NITRO-BID^®
(Nitroglycerin Ointment USP, 2%)

FOR TOPICAL USE ONLY

Rx Only

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.

NITRO-BID^® for topical use contains lactose and 2% nitroglycerin in a base of lanolin, white petrolatum and purified water. Each inch (2.5 cm), as squeezed from the tube, contains approximately 15 mg of nitroglycerin.

The principal pharmacological action of nitroglycerin is relaxation of 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 had been absent from the body for several hours was their anti-anginal efficacy restored.

Nitroglycerin ointment 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 anginal episode.

Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin is contraindicated in patients who are allergic to it.

Amplification of the vasodilatory effects of nitroglycerin by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction 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.

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.

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; for further discussion of its diagnosis and treatment see OVERDOSAGE.

Data are not available to allow estimation of the frequency of adverse reactions during treatment with nitroglycerin ointment.

As noted above (CLINICAL PHARMACOLOGY), controlled trials have demonstrated that nitroglycerin ointment can effectively reduce exercise-related angina for up to 7 hours after a single application. Doses used in clinical trials have ranged from 1/2 inch (1.3 cm; 7.5 mg) to 2 inches (5.1 cm; 30 mg), typically applied to 36 square inches (232 square centimeters) of truncal skin.

It is reasonable to believe that the rate and extent of nitroglycerin absorption from ointment may vary with the site and square measure of the skin over which a given dose of ointment is spread, but these relationships have not been adequately studied.

Controlled trials with other formulations of nitroglycerin have demonstrated that if plasma levels are maintained continuously, all anti-anginal efficacy is lost within 24 hours. This tolerance cannot be overcome by increasing the dose of nitroglycerin. As a result, any regimen of NITRO-BID^® administration should include a daily nitrate-free interval. The minimum necessary length of such an interval has not been defined, but studies with other nitroglycerin formulations have shown that 10 to 12 hours is sufficient.

Thus, one appropriate dosing schedule for NITRO-BID^® would begin with two daily 1/2- inch (7.5 mg) doses, one applied on rising in the morning and one applied six hours later. The dose could be doubled, and even doubled again, in patients tolerating this dose but failing to respond to it. The foilpac is intended as a unit dose package only and is equivalent to approximately 1 inch as squeezed from the tube. Use entire spans of foilpac to obtain full dose and discard immediately after use.

Each tube of ointment and each box of foilpacs is supplied with a pad of ruled, impermeable, paper applicators. These applicators allow ointment to be absorbed through a much smaller area of skin than that used in any of the reported clinical trials, and the significance of this difference is not known. To apply the ointment using one of the applicators, place the applicator on a flat surface, printed side down. Squeeze the necessary amount of ointment from the tube onto the applicator, place the applicator (ointment side down) on the desired area of the skin, and tape the applicator into place.

NITRO-BID^® (Nitroglycerin Ointment USP, 2%), is a pale yellow ointment. (Package includes a supply of ruled applicators for convenient application.)

Close tightly, immediately after each use.

Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].

NITRO-BID^®(Nitroglycerin Ointment USP, 2%)

E. FOUGERA & CO.
a division of Altana Inc.
MELVILLE, NEW YORK 11747

I2326C/ IF2326C
R1/05
#274

• Measure desired dosage of Nitroglycerin Ointment 2% by means of the dose measuring applicator supplied with the tube. Place the applicator on a flat surface, printed side down. Squeeze the necessary amount of ointment from the tube onto the applicator, and place the applicator (ointment side down) on the desired area of the skin.
• Spread the ointment using the dose measuring applicator lightly onto the chest or other areas of skin if preferred. Do not rub into the skin. Coverage of an area approximately the size of the dose measuring applicator (3 ¹/2′′ by 2 ¹/4′′) should be sufficient to obtain the desired clinical effects. A larger area may be used.
• Tape the applicator into place.

NOTE: NITRO-BID^® can stain clothing. Care should be taken to completely cover the dose measuring applicator with a plastic kitchen wrap.

Dosage Instructions: Dosage instructions should be obtained from your physician. One appropriate dosing schedule for NITRO-BID^® would begin with two daily ¹/2 inch (7.5 mg) doses, one applied on rising in the morning and one applied six hours later. The dose could be doubled, and even doubled again, in patients tolerating this dose but failing to respond to it. The foilpac is intended as a unit dose package only and is equivalent to approximately 1 inch as squeezed from the tube. Use entire spans of foilpac to obtain full dose and discard immediately after use.

INFORMATION FOR PATIENTS: Your daily regimen of NITRO-BID^® administration should include a nitrate-free period. Studies have shown 10-12 hours is sufficient. The most common side effect which is encountered is headache. Faintness, flushing and dizziness may occur, especially when suddenly arising from the recumbent (lying horizontal) position. If these latter symptoms do occur, it may warrant discontinuation of therapy, and your physician should be notified. For changes in dosage and frequency of application consult your physician.

TUBE: KEEP TUBE TIGHTLY CLOSED.

foilpac^®: DISCARD IMMEDIATELY AFTER USE.

Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].

E. FOUGERA & CO.
a division of Altana Inc.
MELVILLE, NEW YORK 11747