<br />
<br />
In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.<br />
<br />
5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB<br />
<br />
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB [see Clinical Pharmacology (12.2)].<br />
<br />
5.3 Patients Taking Drugs Metabolized by CYP2D6<br />
<br />
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.<br />
<br />
|clinicalTrials=6.1 Clinical Trials Experience<br />
<br />
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
<br />
In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).<br />
<br />
Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.<br />
<br />
The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.<br />
<br />
Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.<br />
<br />
Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.<br />
<br />
[[File:Mirabegron adverse reactions t 1.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included:<br />
<br />
Cardiac disorders: palpitations, blood pressure increased [see Clinical Pharmacology (12.2)]<br />
<br />
Eye Disorders: glaucoma [see Clinical Pharmacology (12.2)]<br />
<br />
Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension<br />
<br />
Infections and Infestations: sinusitis, rhinitis<br />
<br />
Investigations: GGT increased, AST increased, ALT increased, LDH increased<br />
<br />
Renal and urinary disorders: nephrolithiasis, bladder pain<br />
<br />
Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection<br />
<br />
Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema<br />
<br />
Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.<br />
<br />
[[File:Mirabegron adverse reactions t 2.png|600px|thumbnail|left]]<br />
{{clear}}<br />
<br />
In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq.<br />
<br />
In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.<br />
<br />
In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold). <br />
<br />
<br />
<br />
|postmarketing=Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.<br />
<br />
The following events have been reported in association with mirabegron use in worldwide postmarketing experience:<br />
<br />
Urologic: urinary retention [see Warnings and Precautions (5.2)] <br />
|drugInteractions=* Drug<br />
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<br />
<!--Use in Specific Populations--><br />
|useInPregnancyFDA=* '''Pregnancy Category'''<br />
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|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
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|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
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<br />
* Description<br />
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|overdose====Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
* Description<br />
<br />
====Management====<br />
<br />
* Description<br />
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===Chronic Overdose===<br />
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[[Category:Drug]]</div>Deepika Beereddyhttps://www.wikidoc.org/index.php?title=Mirabegron&diff=1058649Mirabegron2015-01-22T21:13:16Z<p>Deepika Beereddy: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{DB}}<br />
|genericName=Mirabegron<br />
|aOrAn=a<br />
|drugClass=beta-3 adrenergic agonist<br />
|indicationType=treatment<br />
|indication=overactive bladder (OAB) with symptoms of urge [[urinary incontinence]], [[urgency]], and [[urinary frequency]]<br />
|adverseReactions=[[hypertension]], [[nasopharyngitis]], [[urinary tract infection]] and [[headache]]<br />
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span><br />
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* Content<br />
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<!--Adult Indications and Dosage--><br />
<br />
<!--FDA-Labeled Indications and Dosage (Adult)--><br />
|fdaLIADAdult======Bladder muscle dysfunction - overactive, With symptoms of urge urinary incontinence, urgency, and urinary frequency=====<br />
<br />
* Dosing Information<br />
<br />
:*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
:*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
:*'''Dose Adjustments in Specific Populations'''<br />
<br />
:*The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:*Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
<!--Off-Label Use and Dosage (Adult)--><br />
<br />
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<!--FDA-Labeled Indications and Dosage (Pediatric)--><br />
|fdaLIADPed======Condition1=====<br />
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* Dosing Information<br />
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=====Condition2=====<br />
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<br />
<!--Off-Label Use and Dosage (Pediatric)--><br />
<br />
<!--Guideline-Supported Use (Pediatric)--><br />
|offLabelPedGuideSupport======Condition1=====<br />
<br />
* Developed by: <br />
<br />
* Class of Recommendation: <br />
<br />
* Strength of Evidence: <br />
<br />
* Dosing Information<br />
<br />
:* Dosage<br />
<br />
=====Condition2=====<br />
<br />
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Non–Guideline-Supported Use (Pediatric)--><br />
|offLabelPedNoGuideSupport======Condition1=====<br />
<br />
* Dosing Information<br />
<br />
:* Dosage<br />
<br />
=====Condition2=====<br />
<br />
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.<br />
<br />
<!--Contraindications--><br />
|contraindications=* Condition1<br />
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====Precautions====<br />
