INFORMATION FOR HEALTH PROFESSIONALS
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The rate of release of glyceryl trinitrate is proportional to the area of the patch applied to the skin. Approximately 0.75 mg glyceryl trinitrate is released per 24 hours for every square centimetre of patch area. Each patch is packaged in a paper laminate pouch.
When a MINITRAN patch is applied to the skin, glyceryl trinitrate is absorbed continuously through the skin into the systemic circulation. This results in active medication reaching the target organs (heart, vascular system) before deactivation by the liver. Glyceryl trinitrate is a smooth muscle relaxant with vascular effects manifested predominantly by venous dilation with pooling. The major beneficial effect of glyceryl trinitrate in angina pectoris is a reduction in myocardial oxygen consumption secondary to vascular dilation with resultant reduction in cardiac preload and afterload. There is also a direct vasodilator effect of glyceryl trinitrate on the large coronary arteries.
In studies of MINITRAN in healthy volunteers, transdermal absorption of glyceryl trinitrate was demonstrated by attainment of continuous venous plasma levels for a minimum of 24 hours. In most cases, detectable plasma levels were attained within 30 minutes, reaching steady state 2 hours after application of the patch. Levels were maintained for 24 hours and diminished rapidly when the patch was removed. The precise definition of "therapeutic plasma level" for glyceryl trinitrate is not known. The amount of glyceryl trinitrate released (5 mg or 10 mg per 24 hours) represents the mean release rate of glyceryl trinitrate as determined from healthy volunteers and, hence, the amount potentially available for absorption from the skin. Absorption will vary among individuals.
Prevention of chronic stable angina pectoris due to coronary artery disease and vasospasm and the treatment of chronic congestive heart failure.
The initial starting dose is usually one 5mg/24 hr patch appied once a day. To achieve optimum therapeutic effect in some patients, it may be necessary to titrate to a higher dosing strength.
In order to avoid the possible development of tolerance that can occur with long term continuous levels of nitrates, it is recommended that where possible patients be advised to wear the MINITRAN patch for 16-18 hours a day to allow a nitrate free interval of 6-8 hours (usually overnight).
Dosage should be titrated while monitoring clinical response, i.e., blood pressure, episodes of angina and subsequent use of sublingual glyceryl trinitrate. The MINITRAN patch may remain in place for periods of up to 24 hours as required.
The MINITRAN patch may be applied to any convenient skin area; a recommended site of application is the arm or chest. A suitable area may be lightly shaved if necessary. Remove and discard the patch after 24 hours. Place a new patch on a different skin site. Do not apply the MINITRAN patch to the distal part of the extremities, i.e. below the elbow or knees.
No specific information on use in the elderly is available.
The safety and efficacy of MINITRAN in children has yet to be established and recommendations for its use can not be made.
MINITRAN is contraindicated in cases of known hypersensitivity to organic nitrates or to the stated excipients including adhesive in the patch, severe anaemia, increased intraocular and intracranial pressure and marked arterial hypotension or shock. MINITRAN 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 intended for use in the treatment of acute anginal 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 glyceryl trinitrate is used 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.
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 cardioverter/difibrillator 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. MINITRAN 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.
Assigned Category B2 by the Australian Drug Evaluation Committee. The safety of MINITRAN in pregnancy has not been established. As with all medicines, 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.
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.
MINITRAN is unlikely to produce an effect on the ability to drive or use machinery. However, as MINITRAN may lower blood pressure the patient may feel dizzy, particularly when changing position suddenly.
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.
Concomitant use of alcohol may enhance the vascular effects of glyceryl trinitrate. Concomitant use of MINITRAN and other vasodilatory agents, calcium antagonists, beta-blockers, ACE inhibitors, neuroleptics, diuretics, antihyertensives, tricyclic antidepressants, sildenafil 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.
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 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.
The adverse effects of glyceryl trinitrate overdose are generally the results of vasodilatation, venous pooling, reduced cardiac output and hypotension. These haemodynamic 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 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.
Nitrate ions liberated during metabolism of glyceryl trinitrate can oxidise haemoglobin into methaemaoglobin. 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%) methaemoglobinaemia. 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 methaemoglobinaemaia 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 oxygen pressure. 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.
Store below 25°C. Extremes of temperature and/or humidity should be avoided. Product shelf life is 36 months.
Prescription Medicine
Each pack contains 30 patches individually enclosed in paper pouches.
To apply a MINITRAN patch:
3M New Zealand Limited
P.O. Box 33246
Takapuna
AUCKLAND
Telephone: (09) 444 5289
Facsimile: (09) 444 5770
15 October 2002
™MINITRAN and 3M are registered trademarks.