Information for the Patient
Nitro-Dur
Pharmacology
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle and consequent dilation of both peripheral arteries and veins, with more prominent effects on the latter. Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (afterload). Dilation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilation remains undefined.
When NITRO-DUR is applied to the skin, nitroglycerin is absorbed continuously through the skin into the systemic circulation. Thus, the active drug reaches target sites before inactivation by the liver. Nitroglycerin is rapidly metabolized, principally by a liver reductase, to form glycerol nitrate metabolites and inorganic nitrate. Two active major metabolites, the 1,2- and 1,3-dinitroglycerols, the products of hydrolysis, appear to be less potent than nitroglycerin as vasodilators but have longer plasma half-lives. The dinitrates are further metabolized to mononitrates (biologically inactive with respect to cardiovascular effects) and ultimately to glycerol and carbon dioxide. There is extensive first-pass deactivation by the liver following gastrointestinal absorption.
In healthy volunteers, steady-state plasma concentrations of nitroglycerin were reached within one-half hour after application of the patch and were maintained at the same level for the duration of the study (24 hours). Between 2 and 24 hours, the mean steady-state concentration was 0.224 ng/mL (20 cm2 patch); the total amount of nitroglycerin delivered in 24 hours was 5.11±1.69 mg, 10.67±4.78 mg and 17.85±7.40 mg from 10 cm2, 20 cm2, and 40 cm2 patches, respectively, indicating that the dose delivered is proportional to the surface area of the patch. Within 1 hour of removal of the patch, the plasma concentration declines to about 50% of steady-state concentration and to undetectable concentrations by 2 hours.
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 probably inappropriate for organic nitrates. 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, however, have shown the development of tolerance (i.e. complete loss of effect as measured by exercise testing) within the first day. Tolerance has occurred even when doses greater than 4 mg/hour were delivered continuously. This dose is far in excess of the effective dose of 0.2 to 0.8 mg/hour delivered intermittently.
Efficacy of organic nitrates is restored after a period of absence of nitrates from the body. Drug-free intervals of 10 to 12 hours are known to be sufficient to restore response. Several studies have demonstrated that when nitroglycerin is administered according to an intermittent regimen, doses of nitroglycerin 0.4 to 0.8 mg/hour (20 to 40 cm2) have increased exercise capacity for up to 8 hours, with a trend of increased exercise capacity for up to 12 hours. One controlled clinical trial suggested that the intermittent use of nitrates may be associated with a decreased, in comparison to placebo, exercise tolerance during the last part of the nitrate-free interval; the clinical relevance of this observation is unknown. In another clinical trial there was an increase in nocturnal angina attacks during the drug-free period in some patients treated with nitroglycerin as compared to placebo. Therefore the possibility of increased frequency or severity of angina during the nitrate-free interval should be considered.
Indications
NITRO-DUR (nitroglycerin) used intermittently (see Pharmacology), is indicated for the prevention of anginal attacks in patients with stable angina pectoris associated with coronary artery disease. It can be used in conjunction with other antianginal agents such as beta-blockers and/or calcium antagonists.
NITRO-DUR is not intended for the immediate relief of acute attacks of angina pectoris. Sublingual nitroglycerin preparations should be used for this purpose.
Precautions
Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquilizers may potentiate the blood pressure lowering effect of nitroglycerin. Dose adjustment may be necessary.
Nitroglycerin acts directly on vascular muscles. Therefore, any other agent that directly or indirectly acts on vascular smooth muscle may have decreased or increased effect depending upon the agent.
Alcohol may enhance sensitivity to the hypotensive effects of nitrates.
Concomitant use of NITRO-DUR (nitroglycerin) with a phosphodiester inhibitor (e.g. sildenafil citrate, tadalafil) can potentiate the hypotensive effect of NITRO-DUR. This could result in life-threatening hypotension with syncope or myocardial infarction and death. Therefore, phosphodiesterase inhibitor drugs should not be given to patients receiving NITRO-DUR therapy.
Concurrent administration of NITRO-DUR with dihydroergotamine may increase the bioavailability of dihydroergotamine. Special attention should be paid to this point in patients with coronary artery disease, because dihydroergotamine antagonizes the effect of nitroglycerin and may lead to coronary vasconstriction.
The possibility that the ingestion of ASA and nonsteroidal anti-inflammatory drugs might diminish the therapeutic response to nitrates and nitroglycerin cannot be excluded.
As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.
It is not known whether nitroglycerin is excreted in human milk. Benefits to the mother must be weighed against the risk to the infant.
Safety and effectiveness in children have not been established.
It is not known whether NITRO-DUR can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Therefore, use NITRO-DUR only if the potential benefit justifies the risk to the fetus.
Supplied
Each 10 cm2 patch contains: nitroglycerin 40 mg.
Each 30 cm2 patch contains: nitroglycerin 120 mg.
Each 20 cm2 patch contains: nitroglycerin 80 mg.
