Nitroglycerin (Topical ointment): Difference between revisions

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<!--Overview-->
<!--Overview-->


|genericName=
|genericName=nitroglycerin (ointment)




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|hasBlackBoxWarning=
|hasBlackBoxWarning=


Yes
 


|adverseReactions=
|adverseReactions=
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|fdaLIADAdult=
|fdaLIADAdult=
 
*RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.
=====Dosage=====
*Apply 1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks. A finger covering, such as plastic-wrap, disposable surgical glove or a finger cot, should be placed on the finger to apply the ointment. To obtain a 1.5 mg dose of nitroglycerin, the covered finger is laid alongside the 1 inch dosing line on the carton.
: [[File:{{PAGENAME}}02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
*Refer to carton for accurate dosage guide.
*The tube is gently squeezed until a line of ointment the length of the measuring line is expressed onto the covered finger. The ointment is gently inserted into the anal canal using the covered finger no further than to the first finger joint and the ointment is applied around the side of the anal canal. If this cannot be achieved due to pain, application of the ointment should be made directly to the outside of the anus. Treatment may be continued for up to three weeks.
*RECTIV ointment is not for oral, ophthalmic, or intravaginal use. Hands should be washed after application of the ointment.


<!--Off-Label Use and Dosage (Adult)-->
<!--Off-Label Use and Dosage (Adult)-->
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|offLabelPedGuideSupport=
|offLabelPedGuideSupport=


=====Condition1=====


* Developed by:
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.


* Class of Recommendation:
<!--Non–Guideline-Supported Use (Pediatric)-->


* Strength of Evidence:
|offLabelPedNoGuideSupport=


* Dosing Information


:* Dosage


=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Contraindications-->


There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
|contraindications=


<!--Non–Guideline-Supported Use (Pediatric)-->
=====PDE5 inhibitor use=====


|offLabelPedNoGuideSupport=
*Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see 7.1 DRUG INTERACTIONS].


=====Condition1=====
=====Severe anemia


* Dosing Information
=====


:* Dosage
*RECTIV is contraindicated in patients with severe anemia.


=====Condition2=====
=====Increased intracranial pressure


There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
=====


<!--Contraindications-->
*RECTIV is contraindicated in patients with increased intracranial pressure.


|contraindications=
=====Hypersensitivity


* Condition1
=====


*RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates.
<!--Warnings-->
<!--Warnings-->


|warnings=
|warnings=


* Description
=====Cardiovascular disorders=====
 
*Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly.


====Precautions====
=====Headache=====


* Description
*RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.


<!--Adverse Reactions-->
<!--Adverse Reactions-->
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|clinicalTrials=
|clinicalTrials=
*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 practice.


*Adverse reactions to nitroglycerin are generally dose-related, and almost all of these reactions are the result of nitroglycerin's activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each, daily dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon.
*The most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache.


*Allergic reactions to nitroglycerin are also uncommon, and the great majority of those reported have been cases of contact dermatitis or fixed drug eruptions in patients receiving nitroglycerin in ointments or patches. There have been a few reports of genuine anaphylactoid reactions, and these reactions can probably occur in patients receiving nitroglycerin by any route.
*Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment.


*Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients; for further discussion of its diagnosis and treatment, see OVERDOSAGE.
*In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1):


*Data are not available to allow estimation of the frequency of adverse reactions during treatment with Nitroglycerin Extended-Release Capsules.
: [[File:{{PAGENAME}}03.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
=====Hypotension=====
*Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy.


=====Allergic Reactions=====
*Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.
=====Methemoglobinemia=====
*In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia
<!--Postmarketing Experience-->
<!--Postmarketing Experience-->


|postmarketing=
|postmarketing=
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.


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=====Musculoskeletal=====






=====Neurologic=====
<!--Drug Interactions-->


|drugInteractions=


=====PDE5 inhibitors=====


=====Respiratory=====
*Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.


*The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated.


=====Antihypertensives=====


=====Skin and Hypersensitivy Reactions=====
*Patients receiving antihypertensive drugs, beta-adrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.


*Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur.


=====Aspirin=====


=====Special Senses=====
*Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin.


=====Tissue-type Plasminogen Activator (t-PA)=====


*Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy.


