Nitroglycerin

Kremers Urban Pharmaceuticals Inc.

Nitroglycerin Transdermal System

FULL PRESCRIBING INFORMATION: CONTENTS*

• NITROGLYCERIN DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics:
  • Clinical Trials:
• NITROGLYCERIN INDICATIONS AND USAGE
• NITROGLYCERIN CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General:
  • Information for Patients:
  • Drug Interactions:
  • Carcinogenesis, Mutagenesis, Impairment of Fertility:
  • Pregnancy:
  • Nursing Mothers:
  • Pediatric Use:
  • Geriatric Use:
• NITROGLYCERIN ADVERSE REACTIONS
• OVERDOSAGE
  • Hemodynamic Effects:
  • Methemoglobinemia:
• NITROGLYCERIN DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• Patient Information
  • How to use the Nitroglycerin Transdermal System for the prevention of angina
  • Where to place the Nitroglycerin Transdermal System
  • How to Apply the Nitroglycerin Transdermal System
  • Usual Dosage:
  • Precautions:
• PRINCIPAL DISPLAY PANEL - 30 Patch Carton
• PRINCIPAL DISPLAY PANEL - 30 Patch Carton

FULL PRESCRIBING INFORMATION

NITROGLYCERIN 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 Nitroglycerin Transdermal 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 cm² of applied system delivers approximately .02 mg of nitroglycerin per hour. Thus, the 10 cm² and 18 cm² systems deliver approximately 0.2 and 0.4 mg of nitroglycerin per hour, respectively. Each 10 cm² and 18 cm² system contains 20.8 and 37.4 mg of nitroglycerin, 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 12% of its original content of nitroglycerin.

The Nitroglycerin Transdermal System comprises two layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are 1) polypropylene foil backing layer that is impermeable to nitroglycerin and 2) nitroglycerin in an acrylic-based polymer adhesive with a cross-linking agent to provide a continuous source of active ingredient. Prior to use, a peelable protective liner is removed from the adhesive surface. Each unit is sealed in a paper foil-lined pouch.

Cross section of the system:

CLINICAL PHARMACOLOGY

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 antianginal 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 has their antianginal efficacy been restored.

Pharmacokinetics:

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 (nonvasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide.

To avoid development of tolerance to nitroglycerin, drug-free intervals of 10 to 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 2 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.

Clinical Trials:

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 to 12 hours after application, patches that deliver at least 0.4 mg of nitroglycerin per hour have consistently demonstrated greater antianginal 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 antianginal 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 of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

NITROGLYCERIN 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.

NITROGLYCERIN CONTRAINDICATIONS

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.

WARNINGS

Amplification of the vasodilatory effects of Nitroglycerin Transdermal System by phosphodiesterase inhibitors, e.g., 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.

A cardioverter/defibrillator should not be discharged through a paddle electrode that overlies a nitroglycerin 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.

PRECAUTIONS

General:

Severe hypotension, particularly with upright posture, may occur with even small doses of nitroglycerin, particularly in the elderly. This drug should, therefore, be used with caution in elderly patients who may be volume-depleted, are on multiple medications, or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.

Elderly patients may be more susceptible to hypotension and may be at greater risk of falling at the therapeutic doses of nitroglycerin.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.

As tolerance to other forms of nitroglycerin develops, the effects 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- to 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 had 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.

Information for Patients:

Daily headaches sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches 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 antianginal 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.

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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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 the 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. 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 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 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. In this three-generation study, there was no clear evidence of teratogenicity.

Pregnancy:

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.

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.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

Clinical studies of transdermal nitroglycerin did not include sufficient information to determine whether subjects 65 years and older respond differently from younger subjects. Additional clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may result in hypotension and increased risk of falling. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

NITROGLYCERIN ADVERSE REACTIONS

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. 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:

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 control center should be considered.

The ill effects of nitroglycerin overdose are generally the results of nitroglycerin’s capacity to induce vasodilatation, 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.

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 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 (> 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 PO₂. 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 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.

NITROGLYCERIN 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.

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.

HOW SUPPLIED

Nitroglycerin Transdermal System 0.2 mg/hr is a translucent, square patch with rounded corners imprinted with “nitroglycerin” and “0.2 mg/hr”, affixed to a translucent, peelable liner and is supplied in a foil-lined pouch.

Nitroglycerin Transdermal System 0.4 mg/hr is a translucent, square patch with rounded corners imprinted with “nitroglycerin” and “0.4 mg/hr”, affixed to a translucent, peelable liner and is supplied in a foil-lined pouch.

