Cilostazol: Difference between revisions

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{{DrugProjectFormSinglePage
|authorTag={{AK}}
|genericName=Cilostazol
|aOrAn=a
|drugClass=Phosphodiesterase 3 inhibitor
|indication=Intermittent claudication
|hasBlackBoxWarning=Yes
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.
|blackBoxWarningTitle=<b><span style="color:#FF0000;"> Contraindication </span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i>Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV [[congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.
|fdaLIADAdult======Intermittent claudication 1=====


* Dosing Information
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====
* Developed by: American College of Chest Physicians
* Class of Recommendation: (Class II) (Link)
* Strength of Evidence: (Category C) (Link)
* Dosing Information/Recommendation
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal  | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref>
=====Thrombosis prophylaxis in percutaneous coronary intervention =====
* Developed by:  American College of Chest Physicians
* Class of Recommendation: (Class II) (Link)
* Strength of Evidence: (Category C) (Link)
* Dosing Information/Recommendation
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal  | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref>
|offLabelAdultNoGuideSupport======Secondary prevention of femoral artery occlusion after peripheral intervention=====
<ref name="Iida-2013">{{Cite journal  | last1 = Iida | first1 = O. | last2 = Yokoi | first2 = H. | last3 = Soga | first3 = Y. | last4 = Inoue | first4 = N. | last5 = Suzuki | first5 = K. | last6 = Yokoi | first6 = Y. | last7 = Kawasaki | first7 = D. | last8 = Zen | first8 = K. | last9 = Urasawa | first9 = K. | title = Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. | journal = Circulation | volume = 127 | issue = 23 | pages = 2307-15 | month = Jun | year = 2013 | doi = 10.1161/CIRCULATIONAHA.112.000711 | PMID = 23652861 }}</ref>
|fdaLIADPed=<b>Condition 1</b>
* Dosing Information
:: (Dosage)
|offLabelPedGuideSupport=<b>Condition 1</b>
* Developed by: (Organization)
* Class of Recommendation: (Class) (Link)
* Strength of Evidence: (Category A/B/C) (Link)
* Dosing Information/Recommendation
:* (Dosage)
|offLabelPedNoGuideSupport=<b>Condition 1</b>
* Dosing Information
:* There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Cilostazol in pediatric patients.
|contraindications=* [[congestive heart failure]].
* Haemostatic disorders or active pathologic bleeding.
* [[peptic ulcer]].
* [[Intracranial bleeding]].
* Hypersensitivity to any of its components.
|warnings======Hematologic Adverse Reactions=====
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.
=====Use with Clopidogrel=====
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.
======Body as a Whole======
*Common:
:*Abdominal pain
:*Back pain
:*Headache
:*Infection
*Less common:
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].
======Central Nervous System======
*Common:
:*Dizziness
:*Vertigo
*Less common:
[[Anxiety]], [[insomnia]], [[neuralgia]].
======Cardiovascular======
*Common:
:*Palpitation
:*Tachycardia
*Less common:
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].
======Respiratory======
*Common:
:*[[Cough]]
:*[[Pharyngitis]]
:*[[Rhinitis]]
*Less common:
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].
======Gastrointestinal======
*Common:
:*Abnormal stool
:*Diarrhea
:*Dyspepsia
:*Flatulence
:*Nausea
*Less common:
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.
======Hypersensitive Reactions======
: (list/description of adverse reactions)
======Metabolic & Nutritional======
*Common:
:*Peripheral edema
*Less common:
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].
======Musculoskeletal======
*Common:
:*Myalgia
*Less common:
[[Arthralgia]], bone pain, [[bursitis]].
======Miscellaneous======
Less common adverse reactions:
*'''Endocrine:''' [[Diabetes mellitus]].
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.
======Blood and lymphatic system disorders:======
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]],
[[bleeding tendency]]
======Cardiac disorders:======
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)
======Gastrointestinal disorders:======
*Gastrointestinal haemorrhage
======General disorders and administration site conditions:======
*Pain
*[[chest pain]]
*[[hot flushes]]
======Hepatobiliary disorders:======
*Hepatic dysfunction/abnormal liver function tests
*[[jaundice]]
======Injury, poisoning and procedural complications:======
*Extradural [[haematoma ]]
*Subdural haematoma
=====Investigations:=====
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase
======Nervous system disorders:======
*[[Intracranial haemorrhage]]
*[[cerebral haemorrhage]]
*[[cerebrovascular accident]]
======Respiratory, thoracic and mediastinal disorders:======
*Pulmonary haemorrhage
*[[ interstitial pneumonia]]
'''Skin and subcutaneous tissue disorders:'''
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])
======Vascular disorders:======
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)
|drugInteractions======Aspirin=====
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone.