=====Urogenital=====
=====Heparin=====


*Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked.


=====Ergotamine=====


=====Miscellaneous=====
*Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore the possibility of ergotism in patients receiving RECTIV should be considered.


=====Alcohol=====


*The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.<!--Use in Specific Populations-->


<!--Drug Interactions-->
|useInPregnancyFDA=
*Pregnancy Category CAnimal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


|drugInteractions=
*Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested.


* Drug
*A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin.
:* Description
|useInPregnancyAUS=
 
<!--Use in Specific Populations-->
 
|useInPregnancyFDA=
* '''Pregnancy Category'''


|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''


There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
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|useInNursing=
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
*It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman.
 
|useInPed=
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
*The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established.
 
|useInGeri=
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
*Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
 
|useInGender=
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
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|overdose=
|overdose=


Hemodynamic Effects: The ill effects of nitroglycerin overdose are generally the result of nitroglycerin's capacity to induce vasodilation, venous pooling, reduced cardiac output, and hypotension, These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.
*Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered.
 
*Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose.


Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose.
*No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis.


No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which – if any – of these substances can usefully be removed from the body by hemodialysis.
*No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.


No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been the subject of controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patients legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.
*The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended.


The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.
*In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required.


In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
=====Methemoglobinemia=====


Methemoglobinemia: Nitrate ions liberated during metabolism of nitroglycerin can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity; however, and even assuming that the nitrate moieties of nitroglycerin are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of nitroglycerin should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of nitroglycerin. In one study in which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr, the average methemoglobin level measured 0.2%; this was comparable to that observed in parallel patients who received placebo.
*Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.


Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible. Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial p02. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.
*If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.


When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.
<!--Pharmacology-->
<!--Pharmacology-->


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|mechAction=
|mechAction=


* The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle and consequent dilation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined. Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates had been absent from the body for several hours was their anti-anginal efficacy restored.
* Nitroglycerin forms free radical nitric oxide (NO), which activates guanylate cyclase, resulting in an increase of guanosine 3',5'-monophosphate (cyclic GMP) in smooth muscle and other tissues. This leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.
 
<!--Structure-->
<!--Structure-->


|structure=
|structure=


* Nitroglycerin is 1,2,3-propanetriol trinitrate, an organic nitrate whose structural formula is:
*Nitroglycerin is 1,2,3,-propanetriol trinitrate, an organic nitrate whose structural formula is as follows:
 
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
*The organic nitrates are vasodilators, active on both arteries and veins. Each Extended-Release Capsule, for oral administration contains 2.5 mg, 6.5 mg, or 9 mg of Nitroglycerin.
and whose molecular weight is 227.09. RECTIV (nitroglycerin) Ointment 0.4% contains 0.4% nitroglycerin w/w (4 mg nitroglycerin/1 g ointment), propylene glycol, lanolin, sorbitan sesquioleate, paraffin wax, and white petrolatum. RECTIV (nitroglycerin) Ointment 0.4% is available in tubes with a one-inch dosing line on the carton allowing the measurement of approximately 375 mg of nitroglycerin ointment 0.4% (1.5 mg nitroglycerin) for application.
 
*The inactive ingredients in each capsule are corn starch, ethylcellulose, gelatin, lactose monohydrate, pharmaceutical glaze, sugar, talc, and wax. Additionally the 2.5 mg capsule contains FD&C Blue #1, D&C Yellow #10, FD&C Red #40, D&C Red #28; the 6.5 mg capsule contains D&C Yellow #10, FD&C Yellow #6, FD&C Blue #1, D&C Red #33; the 9 mg capsule contains D&C Yellow #10, FD&C Yellow #6, FD&C Green #3, and titanium dioxide.
 
<!--Pharmacodynamics-->
<!--Pharmacodynamics-->
|PD=
|PD=


There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
*The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Intra-anal application of nitroglycerin reduces sphincter tone and resting intra-anal pressure.
 
<!--Pharmacokinetics-->
<!--Pharmacokinetics-->


|PK=
|PK=


*The volume of distribution of nitroglycerin is about 3 L/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. *The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow; known sites of extrahepatic metabolism include red blood cells and vascular walls.
*Absorption: In six healthy subjects, the average absolute bioavailability of nitroglycerin applied to the anal canal as a 0.2% w/w ointment was approximately 50% of the 0.75 mg nitroglycerin dose.


