Minitran – Product Information
|Condition:||Angina, Angina Pectoris Prophylaxis, Heart Attack (Myocardial Infarction), Heart Failure (Congestive Heart Failure), High Blood Pressure (Hypertension), Pain|
|Class:||Antianginal agents, Vasodilators|
|Form:||Skin patch (transdermal)|
|Ingredients:||glyceryl trinitrate, polymer 3273, ethyl oleate, glyceryl laurate|
Transdermal delivery system
Name of the drug
Glyceryl trinitrate (GTN) is a 1,2,3-propanetriol trinitrate, an organic nitrate whose structural formula is:
and has a molecular weight of 227.09. GTN is also known as nitroglycerin.
The Minitran Transdermal Delivery System is a unit designed to provide continuous controlled release of glyceryl trinitrate through intact skin to overcome the problems of the short half-life and extensive first-pass metabolism of glyceryl trinitrate.
The rate of release of glyceryl trinitrate from Minitran is linearly dependent upon the area of the applied system; each cm2 of applied system delivers approximately 0.75 mg of glyceryl trinitrate over 24 hours which is equivalent to 0.03 mg/h.
|System||Total GTN in System||System Size||Rate of Release in-vivo||Amount of GTN Released over 24 hours|
|MINITRAN 5||18 mg||6.7 cm2||0.2 mg/h||5 mg|
|MINITRAN 10||36 mg||13.3 cm2||0.4 mg/h||10 mg|
|MINITRAN 15||54 mg||20 cm2||0.6 mg/h||15 mg|
The remainder of the glyceryl trinitrate in the system serves as a reservoir and is not delivered in normal use.
The Minitran Transdermal Delivery System consists of a thin, transparent, low-density, polyethylene film covered by hypoallergenic, medical grade, acrylate-based polymer adhesive containing glyceryl trinitrate. The excipients in Minitran are ethyl oleate, glyceryl laurate and polymer 3273. Each patch is packaged in foil/polymer film laminate. Prior to use, a protective peel strip is removed from the adhesive surface.
The principal pharmacological action of glyceryl trinitrate is relaxation of the vascular smooth muscle and consequent dilation of peripheral arteries and veins, especially the latter. Dilation 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). Dilation of the coronary arteries also occurs which is of importance in the treatment of coronary spasm.
When a Minitran Transdermal Delivery System is applied to the skin, glyceryl trinitrate is absorbed continuously through the skin into the systemic circulation maintaining constant blood levels. In healthy volunteers, steady-state plasma concentrations of glyceryl trinitrate are reached by about two hours after application of a patch and are maintained for the duration of wearing the patch. Upon removal of the patch, the plasma concentration declines with a half-life of about an hour.
Prevention of chronic, stable angina pectoris due to coronary artery disease.
Minitran is contraindicated in cases of known hypersensitivity to organic nitrates or to the stated excipients including adhesive in the patch, severe anaemia, increased intra-ocular and intracranial pressure and marked arterial hypotension or shock. It is also contraindicated in acute myocardial insufficiency due to obstruction as in aortic or mitral stenosis or constrictive pericarditis.
Concomitant use of Minitran and Viagra (sildenafil) is contraindicated because sildenafil may amplify the vasodilatory effects of Minitran resulting in severe hypotension.
Minitran is not indicated for the treatment of acute angina attacks requiring rapid relief. The benefits of transdermal glyceryl trinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use glyceryl trinitrate in these conditions, careful clinical or haemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Minitran should be used with caution in patients with hypoxaemia or ventilation perfusion imbalance, as a decrease in available oxygen may diminish the anti-anginal effect of Minitran. Nitrate therapy, including Minitran, may aggravate the angina caused by hypertrophic cardiomyopathy.
The appearance of tolerance (the decline in, or loss of efficacy) to the preparation and of cross tolerance with other nitrates may occur with repeated or continuous administration of long-acting nitrates, including Minitran and other transdermal systems. This can be prevented by keeping plasma glyceryl trinitrate levels low for a certain period of the dosing interval and for this reason intermittent therapy is preferable. (See "Dosage and method of administration".)
As all nitrate vasodilators can induce withdrawal reactions, abrupt withdrawal of Minitran should be avoided. It is advisable to gradually reduce the dosage over a period of 4 to 6 weeks to prevent a potential withdrawal reaction. Minitran should be removed before attempting cardioversion or defibrillation. A cardiovertor/defibrillator should not be discharged through a paddle electrode that overlies a Minitran patch due to the risk of burns to the patient and damage to the paddle.
Severe hypotension, particularly with upright posture, may occur with even small doses of glyceryl trinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by glyceryl trinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
The use of products for topical application, especially if prolonged, may give rise to sensitisation phenomena, in which case treatment should be suspended and suitable therapeutic measures adopted.
Use in Pregnancy (Category B2)
The safety of Minitran in pregnancy has not been established. As with all drugs, Minitran should not be prescribed during pregnancy, particularly during the first trimester, unless there are compelling reasons for doing so. If Minitran is in regular use and pregnancy occurs, the physician should be notified immediately.
Use in Lactation
It is not known whether glyceryl trinitrate passes into the breast milk. The benefits for the mother must be weighed against the risks to the child.
Interactions with other Drugs
Concomitant use of alcohol may enhance the vascular effects of glyceryl trinitrate. Concomitant use of Minitran and other vasodilatory agents, calcium antagonists,β-blockers, ACE inhibitors, neuroleptics, diuretics, antihypertensives, tricyclic antidepressants, sildenafil (Viagra) and alcohol may enhance the blood pressure lowering effects of glyceryl trinitrate. Use of Minitran with sildenafil is contraindicated (see Contraindications). There is a risk of coronary artery constriction with concurrent administration of dihydroergotamine.
