DailyMed Label: Nitroglycerin Transdermal Delivery System

DailyMed Label: Nitroglycerin Transdermal Delivery System

2009

DailyMed Prescription

Nitroglycerin Transdermal Delivery System

nitroglycerin

Graceway Pharmaceuticals, LLC

NDC: 29336-321

NDC: 29336-321

NDC: 29336-322

NDC: 29336-322

NDC: 29336-323

NDC: 29336-323

NDC: 29336-324

NDC: 29336-324

Nitroglycerin is a 1,2,3-propanetriol trinitrate, an organic nitrate whose structural formula is and whose molecular weight is 227.09. The organic nitrates are vasodilators, active on both arteries and veins. The Nitroglycerin Transdermal Delivery System is a unit designed to provide continuous controlled release of nitroglycerin through intact skin. The rate of release of nitroglycerin is linearly dependent upon the area of the applied system; each cm 2 of applied system delivers approximately 0.03 mg of nitroglycerin per hour. Thus, the 3.3, 6.7, 13.3 and 20 cm 2 system delivers approximately 0.1, 0.2, 0.4 and 0.6 mg of nitroglycerin per hour, respectively. The remainder of the nitroglycerin in each system serves as a reservoir and is not delivered in normal use. After 12 hours, for example, each system has delivered about 14% of its original content of nitroglycerin. The Nitroglycerin Transdermal Delivery System contains nitroglycerin as the active component. The remaining components of the system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive. Each patch is packaged in foil/polymer film laminate. Prior to use, a protective peel strip is removed from the adhesive surface. Following use, the patch should be discarded in a manner that prevents accidental application or ingestion by children or others.

Transdermal nitroglycerin is indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute attack.

The suggested starting dose is between 0.2 mg/hr and 0.4 mg/hr. Doses between 0.4 mg/hr and 0.8 mg/hr have shown continued effectiveness for 10-12 hours daily for at least one month (the longest period studied) of intermittent administration. Although the minimum nitrate-free interval has not been defined, data show that a nitrate-free interval of 10-12 hours is sufficient (see CLINICAL PHARMACOLOGY ). Thus, an appropriate dosing schedule for nitroglycerin patches would include a daily patch-on period of 12-14 hours and a daily patch-off period of 10-12 hours. Although some well-controlled clinical trials using exercise tolerance testing have shown maintenance of effectiveness when patches are worn continuously, the large majority of such controlled trials have shown the development of tolerance (i.e., complete loss of effect) within the first 24 hours after therapy was initiated. Dose adjustment, even to levels much higher than generally used, did not restore efficacy.

Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin is contraindicated in patients who are allergic to it. Allergy to the adhesives used in nitroglycerin patches has also been reported, and it similarly constitutes a contraindication to the use of this product.

Severe hypotension, particularly with upright posture, may occur with even small doses of nitroglycerin. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. As tolerance to other forms of nitroglycerin develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted. In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. Several clinical trials in patients with angina pectoris have evaluated nitroglycerin regimens which incorporated a 10-12 hour nitrate-free interval. In some of these trials, an increase in the frequency of anginal attacks during the nitrate-free interval was observed in a small number of patients. In one trial, patients demonstrated decreased exercise tolerance at the end of the nitrate-free interval. Hemodynamic rebound has been observed only rarely; on the other hand, few studies were so designed that rebound, if it had occurred, would have been detected. The importance of these observations to the routine, clinical use of transdermal nitroglycerin is unknown. Daily headaches sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headache may be a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with nitroglycerin, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Treatment with nitroglycerin may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. After normal use, there is enough residual nitroglycerin in discarded patches that they are a potential hazard to children and pets. A patient leaflet is supplied with the systems. The vasodilating effects of nitroglycerin may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary. Animal carcinogenesis 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 high dose, the incidences of hepatocellular carcinomas in both sexes were 52% vs 0% in controls, and incidences of testicular tumors were 52% vs 8% in controls. Incidences of pituitary adenomas and female mammary tumors normally seen in aged rats were significantly reduced, consistent with treatment-related decrease in food intake and body weight; increased life span was also seen in the high-dose females. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice. Nitroglycerin was weakly mutagenic in Ames tests performed in two different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, p.o., or in vitro cytogenetic tests in rat and dog tissues. In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F 0 generation with treatment continuing through successive F 1 and F 2 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 F 0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males. In this three-generation study there was no clear evidence of teratogenicity. Animal teratology studies have not been conducted with nitroglycerin transdermal systems. Teratology studies in rats and rabbits, however, 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. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed. It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman. Safety and effectiveness in pediatric patients have not been established.