*The first products in the metabolism of nitroglycerin are inorganic nitrate, and the 1,2- and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than nitroglycerin, but they are longer-lived in the serum, and their net contribution to the overall effect of chronic nitroglycerin regimens is not known. The dinitrates are further metabolized to (non-vasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide.
*Distribution: The volume of distribution of nitroglycerin following intravenous administration is about 3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60% and 30%, respectively.


*To avoid development of tolerance to nitroglycerin, drug-free intervals of 10-12 hours are known to be sufficient; shorter intervals have not been well studied. In one well-controlled clinical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo.
*Metabolism: Nitroglycerin is metabolized by a liver reductase enzyme to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to nitroglycerin, the two major metabolites, 1,2- and 1,3- dinitroglycerols are found in plasma. The contribution of metabolites to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide.
 
*Reliable assay techniques for plasma nitroglycerin levels have only recently become available, and studies using these techniques to define the pharmacokinetics of oral nitroglycerin preparations have not been reported. Published studies using older techniques provide results that often differ, in similar experimental settings, by an order of magnitude.
<!--Nonclinical Toxicology-->


*Elimination: Metabolism is the primary route of drug elimination. Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of two to three minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow.<!--Nonclinical Toxicology-->
|nonClinToxic=
|nonClinToxic=
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====


There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
*Animal carcinogenicity studies with topically applied nitroglycerin have not been performed.


<!--Clinical Studies-->
*Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At the highest dose, the incidence of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidence of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.


|clinicalStudies=
*Nitroglycerin was mutagenic in the in vitro bacterial reverse mutation (Ames) assay with Salmonella typhimurium. A similar mutation in this S. typhimurium was also reported with other NO donors. There was no evidence of clastogenic potential in multiple assays including a rodent dominant lethal assay, an in vitro Chinese Hamster Ovary assay that was conducted in the absence of metabolic activation, and several in vivo chromosomal aberration assays conducted in rats and dogs.


*Controlled trials of single oral doses of nitroglycerin have demonstrated that nitroglycerin capsules can effectively reduce exercise-related angina for up to 5 hours. Anti-anginal activity is present about 1 hour after ingestion of a capsule.
*In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to approximately 434 mg/kg/day for 6 months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.


*Controlled trials of multiple-dose oral nitroglycerin have shown statistically significant anti-anginal efficacy 2½ and 4 hours after a dose when oral nitroglycerin had been administered four times a day for 2 weeks or three times a day for 1 week. As noted above, careful studies with other formulations of nitroglycerin have shown that maintenance of continuous 24-hour plasma levels of nitroglycerin results in insurmountable tolerance. Presumably, the studied 1-week and 2-week regimens of oral nitroglycerin therapy achieved adequate nitrate-free intervals by non-uniformity of dosing interval, with longer intervals overnight. The investigators did not report how subjects interpreted their dosing instructions, and they similarly did not report which dose of the day was the one after which they obtained the end-of-trial exercise results.
<!--Clinical Studies-->


*Thus, these studies of oral nitroglycerin should not be interpreted as demonstrations that these regimens provide round-the-clock anti-anginal protection. From large, well-controlled studies of other nitroglycerin formulations, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from Nitroglycerin Extended-Release Capsules is about 12 hours.
|clinicalStudies=


*In some controlled trials of other organic nitrate formulations, efficacy has declined with time. Because the controlled, multiple-dose trials of oral nitroglycerin did not include exercise tests before the last day of treatment, it is not known how the efficacy of Nitroglycerin Extended-Release Capsules may vary during extended therapy.
*RECTIV ointment was evaluated in a 3-week double-blind, randomized, multi-center, placebo-controlled study. Patients with a painful chronic anal fissure for at least 6 weeks and moderate or severe pain prior to treatment (≥ 50 mm on the 100 mm visual analog scale, VAS) were randomized to receive 0.4% (1.5 mg) nitroglycerin or placebo ointment applied to the anal canal every 12 hours. Pain as assessed by the change in VAS from baseline to Days 14-18 was lower in patients receiving 0.4% ointment compared to placebo. The mean change from baseline was 44 mm for RECTIV and 37 mm for placebo. The difference in the mean change in pain between RECTIV and placebo was -7.0 mm (95% Confidence Interval: -13.6 to -0.4 mm).
<!--How Supplied-->
<!--How Supplied-->


|howSupplied=
|howSupplied=


*  
*RECTIV (nitroglycerin) Ointment 0.4% is available in 30 g (NDC 42747-235-30) aluminum tubes with polyethylene screw caps.
*Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
 
*Keep the tube tightly closed. Use within 8 weeks of first opening.


