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.

WARNINGS Amplification of the vasodilatory effects of the NITRO-DUR patch by phosphodiesterase inhibitors, eg, sildenafil can result in severe hypotension. The time course and dose dependence of this inter action have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion. The benefits of transdermal nitroglycerin in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use nitroglycerin in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. A cardioverter/defibrillator should not be discharged through a paddle electrode that overlies a NITRO-DUR patch. The arcing that may be seen in this situation is harmless in itself, but it may be associated with local current concentration that can cause damage to the paddles and burns to the patient.

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.

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 ).

Pregnancy: Pregnancy Category C: 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 wellcontrolled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

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 nitroglycerin is administered to a nursing woman.

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.