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* Description<br />
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<!--Adverse Reactions--><br />
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<!--Clinical Trials Experience--><br />
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.<br />
<br />
=====Body as a Whole=====<br />
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<br />
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=====Cardiovascular=====<br />
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=====Digestive=====<br />
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=====Endocrine=====<br />
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=====Hematologic and Lymphatic=====<br />
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=====Metabolic and Nutritional=====<br />
<br />
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=====Musculoskeletal=====<br />
<br />
<br />
<br />
<br />
=====Neurologic=====<br />
<br />
<br />
<br />
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=====Respiratory=====<br />
<br />
<br />
<br />
<br />
=====Skin and Hypersensitivy Reactions=====<br />
<br />
<br />
<br />
<br />
=====Special Senses=====<br />
<br />
<br />
<br />
<br />
=====Urogenital=====<br />
<br />
<br />
<br />
<br />
=====Miscellaneous=====<br />
<br />
<br />
<br />
<!--Postmarketing Experience--><br />
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.<br />
<br />
=====Body as a Whole=====<br />
<br />
<br />
<br />
=====Cardiovascular=====<br />
<br />
<br />
<br />
=====Digestive=====<br />
<br />
<br />
<br />
=====Endocrine=====<br />
<br />
<br />
<br />
=====Hematologic and Lymphatic=====<br />
<br />
<br />
<br />
=====Metabolic and Nutritional=====<br />
<br />
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<br />
=====Musculoskeletal=====<br />
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=====Neurologic=====<br />
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=====Respiratory=====<br />
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=====Skin and Hypersensitivy Reactions=====<br />
<br />
<br />
<br />
=====Special Senses=====<br />
<br />
<br />
<br />
=====Urogenital=====<br />
<br />
<br />
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=====Miscellaneous=====<br />
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<br />
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<!--Drug Interactions--><br />
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<br />
<!--Use in Specific Populations--><br />
|useInPregnancyFDA=* '''Pregnancy Category'''<br />
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''<br />
<br />
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.<br />
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.<br />
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.<br />
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.<br />
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.<br />
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.<br />
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.<br />
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.<br />
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.<br />
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.<br />
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.<br />
<br />
<!--Administration and Monitoring--><br />
|administration='''Dosing Information'''<br />
<br />
*The recommended starting dose of Myrbetriq is 25 mg once daily with or without food. Myrbetriq 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.<br />
<br />
*Myrbetriq should be taken with water, swallowed whole and should not be chewed, divided, or crushed.<br />
<br />
'''Dose Adjustments in Specific Populations'''<br />
<br />
* The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:<br />
<br />
:*Patients with severe renal impairment (CL cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m 2).<br />
<br />
:*Patients with moderate hepatic impairment (Child-Pugh Class B).<br />
<br />
:* Myrbetriq is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).<br />
<br />
'''DOSAGE FORMS AND STRENGTHS'''<br />
<br />
* Myrbetriq extended-release tablets are supplied in two different strengths as described below:<br />
<br />
:*25 mg oval, brown, film coated tablet, debossed with the Astellas logo (Astellas logo) and “325”<br />
<br />
:*50 mg oval, yellow, film coated tablet, debossed with theAstellas logo (Astellas logo) and "355"<br />
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.<br />
<br />
* Description<br />
<br />
<!--IV Compatibility--><br />
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Overdosage--><br />
|overdose====Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
* Description<br />
<br />
====Management====<br />
<br />
* Description<br />
<br />
===Chronic Overdose===<br />
<br />
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Pharmacology--><br />
<br />
<!--Drug box 2--><br />
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<!--Pharmacodynamics--><br />
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<br />
<!--Pharmacokinetics--><br />
|PK=There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.<br />
<br />
<!--Nonclinical Toxicology--><br />
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<br />
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<br />
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<br />
<!--Precautions with Alcohol--><br />
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<br />
<!--Brand Names--><br />
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[[Category:Drug]]</div>Deepika Beereddy