<!--Patient Counseling Information-->
<!--Patient Counseling Information-->


|fdaPatientInfo=
|fdaPatientInfo=
=====Interaction with PDE5 inhibitors=====
*Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs.
=====Hypotension=====
*Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly.
=====Headaches=====
*Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops. Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches.
=====Dizziness=====
*Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV.


There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
*Advise patients not to drive or operate machinery immediately after applying RECTIV.


=====FDA-Approved Patient Labeling=====
<!--Precautions with Alcohol-->
<!--Precautions with Alcohol-->


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|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>


<!--Drug Shortage Status-->
<!--Drug Shortage Status-->
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{{LabelImage
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Revision as of 14:35, 29 April 2015

Nitroglycerin (Topical ointment)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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Overview

Nitroglycerin (Topical ointment) is a that is FDA approved for the {{{indicationType}}} of . Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.
Dosage
  • Apply 1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks. A finger covering, such as plastic-wrap, disposable surgical glove or a finger cot, should be placed on the finger to apply the ointment. To obtain a 1.5 mg dose of nitroglycerin, the covered finger is laid alongside the 1 inch dosing line on the carton.
This image is provided by the National Library of Medicine.
  • Refer to carton for accurate dosage guide.
  • The tube is gently squeezed until a line of ointment the length of the measuring line is expressed onto the covered finger. The ointment is gently inserted into the anal canal using the covered finger no further than to the first finger joint and the ointment is applied around the side of the anal canal. If this cannot be achieved due to pain, application of the ointment should be made directly to the outside of the anus. Treatment may be continued for up to three weeks.
  • RECTIV ointment is not for oral, ophthalmic, or intravaginal use. Hands should be washed after application of the ointment.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nitroglycerin (Topical ointment) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitroglycerin (Topical ointment) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Nitroglycerin (Topical ointment) in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Nitroglycerin (Topical ointment) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitroglycerin (Topical ointment) in pediatric patients.

Contraindications

PDE5 inhibitor use
  • Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see 7.1 DRUG INTERACTIONS].

=====Severe anemia

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  • RECTIV is contraindicated in patients with severe anemia.

=====Increased intracranial pressure

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  • RECTIV is contraindicated in patients with increased intracranial pressure.

=====Hypersensitivity

=

  • RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

Warnings

Cardiovascular disorders
  • Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly.
Headache
  • RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

Adverse Reactions

Clinical Trials Experience

  • 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 practice.
  • The most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache.
  • Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment.
  • In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1):
This image is provided by the National Library of Medicine.
Hypotension
  • Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy.
Allergic Reactions
  • Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.
Methemoglobinemia
  • In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Nitroglycerin (Topical ointment) in the drug label.

Drug Interactions

PDE5 inhibitors
  • Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.
  • The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated.
Antihypertensives
  • Patients receiving antihypertensive drugs, beta-adrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.
  • Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur.
Aspirin
  • Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin.
Tissue-type Plasminogen Activator (t-PA)
  • Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy.
Heparin
  • Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked.
Ergotamine
  • Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore the possibility of ergotism in patients receiving RECTIV should be considered.
Alcohol
  • The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category CAnimal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested.
  • A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitroglycerin (Topical ointment) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Nitroglycerin (Topical ointment) during labor and delivery.

Nursing Mothers

  • It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman.

Pediatric Use

  • The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established.

Geriatic Use

  • Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Nitroglycerin (Topical ointment) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Nitroglycerin (Topical ointment) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Nitroglycerin (Topical ointment) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Nitroglycerin (Topical ointment) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Nitroglycerin (Topical ointment) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Nitroglycerin (Topical ointment) in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Nitroglycerin (Topical ointment) in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Nitroglycerin (Topical ointment) in the drug label.