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
=====Warfarin=====
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
=====Clopidogrel=====
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.
=====Inhibitors of CYP3A4=====
======Strong Inhibitors of CYP3A4======
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect
======Moderate Inhibitors of CYP3A4======
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.
=====Inhibitors of CYP2C19=====
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19
=====Quinidine =====
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.
=====Lovastatin=====
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.
|FDAPregCat=C
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).
There are no adequate and well-controlled studies in pregnant women.
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.
Special caution is advised when cilostazol is used in such patients.
|othersTitle=Smokers
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
|administration=Oral
====Discontinuation of Therapy====
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.
|drugBox={{Drugbox2
| verifiedrevid = 460037234
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone
| image = Cilostazol.JPG
| width = 300
<!--Clinical data-->
| tradename = Pletal
| Drugs.com = {{drugs.com|monograph|cilostazol}}
| MedlinePlus = a601038
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_category = 
| legal_AU = <!-- Unscheduled / S2 / S3 / S4  / S8 -->
| legal_UK = <!-- GSL        / P      / POM / CD -->
| legal_US = <!-- OTC                  / Rx-only  -->
| legal_status = 
| routes_of_administration = Oral
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 95–98%
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)
| elimination_half-life = 11–13 hours
| excretion = Renal
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 73963-72-1
| ATC_prefix = B01
| ATC_suffix = AC23
| PubChem = 2754
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01166
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2652
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = N7Z035406B
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01896
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 31401
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 799
<!--Chemical data-->
| C=20 | H=27 | N=5 | O=2
| molecular_weight = 369.46 g/mol
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N
}}
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).
====Cardiovascular Effects====
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below
{|
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]
|}
====Distribution====
'''Plasma Protein and Erythrocyte Binding'''
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
====Metabolism and Excretion====
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials
{|
| [[image:Cilo2.png|400px|thumb]]
|}
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.
*The corresponding changes in the placebo group were –10% to 41%.
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].
|packLabel={|
| [[image:Cilostazollabel.jpg|400px|thumb]]
|}
{|
| [[image:Cilostazollabel1.png|400px|thumb]]
|}
|fdaPatientInfo=(sil-OS-tah-zol)
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.
'''What is cilostazol for?'''
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.
What is intermittent claudication?
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.
'''What treatments are available for intermittent claudication?'''
The three main treatments available for intermittent claudication are:
*Exercise. Your doctor may advise an exercise program.
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.
'''How does cilostazol work?'''
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.
'''Who should not take cilostazol tablets?'''
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.
'''How should cilostazol tablets be taken?'''
*Follow your doctor’s advice about how to take cilostazol tablets.
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.
*Keep cilostazol tablets and all drugs out of the reach of children.
'''Can cilostazol tablets be taken with other drugs?'''
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.
Drugs Interacting with Cilostazol
Generic Name (Brand Names)Type of Drug
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal
[[diltiazem]] (Cardizem®) Antihypertensive
[[omeprazole]] (Prilosec®) Gastric acid reducer
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.
'''What are the possible side effects of cilostazol tablets?'''
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''
|alcohol=Alcohol-Cilostazol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|price=[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]
|nlmPatientInfo=For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500
|manBy=Sandoz Inc.Princeton, NJ 08540
|distBy=Bryant Ranch Prepack
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|pillImprint=E 123
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! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]
|-
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]
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|-
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]
|-
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]
|-
|}
<div style="width: 80%">
__NOTOC__
{{CMG}}
{{SB}} Cilostazol®, Pletal®
==Disclaimer==
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature.  The information provided is not a medical advice or treatment.  WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.
{| style="border: 3px solid #696969;"
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |
<center>
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font>
</center>
<center>
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font>
</center>
<font color="#F8F8FF" style="font-weight: bold;">
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.
</font>
|}
==Overview==
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of  intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.
==Adult Indications and Dosage==
===FDA-Labeled Indications and Dosage (Adult)===
=====Intermittent claudication=====
* Dosing Information
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
===Off-Label Use and Dosage (Adult)===
====Guideline-Supported Use====
=====Secondary prevention of stroke and TIA=====
* Developed by: American College of Chest Physicians
* Class of Recommendation: (Class II) (Link)
* Strength of Evidence: (Category C) (Link)
* Dosing Information/Recommendation
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal  | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref>
=====Condition 2=====
* Developed by:  American College of Chest Physicians
* Class of Recommendation: (Class II) (Link)
* Strength of Evidence: (Category C) (Link)
* Dosing Information/Recommendation
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal  | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref>
====Non–Guideline-Supported Use====
=====Condition 1=====
* Dosing Information
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.