Carcinogenicity, Mutagenesis & Impairment of Fertility
Studies in animals have not been performed with Minitran patches to evaluate the carcinogenic and mutagenic potential and effects on fertility. Glyceryl trinitrate, the active component of the Minitran patch, given in the diet to rats at doses up to 1% caused an increase in the incidence of hepatic cholangiofibrosis, hepatocellular carcinomas and/or neoplastic nodules and Leydig cell tumours in the testis. No genotoxicity studies were undertaken with glyceryl trinitrate. Lower doses of glyceryl trinitrate did not affect fertility in rats but doses up to 230 mg/kg/day caused moderate to severe testicular degeneration and/or atrophy with severe to complete aspermatogenesis. The Minitran patch contains an acrylate-based polymer adhesive. One of the unpolymerised acrylate monomers has been characterised as a carcinogen in animals and has been shown to have genotoxic potential in animals and in vitro which appears more pronounced in germ cells as compared to somatic cells. However, the risk of the very low lev ls of unpolymerised monomer causing tumours in humans following dermal application of the Minitran patch is very minimal.
Adverse reactions to glyceryl trinitrate are generally dose-related and almost all of these reactions are the result of its vasodilatory activity. Headache is the most frequently encountered adverse reaction, particularly when high doses are used. This usually regresses after a few days despite the continuation of therapy. However, if headache is persistent, it may be necessary to reduce the dose or interrupt treatment.
Reddening of the skin, with or without itching or a slight erythematous reaction, sometimes develops and generally disappears a few hours after removal of the patch without adopting other measures. The site of application should be altered daily to avoid local irritation.
Central Nervous System: Headache Cardiovascular: Hypotension (postural), dizziness, lightheadedness, hot flushes
Dermatological: Application site reaction (redness)
Gastrointestinal: Nausea, vomiting
Uncommon (≥0.1% to<1%):
Cardiovascular: Palpitations, tachycardia, angina aggravated, fainting
Cardiovascular: Rebound hypertension
Hypersensitivity: Anaphylaxis, allergic contact dermatitis
Dosage and administration
The response to nitrates differs between individuals and the minimum effective dose should be prescribed in each case. It is, therefore, recommended that treatment is started with one Minitran 5 patch per day, with upward dosage titration when necessary.
Attenuation of effect has occurred in some patients being treated with sustained release nitrate preparations. To avoid the development of tolerance (loss of effect) with continuous application and on the basis of current clinical studies, it is recommended that Minitran should be applied daily with a patch free interval of 8-12 hours (usually at night).
Each Minitran patch is contained in a sealed pouch. The adhesive layer is covered by a protective film which should be removed before application. The Minitran patch should be applied to a clean, dry, healthy area of skin on the upper arm or chest and should not be applied to the distal parts of the extremities. Subsequent patches should not be applied to the same area of skin until several days have elapsed. Minitran patches adhere easily to the skin and also stay in place whilst bathing or during physical exercise.
Use in the Elderly
No specific information on use in the elderly is available.
Use in Children
The safety and efficacy of Minitran in children has yet to be established and, therefore, recommendations for its use cannot be made.
High doses of glyceryl trinitrate may induce rapid reduction in arterial pressure, causing collapse. Due to the controlled release of glyceryl trinitrate from Minitran, overdosage is likely to be rare. In cases of suspected overdosage, the Minitran patch should be removed and any reduction in arterial blood pressure and symptoms of collapse should be treated by appropriate measures.
Haemodynamic Effects: The adverse effects of glyceryl trinitrate overdose are generally the results of vasodilation, venous pooling, reduced cardiac output and hypotension. These haemodynamic changes may have protean manifestations, including increased intra -cranial 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 diarrhoea); syncope (especially in the upright posture); air hunger and dyspnoea, 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.
Because the hypotension associated with glyceryl trinitrate overdose is the result of venodilation and arterial hypovolaemia, prudent therapy should be directed towards an increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or a similar fluid may also be necessary. The use of adrenaline 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 glyceryl trinitrate overdose in these patients may be subtle and difficult and invasive monitoring may be required.
Methaemoglobinaemia: Nitrate ions liberated during metabolism of glyceryl trinitrate can oxidise haemoglobin into methaemoglobin. Assuming that nitrate moieties of glyceryl trinitrate are quantitatively applied to the oxidation of haemoglobin, patients without cytochrome b5 reductase activity would require about 1 mg/kg of glyceryl trinitrate before manifesting clinically significant (≥10%) methaemo-globinaemia. Patients with normal reductase function would require even larger doses of glyceryl trinitrate before manifesting clinically significant methaemoglobinaemia. Continuous glyceryl trinitrate infusion at 3.1 to 4.0 mg/hr for 2-4 weeks in 36 patients resulted in an average methaemoglobin level of 0.2%, which was comparable to the level observed in patients receiving placebo. Nevertheless, there are case reports of significant methaemoglobinaemia in association with moderate overdoses of organic nitrates in patients who were thought not to be susceptible.
Methaemoglobin levels are available from most clinical laboratories. The diagnosis should be carried out in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2.. Classically, methaemoglobinaemic blood is described as chocolate brown without colour change on exposure to air. When methaemoglobinaemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.
MINITRAN 5: 30's; MINITRAN 10: 30's; MINITRAN 15: 30’s