Overdosage

  • Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered.
  • Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose.
  • No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis.
  • No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.
  • The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended.
  • In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
Methemoglobinemia
  • Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.
  • If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

Pharmacology

There is limited information regarding Nitroglycerin (Topical ointment) Pharmacology in the drug label.

Mechanism of Action

  • Nitroglycerin forms free radical nitric oxide (NO), which activates guanylate cyclase, resulting in an increase of guanosine 3',5'-monophosphate (cyclic GMP) in smooth muscle and other tissues. This leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.

Structure

  • Nitroglycerin is 1,2,3,-propanetriol trinitrate, an organic nitrate whose structural formula is as follows:
This image is provided by the National Library of Medicine.

and whose molecular weight is 227.09. RECTIV (nitroglycerin) Ointment 0.4% contains 0.4% nitroglycerin w/w (4 mg nitroglycerin/1 g ointment), propylene glycol, lanolin, sorbitan sesquioleate, paraffin wax, and white petrolatum. RECTIV (nitroglycerin) Ointment 0.4% is available in tubes with a one-inch dosing line on the carton allowing the measurement of approximately 375 mg of nitroglycerin ointment 0.4% (1.5 mg nitroglycerin) for application.

Pharmacodynamics

  • The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Intra-anal application of nitroglycerin reduces sphincter tone and resting intra-anal pressure.

Pharmacokinetics

  • Absorption: In six healthy subjects, the average absolute bioavailability of nitroglycerin applied to the anal canal as a 0.2% w/w ointment was approximately 50% of the 0.75 mg nitroglycerin dose.
  • Distribution: The volume of distribution of nitroglycerin following intravenous administration is about 3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60% and 30%, respectively.
  • Metabolism: Nitroglycerin is metabolized by a liver reductase enzyme to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to nitroglycerin, the two major metabolites, 1,2- and 1,3- dinitroglycerols are found in plasma. The contribution of metabolites to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide.
  • Elimination: Metabolism is the primary route of drug elimination. Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of two to three minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Animal carcinogenicity studies with topically applied nitroglycerin have not been performed.
  • Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At the highest dose, the incidence of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidence of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.
  • Nitroglycerin was mutagenic in the in vitro bacterial reverse mutation (Ames) assay with Salmonella typhimurium. A similar mutation in this S. typhimurium was also reported with other NO donors. There was no evidence of clastogenic potential in multiple assays including a rodent dominant lethal assay, an in vitro Chinese Hamster Ovary assay that was conducted in the absence of metabolic activation, and several in vivo chromosomal aberration assays conducted in rats and dogs.
  • In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to approximately 434 mg/kg/day for 6 months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.

Clinical Studies

  • RECTIV ointment was evaluated in a 3-week double-blind, randomized, multi-center, placebo-controlled study. Patients with a painful chronic anal fissure for at least 6 weeks and moderate or severe pain prior to treatment (≥ 50 mm on the 100 mm visual analog scale, VAS) were randomized to receive 0.4% (1.5 mg) nitroglycerin or placebo ointment applied to the anal canal every 12 hours. Pain as assessed by the change in VAS from baseline to Days 14-18 was lower in patients receiving 0.4% ointment compared to placebo. The mean change from baseline was 44 mm for RECTIV and 37 mm for placebo. The difference in the mean change in pain between RECTIV and placebo was -7.0 mm (95% Confidence Interval: -13.6 to -0.4 mm).

How Supplied

  • RECTIV (nitroglycerin) Ointment 0.4% is available in 30 g (NDC 42747-235-30) aluminum tubes with polyethylene screw caps.
  • Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
  • Keep the tube tightly closed. Use within 8 weeks of first opening.

Storage

There is limited information regarding Nitroglycerin (Topical ointment) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Interaction with PDE5 inhibitors
  • Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs.
Hypotension
  • Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly.
Headaches
  • Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops. Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches.
Dizziness
  • Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV.
  • Advise patients not to drive or operate machinery immediately after applying RECTIV.
FDA-Approved Patient Labeling

Precautions with Alcohol

  • Alcohol-Nitroglycerin (Topical ointment) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Nitroglycerin (Topical ointment) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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