Each 40 cm2 patch contains: nitroglycerin 160 mg.
Each unit is sealed in a paper polyethylene-foil pouch. Retail unit dose boxes of 30. Hospital unit dose boxes of 100. Store between 15 to 30°C. Do not refrigerate.
Contraindications
Known hypersensitivity or idiosyncrasy to nitroglycerin or other nitrates or nitrites. Allergy to the adhesive used in nitroglycerin patches has been reported and constitutes a contraindication to the use of this product. Acute circulatory failure associated with marked hypotension (shock and states of collapse). Postural hypotension. Myocardial insufficiency due to obstruction (e.g. in the presence of aortic or mitral stenosis or of constrictive pericarditis). Increased intracranial pressure. Increased intraocular pressure. Severe anemia.
Concomitant use of NITRO-DUR (nitroglycerin) either regularly and/or intermittently, with a phosphodiesterase inhibitor (e.g. sildenafil citrate, tadalafil) is absolutely contraindicated.
Warnings
The benefits and safety of transdermal nitroglycerin in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use NITRO-DUR in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.
NITRO-DUR must be removed before cardioversion or DC defibrillation is attempted, as well as before applying diathermy treatment, since it may be associated with damage to the paddles and burns to the patient.
Adverse Effects
Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses of nitroglycerin. Headaches may be treated with concomitant administration of mild analgesics. If such headaches are unresponsive to treatment, the nitroglycerin dosage should be reduced or the product discontinued. 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.
Reddening of the skin, with or without a mild local itching or burning sensation, as well as allergic contact dermatitis may occasionally occur. Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.
Less frequently reported adverse reactions include dizziness, faintness, facial flushing, postural hypotension which may be associated with reflex tachycardia. Syncope, crescendo angina and rebound hypertension have been reported but are uncommon. Nausea and vomiting have been reported rarely.
Overdose
Nitroglycerin overdose may result in severe hypotension, persistent throbbing headache, vertigo, palpitations, visual disturbances, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis, initial hyperpnea, dyspnea, and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis, coma, clonic convulsions and death due to circulatory collapse.
The patch should be removed immediately and the underlying skin scrubbed thoroughly. 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 venodilation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Specific elements of such therapy might include any or all of the following: elevation of the patient's legs, passive motion of the patient's extremities, and i.v. infusion of normal saline or similar fluid. In patients with renal disease or congestive heart failure, 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.
Keep the patient recumbent in a shock position and comfortably warm. Remove the NITRO-DUR patch. Passive movement of the extremities may aid venous return. Administer oxygen and artificial ventilation if necessary. Epinephrine is ineffective in reversing the severe hypotensive events associated with overdose; it and related compounds are contraindicated in this situation.
Methemoglobinemia: Case reports of clinically significant methemoglobinemia are rare at conventional doses of nitroglycerin. The formation of methemoglobin is dose-related, and in the case of genetic abnormalities of hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates can produce harmful concentrations of methemoglobin.
Methemoglobinemia should be treated with methylene blue if the patient develops cardiac or CNS effects of hypoxia. The initial dose is 1-2 mg/kg infused intravenously over 5 minutes. Repeat methemoglobin levels should be obtained 30 minutes later and a repeat dose of 0.5-1.0 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 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.
Dosage
Daily Dosage Schedule: The daily dosage schedule is based on intermittent therapy to prevent the development of tolerance to nitroglycerin. The optimal dose should be selected based upon the clinical response, side effects, and the effects of therapy on blood pressure.
Starting dose is 1 NITRO-DUR 0.2 patch (10 cm2), usually applied in the morning. If 0.2 mg/hour (10 cm2) is well tolerated, the dose can be increased to 0.4 mg/hour (20 cm2) if required. A maximum of 0.8 mg/hour (40 cm2) may be used.
Prevention of Tolerance: Although some 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 adjustments even to levels much higher than generally used did not prevent the development of tolerance.
Tolerance can be prevented or attenuated by use of an intermittent dosage schedule. Although the minimum nitrate-free interval has not been defined, clinical trials have demonstrated that an appropriate dosing schedule for nitroglycerin patches would provide for a daily patch-on period of 12 to 14 hours and a daily patch-off period of 10 to 12 hours. The patch-free time should coincide with the period in which angina pectoris is least likely to occur (usually at night). Patients should be watched carefully for an increase of angina pectoris during the patch-free period. Adjustment of background medication may be required.
The dose of NITRO-DUR should be periodically reviewed in relation to continuing antianginal control.
Site of Application: The NITRO-DUR nitroglycerin transdermal system may be applied to any convenient skin area; a recommended site of application is the arm or chest. Application sites should be rotated. A suitable area may be shaved if necessary. Do not apply NITRO-DUR to the distal part of the extremities. Hands should be washed thoroughly after application. Following use, the patch should be discarded in a manner that prevents accidental application or ingestion by curious children or others.
