NITRO-DUR

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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 to 12 hours daily for at least 1 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 to 12 hours is sufficient (see CLINICAL PHARMACOLOGY ). Thus, an appropriate dosing schedule for nitroglycerin patches would include a daily patch-on period of 12 to 14 hours and a daily patch-off period of 10 to 12 hours. *Release rates were formerly described in terms of drug delivered per 24 hours. In these terms, the supplied NITRO-DUR systems would be rated at 2.5 mg/24 hours (0.1 mg/hour), 5 mg/24 hours (0.2 mg/hour), 7.5 mg/24 hours (0.3 mg/hour), 10 mg/24 hours (0.4 mg/hour), and 15 mg/24 hours (0.6 mg/hour). 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 (ie, 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.

CONTRAINDICATIONS 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. Do not use NITRO-DUR in patients who are taking phosphodiesterase inhibitors (such as sildenafil, tadalafil, or vardenafil) for erectile dysfunction or pulmonary arterial hypertension. Concomitant use can cause severe drops in blood pressure. Do not use NITRO-DUR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

ADVERSE REACTIONS Adverse reactions to nitroglycerin are generally dose related, and almost all of these reactions are the result of nitroglycerins 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. 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. Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSAGE ). Application-site irritation may occur but is rarely severe. In two placebo-controlled trials of intermittent therapy with nitroglycerin patches at 0.2 to 0.8 mg/hr, the most frequent adverse reactions among 307 subjects were as follows: Placebo Patch Headache 18% 63% Lightheadedness 4% 6% Hypotension, and/or Syncope 0% 4% Increased Angina 2% 2% To report SUSPECTED ADVERSE REACTIONS, contact USPharma Ltd at 1(844)-750-3729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions: 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. Concomitant use of NITRO-DUR with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS ). Concomitant use of NITRO-DUR with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS ).

DESCRIPTION Nitroglycerin is 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 NITRO-DUR ® (nitroglycerin) Transdermal Infusion System is a flat 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 0.02 mg of nitroglycerin per hour. Thus, the 5-,10-, 15-, 20-, 30-, and 40-cm2 systems deliver approximately 0.1, 0.2, 0.3, 0.4, 0.6, and 0.8 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 approximately 6% of its original content of nitroglycerin. The NITRO-DUR transdermal system contains nitroglycerin in acrylic-based polymer adhesives with a resinous cross-linking agent to provide a continuous source of active ingredient. Each unit is sealed in a paper polyethylene-foil pouch. Cross section of the system. nitroglycerin chemical structure cross section of system

OVERDOSAGE Hemodynamic Effects: 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 (eg, 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 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 nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required. 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 ( 3 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 was 0.2%; this was comparable to that observed in parallel patients who received placebo. 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 PO 2 . Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. Methemoglobinemia should be treated with methylene blue if the patient develops cardiac or CNS effects of hypoxia. The initial dose is 1 to 2 mg/kg infused intravenously over 5 minutes. Repeat methemoglobin levels should be obtained 30 minutes later and a repeat dose of 0.5 to 1.0 mg/kg may be used if the level remains elevated and the patient is still symptomatic. Relative contraindications for methylene blue include known NADH methemoglobin reductase deficiency or G-6-PD deficiency. Infants under the age of 4 months may not respond to methylene blue due to immature NADH methemoglobin reductase. Exchange transfusion has been used successfully in critically ill patients when methemoglobinemia is refractory to treatment.

HOW SUPPLIED NITRO-DUR System Rated Release In Vivo* Total nitroglycerin content System size Package Size 0.1 mg/hr 20 mg 5cm 2 Unit Dose 30 (NDC 50742-513-01) Package 30 (NDC 50742-513-30) 0.2 mg/hr 40 mg 10 cm 2 Unit Dose 30 (NDC 50742-514-01) Package 30 (NDC 50742-514-30) 0.3 mg/hr 60 mg 15 cm 2 Unit Dose 30 (NDC 50742-515-01) Package 30 (NDC 50742-515-30) 0.4 mg/hr 80 mg 20 cm 2 Unit Dose 30 (NDC 50742-516-01) Package 30 (NDC 50742-516-30) 0.6 mg/hr 120 mg 30 cm 2 Unit Dose 30 (NDC 50742-517-01) Package 30 (NDC 50742-517-30) 0.8 mg/hr 160 mg 40 cm 2 Unit Dose 30 (NDC 50742-518-01) Package 30 (NDC 50742-518-30) *Release rates were formerly described in terms of drug delivered per 24 hours. In these terms, the supplied NITRO-DUR systems would be rated at 2.5 mg/24 hours (0.1 mg/hour), 5 mg/24 hours (0.2 mg/hour), 7.5 mg/24 hours (0.3 mg/hour), 10 mg/24 hours (0.4 mg/hour), and 15 mg/24 hours (0.6 mg/hour). Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not refrigerate.