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 vasodilating effects of nitroglycerin may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary.

Nitroglycerin Transdermal Delivery System Rated Release In Vivo System Size Total Nitro- glycerin In System NDC Number 0.1 mg/hr 3.3 cm 2 9 mg NDC-29336-321-30 0.2 mg/hr 6.7 cm 2 18 mg NDC-29336-322-30 0.4 mg/hr 13.3 cm 2 36 mg NDC-29336-323-30 0.6 mg/hr 20.0 cm 2 54 mg NDC-29336-324-30 Nitroglycerin Transdermal Delivery System, 0.1 mg/hr, 0.2 mg/hr, 0.4 mg/hr, 0.6 mg/hr is available in cartons of 30 patches. Store at controlled room temperature 15°-30°C (59°-86°F). Extremes of temperature and/or humidity should be avoided. Rx only US30   Rev. 4-07 Manufactured for: Graceway Pharmaceuticals, LLC Bristol, TN 37620 by: 3M Drug Delivery Systems Northridge, CA 91324

The principal pharmacological action of nitroglycerin is relaxation of the vascular smooth muscle and consequent dilatation 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 have been absent from the body for several hours was their anti-anginal efficacy restored. 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. 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. 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. In healthy volunteers, steady-state plasma concentrations of nitroglycerin are reached by about two hours after application of a patch and are maintained for the duration of wearing the system (observations have been limited to 24 hours). Upon removal of the patch, the plasma concentration declines with a half-life of about an hour. Regimens in which nitroglycerin patches were worn for 12 hours daily have been studied in well-controlled trials up to 4 weeks in duration. Starting about 2 hours after application and continuing until 10-12 hours after application, patches that deliver at least 0.4 mg of nitroglycerin per hour have consistently demonstrated greater anti-anginal activity than placebo. Lower-dose patches have not been as well studied, but in one large, well-controlled trial in which higher-dose patches were also studied, patches delivering 0.2 mg/hr had significantly less anti-anginal activity than placebo. It is reasonable to believe that the rate of nitroglycerin absorption from patches may vary with the site of application, but this relationship has not been adequately studied. The onset action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

Regimens in which nitroglycerin patches were worn for 12 hours daily have been studied in well-controlled trials up to 4 weeks in duration. Starting about 2 hours after application and continuing until 10-12 hours after application, patches that deliver at least 0.4 mg of nitroglycerin per hour have consistently demonstrated greater anti-anginal activity than placebo. Lower-dose patches have not been as well studied, but in one large, well-controlled trial in which higher-dose patches were also studied, patches delivering 0.2 mg/hr had significantly less anti-anginal activity than placebo. It is reasonable to believe that the rate of nitroglycerin absorption from patches may vary with the site of application, but this relationship has not been adequately studied. The onset action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

NDC 29336-321-30 Nitroglycerin Transdermal Delivery System 0.1 mg/hr Contents: 1 System Each 3.3 cm 2 sytem contains 9 mg of nitroglycerin. Rated release in vivo, 0.1 mg/hr. Rx Only Manufactured for: Graceway Pharmaceuticals, LLC, Bristol, TN 37620 by: 3M Drug Delivery Systems, Northridge, CA 91324 438200 US23 Rev0407 NDC 29336-322-30 Nitroglycerin Transdermal Delivery System 0.2 mg/hr Contents: 1 System Each 6.7 cm 2 sytem contains 18 mg of nitroglycerin. Rated release in vivo, 0.2 mg/hr. Rx Only Manufactured for: Graceway Pharmaceuticals, LLC, Bristol, TN 37620 by: 3M Drug Delivery Systems, Northridge, CA 91324 438300 US24 Rev0407 NDC 29336-323-30 Nitroglycerin Transdermal Delivery System 0.4 mg/hr Contents: 1 System Each 13.3 cm 2 sytem contains 36 mg of nitroglycerin. Rated release in vivo, 0.4 mg/hr. Rx Only Manufactured for: Graceway Pharmaceuticals, LLC, Bristol, TN 37620 by: 3M Drug Delivery Systems, Northridge, CA 91324 438400 US26 Rev0407 NDC 29336-324-30 Nitroglycerin Transdermal Delivery System 0.6 mg/hr Contents: 1 System Each 20 cm 2 sytem contains 54 mg of nitroglycerin. Rated release in vivo, 0.6 mg/hr. Rx Only Manufactured for: Graceway Pharmaceuticals, LLC, Bristol, TN 37620 by: 3M Drug Delivery Systems, Northridge, CA 91324 438600 US27 Rev0407