Trinipatch (Nitroglycerin)

TRINIPATCH® 0.2 TRINIPATCH® 0.4 TRINIPATCH® 0.6 Sanofi-Synthelabo Nitroglycerin Transdermal Delivery System Antianginal

Action and Clinical

The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle, producing a vasodilator effect on 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 system 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 Trinipatch is applied to the skin, nitroglycerin is absorbed directly into the systemic circulation. Thus, the active drug reaches target organs before inactivation by the liver. The transdermal absorption of nitroglycerin occurs in a continuous and well-controlled manner. 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.

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.

In healthy volunteers, after the application of the system in different dosages.

Although dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration, such a strategy is probably inappropriate for organic nitrates. 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, however, have shown the development of tolerance (i.e., complete loss of effect as measured by exercise testing) within the first day. Tolerance has appeared even when doses greater than 4 mg/hour were delivered continuously. This dose is far in excess of the effective dose 0.2 to 0.8 mg/hour applied 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 0.4 to 0.8 mg/hour have increased exercise capacity for up to 8 hours, with a trend of increased exercise capacity to 12 hours. One controlled clinical trial suggested that the intermittent use of nitrates may be associated with a decreased exercise tolerance, in comparison to placebo, during the last part of the nitrate-free interval; the clinical relevance of this observation is unknown, but the possibility of increased frequency or severity of angina during the nitrate-free interval should be considered.

Indications And Clinical Uses:

Nitroglycerin used intermittently 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.

Not intended for the immediate relief of acute attacks of angina pectoris. Sublingual nitroglycerin preparations should be used for this purpose.

Contra-Indications:

Known hypersensitivity to nitroglycerin and related organic nitrate compounds. Known or suspected hypersensitivity to components of the patch. 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.

Warnings in Clinical States:

Trinipatch 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.

The benefits and safety of transdermal nitroglycerin in angina patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use transdermal nitroglycerin in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the potentially deleterious effects of induced hypotension and tachycardia.

Precautions:

Headaches or symptoms of hypotension, such as weakness or dizziness, particularly when arising suddenly from a recumbent position, may occur. A reduction in dose or discontinuation of treatment may be necessary.

Caution should be exercised when using nitroglycerin in patients prone to, or who might be affected by hypotension. The drug therefore should be used with caution in patients who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mm Hg). Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of nitroglycerin, tolerance clearly occurs. There is moreover, physical dependence since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitroglycerin from these workers. In clinical trials of angina patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. The importance of these observations to the routine clinical use of nitroglycerin has not been fully elucidated, but patients should be monitored closely for increased anginal symptoms during drug-free periods.

Caution should be exercised in patients with arterial hypoxemia due to anemia (see Contraindications), because in such patients the biotransformation of nitroglycerin is reduced. Similarly, caution is called for in patients with hypoxemia and a ventilation/perfusion imbalance due to lung disease or ischemic heart failure. Patients with angina pectoris, myocardial infarction, or cerebral ischemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion to poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.

Tolerance to nitroglycerin with cross tolerance to other nitrates or nitrites may occur. Coadministration of other long-acting nitrates could jeopardize the integrity of the nitrate-free interval and therefore must be avoided. As tolerance to nitroglycerin patches develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Occupational Hazards: As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.

Pregnancy: Animal reproduction studies have not been conducted with nitroglycerin. It is not known whether nitroglycerin can cause fetal harm when administered to a pregnant woman. Therefore use nitroglycerin only if the potential benefit justifies the risk to the fetus.

Lactation: It is not known whether nitroglycerin is excreted into breast milk. Benefits to the mother must be weighed against the risks to the child.

Children: Safety and effectiveness have not been established in children.

Drug Interactions:

Concomitant treatment with other vasodilators, calcium channel blockers, 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.

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dosage adjustments of either class of agents may be necessary.

Alcohol may enhance sensitivity to the hypotensive effects of nitrates.

Concurrent administration of nitroglycerin 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 vasoconstriction.

The possibility that the ingestion of ASA and nonsteroidal anti-inflammatory drugs might diminish the therapeutic response to nitrates and nitroglycerin cannot be excluded.

Information to be provided to the Patient: 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 patches.

Adverse Reactions:

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. Rarely nausea, and vomiting.

Symptoms And Treatment Of Overdose:

Symptoms:

Nitroglycerin overdose may result in severe hypotension, persistent throbbing headache, vertigo, palpitations, visual disturbances, flushing and perspiring skin (later becoming cold and cyanotic), anorexia, nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis, hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block and bradycardia, increased intracranial pressure with cerebral symptoms of fever, confusion, and coma possibly followed by paralysis, clonic convulsions and death due to circulatory collapse.

Treatment:

Keep the patient recumbent in a shock position and comfortably warm. Remove the patch.

Passive movement of the extremities may aid venous return. Administer oxygen and artificial ventilation if necessary.

I.V. infusion of normal saline or similar fluid may also be required to produce sufficient central volume expansion. However, 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.

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. 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. If methemoglobinemia is present, administration of methylene blue (1% solution), 1 to 2 mg/kg i.v., may be required.

Dosage And Administration:

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 one 0.2 patch

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 transdermal nitroglycerin should be periodically reviewed in relation to continuing antianginal control.

Site of Application: The patch can be applied to any area of skin except the distal extremities. Many patients prefer the chest. Each successive application should be to a different site.

The area should be clean, dry, and preferably hairless. If hair is likely to interfere with patch adhesion or removal, clipping may be necessary prior to application. Take care to avoid areas with cuts or irritations.

Availability And Storage:

The Trinipatch (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 cm.

The Trinipatch system comprises three layers: a thin, occlusive, LDPE backing film layer, an acrylic adhesive matrix/drug reservoir layer and a layer of siliconized polyester release liner comprised of overlapped liner strips that form an easy-opening tab.

Trinipatch 0.2: Each 7 cm;

Trinipatch 0.4: Each 14 cm;

Trinipatch 0.6: Each 21 cm.

Nonmedicinal ingredients: sorbitan mono-oleate and DuroTak 80-1196. Each system is individually sealed in a separate pouch. Boxes of 30. Store under controlled room temperature (between 15 and 30°C). Shelf-life: 2 years. Do not store out of the pouch. Keep out of reach of children and pets before use and when disposing of used patches.

TRINIPATCH® 0.2 TRINIPATCH® 0.4 TRINIPATCH® 0.6 Sanofi-Synthelabo Nitroglycerin Transdermal Delivery System Antianginal