=====Condition 2=====
* Dosing Information
:* (Dosage)
=====Condition 3=====
* Dosing Information
:* (Dosage)
==Pediatric Indications and Dosage==
The safety and effectiveness of cilostazol in pediatric patients have not been established.
==Contraindications==
* [[congestive heart failure]].
* Haemostatic disorders or active pathologic bleeding.
* [[peptic ulcer]].
* [[Intracranial bleeding]].
* Hypersensitivity to any of its components.
==Warnings==
=====Hematologic Adverse Reactions=====
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.
=====Use with Clopidogrel=====
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.
==Adverse Reactions==
===Clinical Trials Experience===
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.
======Body as a Whole======
*Common:
:*Abdominal pain
:*Back pain
:*Headache
:*Infection
*Less common:
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].
======Central Nervous System======
*Common:
:*Dizziness
:*Vertigo
*Less common:
[[Anxiety]], [[insomnia]], [[neuralgia]].
======Cardiovascular======
*Common:
:*Palpitation
:*Tachycardia
*Less common:
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].
======Respiratory======
*Common:
:*[[Cough]]
:*[[Pharyngitis]]
:*[[Rhinitis]]
*Less common:
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].
======Gastrointestinal======
*Common:
:*Abnormal stool
:*Diarrhea
:*Dyspepsia
:*Flatulence
:*Nausea
*Less common:
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.
======Hypersensitive Reactions======
: (list/description of adverse reactions)
======Metabolic & Nutritional======
*Common:
:*Peripheral edema
*Less common:
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].
======Musculoskeletal======
*Common:
:*Myalgia
*Less common:
[[Arthralgia]], bone pain, [[bursitis]].
======Miscellaneous======
Less common adverse reactions:
*'''Endocrine:''' [[Diabetes mellitus]].
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.
===Postmarketing Experience===
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.
======Blood and lymphatic system disorders:======
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]],
[[bleeding tendency]]
======Cardiac disorders:======
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)
======Gastrointestinal disorders:======
*Gastrointestinal haemorrhage
======General disorders and administration site conditions:======
*Pain
*[[chest pain]]
*[[hot flushes]]
======Hepatobiliary disorders:======
*Hepatic dysfunction/abnormal liver function tests
*[[jaundice]]
======Injury, poisoning and procedural complications:======
*Extradural [[haematoma ]]
*Subdural haematoma
=====Investigations:=====
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase
======Nervous system disorders:======
*[[Intracranial haemorrhage]]
*[[cerebral haemorrhage]]
*[[cerebrovascular accident]]
======Respiratory, thoracic and mediastinal disorders:======
*Pulmonary haemorrhage
*[[ interstitial pneumonia]]
'''Skin and subcutaneous tissue disorders:'''
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])
======Vascular disorders:======
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)
==Drug Interactions==
=====Aspirin=====
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone.
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
=====Warfarin=====
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
=====Clopidogrel=====
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.
=====Inhibitors of CYP3A4=====
======Strong Inhibitors of CYP3A4======
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect
======Moderate Inhibitors of CYP3A4======
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.
=====Inhibitors of CYP2C19=====
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19
=====Quinidine =====
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.
=====Lovastatin=====
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.
==Use in Specific Populations==
====Pregnancy====
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).
There are no adequate and well-controlled studies in pregnant women.
====Labor and Delivery====
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"
====Nursing Mothers====
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.
====Pediatric Use====
The safety and effectiveness of cilostazol in pediatric patients have not been established.
====Geriatric Use====
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.
====Gender====
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range
====Race====
(Description)
====Renal Impairment====
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.
====Hepatic Impairment====
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.
Special caution is advised when cilostazol is used in such patients.
====Carcinogenesis, Mutagenesis, Impairment of Fertility====
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.
====Immunocompromised Patients====
(Description)
====Miscellaneous====
=====Smokers=====
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
==Administration and Monitoring==
====Administration====
Oral
====Monitoring====
FDA package insert does't contain any information regarding "'''Monitoring'''"
====Discontinuation of Therapy====
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).
==IV Compatibility==
FDA package insert doesn't contain any information regarding '''IV Compatibility'''
==Overdosage==
===Acute Overdose===
====Signs and Symptoms====
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.