Nitroglycerin Transdermal Systems are available as follows:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate.

Manufactured for:
Kremers Urban Pharmaceuticals Inc.
Princeton, NJ 08540, USA
By LTS Lohmann Therapie-Systeme AG
Andernach, Federal Republic of Germany

L2826D Rev. 2E 02/2011
4013835 11/346 2393

Patient Information

How to use the Nitroglycerin Transdermal System for the prevention of angina

The Nitroglycerin Transdermal System is easy to use – it has a translucent plastic backing and a special adhesive that keeps the system firmly in place.

Where to place the Nitroglycerin Transdermal System

Select any area of skin on the body, EXCEPT the extremities below the knee or elbow. The chest is the preferred site. The area should be clean, dry, and hairless. If hair is likely to interfere with system adhesion or removal, it can be clipped but not shaved. Take care to avoid areas with cuts or irritations. Do NOT apply the system immediately after showering or bathing. It is best to wait until you are certain the skin is completely dry.

How to Apply the Nitroglycerin Transdermal System

1. Each Nitroglycerin Transdermal System is individually sealed in a protective pouch. Tear open this pouch at the indicated slits. Carefully remove the system from the pouch. The system is printed with the wording “nitroglycerin” and the amount of nitroglycerin delivered each hour. The system is attached to a protective peelable liner.

2. Holding both sides of the system with the “S”-shaped cut in the plastic backing facing you, bend it in half. Notice that the “S”-shaped cut creates two big-grab tabs. Grip one tab and remove one side of the plastic backing (Figure A). Without touching the exposed adhesive (sticky) side of the system, apply it to the chosen skin site as you would apply an adhesive bandage.

Figure A

3. Hold the system on the skin site with one hand, bend back the unattached side of the system, grab the plastic tab, and remove the other half of the plastic backing with your free hand (Figure B).

Figure B

4. Press firmly in place with the palm of your hand (Figure C). Maintain pressure for several seconds to ensure good contact with the skin. Once the system is in place, do not test the adhesion by pulling on it.

Figure C

When the Nitroglycerin Transdermal System is applied to your body, the nitroglycerin contained in the system begins to flow from the adhesive surface through your skin and into the body at a uniform rate.

5. After applying the system, wash hands to remove any drug.

6. At the time recommended by your doctor, remove and discard the system.

7. Place a new system on a different skin site, following steps 1 – 5, according to your doctor’s instructions.

Usual Dosage:

Each 24-hour period should include a patch-on period of 12 to 14 hours, followed by a patch-free interval, unless otherwise directed by your physician.

Please note:

Contact with water, as in bathing, swimming, or showering will not affect the system. In the unlikely event that a system falls off, discard it and put a new one on a different skin site.

Precautions:

The most common side effect is headache, which often decreases as therapy is continued, but may require treatment with a mild analgesic. Although uncommon, faintness, flushing, and dizziness may occur, especially when suddenly rising from the recumbent (lying horizontal) position. If these symptoms occur, remove the system and notify your physician.

Skin irritation may occur. If it persists, consult your physician.

Keep these systems and all drugs out of the reach of children.

Important:

Your doctor may decide to increase or decrease the size of the system, or prescribe a combination of systems, to suit your particular needs. The dose may vary depending on your individual response to the system.

This system is used for preventing angina, not for treating an acute attack.

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate.

Do not store unpouched. Apply immediately upon removal from the protective pouch.

Distributed by:
Kremers Urban Pharmaceuticals Inc.
Princeton, NJ 08540

L2825C Rev. 2E 02/2011
4013832 11/347 2394

PRINCIPAL DISPLAY PANEL - 30 Patch Carton

NDC 62175-123-01

Contents: 30 systems

Nitroglycerin
Transdermal System
0.2 mg/hr (10 cm²)

Each 10 cm² unit contains 20.8 mg of nitroglycerin in an
acrylic-based polymer adhesive with a cross-linking agent.
Approximate rated release in vivo 0.2 mg/hr.

FOR TRANSDERMAL USE ONLY.

Rx Only

PRINCIPAL DISPLAY PANEL - 30 Patch Carton

NDC 62175-124-01

Contents: 30 systems

Nitroglycerin
Transdermal System
0.4 mg/hr (18 cm²)

Each 18 cm² unit contains 37.4 mg of nitroglycerin in an
acrylic-based polymer adhesive with a cross-linking agent.
Approximate rated release in vivo 0.4 mg/hr.

FOR TRANSDERMAL USE ONLY.

Rx Only