====Management====
FDA package insert doesn't contain any information regarding "'''Management '''"
==Pharmacology==
{{Drugbox2
| verifiedrevid = 460037234
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone
| image = Cilostazol.JPG
| width = 300
<!--Clinical data-->
| tradename = Pletal
| Drugs.com = {{drugs.com|monograph|cilostazol}}
| MedlinePlus = a601038
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_category = 
| legal_AU = <!-- Unscheduled / S2 / S3 / S4  / S8 -->
| legal_UK = <!-- GSL        / P      / POM / CD -->
| legal_US = <!-- OTC                  / Rx-only  -->
| legal_status = 
| routes_of_administration = Oral
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 95–98%
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)
| elimination_half-life = 11–13 hours
| excretion = Renal
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 73963-72-1
| ATC_prefix = B01
| ATC_suffix = AC23
| PubChem = 2754
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01166
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2652
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = N7Z035406B
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01896
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 31401
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 799
<!--Chemical data-->
| C=20 | H=27 | N=5 | O=2
| molecular_weight = 369.46 g/mol
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N
}}
===Mechanism of Action===
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).
====Cardiovascular Effects====
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.
===Structure===
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.
===Pharmacodynamics===
(Description)
===Pharmacokinetics===
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below
{|
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]
|}
====Distribution====
'''Plasma Protein and Erythrocyte Binding'''
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
====Metabolism and Excretion====
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
===Nonclinical Toxicology===
==Clinical Studies==
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials
{|
| [[image:Cilo2.png|400px|thumb]]
|}
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.
*The corresponding changes in the placebo group were –10% to 41%.
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.
==How Supplied==
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:
* National Drug Code (NDC):  0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].
* Manufactured by: Sandoz Inc.Princeton, NJ 08540
* Distributed by:Bryant Ranch Prepack
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].
* Manufactured by: Sandoz Inc.Princeton, NJ 08540
* Distributed by:Bryant Ranch Prepack
==Images==
===Drug Images===
{|
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;">
'''Drug Name''':  Cilostazol 50 MG Oral Tablet  <BR>
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR>
'''Imprint''':  E;123 <BR>
'''Color(s)''':  White<BR>
'''Shape''': Round <BR>
'''Size (mm)''': 9 mm <BR>
'''Score''': 1 <BR>
'''Drug Label Author''': Bryant Ranch Prepack ]]</p>
|}
{|
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;">
'''Drug Name''':  Cilostazol 100 MG Oral Tablet  <BR>
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR>
'''Imprint''':  E;223 <BR>
'''Color(s)''':  White<BR>
'''Shape''': Round <BR>
'''Size (mm)''': 9 mm <BR>
'''Score''': 1 <BR>
'''Drug Label Author''': Bryant Ranch Prepack ]]</p>
|}
===Package and Label Display Panel===
Sandoz Inc.
Princeton, NJ 08540
OS8128
Rev. 02/13
MF0223REV02/13
Cilostazol 100mg Tablet
{|
| [[image:Cilostazollabel.jpg|400px|thumb]]
|}
{|
| [[image:Cilostazollabel1.png|400px|thumb]]
|}
==Patient Information==
===Patient Information from FDA===
(sil-OS-tah-zol)
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.
What is cilostazol for?
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.
What is intermittent claudication?
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.
'''What treatments are available for intermittent claudication?'''
The three main treatments available for intermittent claudication are:
*Exercise. Your doctor may advise an exercise program.
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.
'''How does cilostazol work?'''
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.
'''Who should not take cilostazol tablets?'''
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.
'''How should cilostazol tablets be taken?'''
*Follow your doctor’s advice about how to take cilostazol tablets.
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.
*Keep cilostazol tablets and all drugs out of the reach of children.
'''Can cilostazol tablets be taken with other drugs?'''
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.
Drugs Interacting with Cilostazol
Generic Name (Brand Names)Type of Drug
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal
[[diltiazem]] (Cardizem®) Antihypertensive
[[omeprazole]] (Prilosec®) Gastric acid reducer
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.
'''What are the possible side effects of cilostazol tablets?'''
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''
===Patient Information from NLM===
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].
==Precautions with Alcohol==
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
==Brand Names==
Cilostazol®, Platel®.
==Look-Alike Drug Names==
* (Paired Confused Name 1a) — (Paired Confused Name 1b)
* (Paired Confused Name 2a) — (Paired Confused Name 2b)
* (Paired Confused Name 3a) — (Paired Confused Name 3b)
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==
==References==
{{reflist}}
</div>

Revision as of 22:02, 27 June 2014

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