INFORMATION FOR HEALTH PROFESSIONALS
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Metered dose (aerosol, CFC free) oromucosal (sublingual) spray solution delivering 400 micrograms glyceryl trinitrate per spray (200 metered doses per aluminium canister).
Glyceryl trinitrate acts on vascular smooth muscles to produce arterial and venous vasodilation. The vasodilation results in a reduction of venous return and an improvement in myocardial perfusion with the result of a reduction in the work performed by the heart and hence reduced oxygen demand.
Glyceryl trinitrate is rapidly absorbed through the buccal and sublingual mucosa, and in man peak concentrations in plasma are observed within four minutes of sublingual administration.
The absolute bioavailability after sublingual administration is approximately 39%. After sublingual administration the plasma levels have shown a wide range of intra and inter-individual variability.
The compound is extensively metabolised by liver enzymes and has a plasma half life of 1-3 minutes. The principle mechanism of metabolism involves denitration.
Treatment of acute angina pectoris. As well as relieving the pain of an acute attack, GLYTRIN Spray may be used prophylactically five to ten minutes prior to engaging in activities which may precipitate an acute attack.
At the onset of an attack, initially one spray (400 microgram) should be sprayed under the tongue, followed by a second spray if pain relief has not occurred within 5 minutes. No more than two metered doses are recommended. If chest pain persists, seek prompt attention.
During application the patient should rest, ideally in the sitting position. The canister should be held vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should be sprayed under the tongue and the mouth should be closed immediately after each dose. The spray should not be inhaled. Patients should be instructed to familiarise themselves with the position of the spray orifice, which can be identified by the finger rest on top of the valve, in order to facilitate orientation for administration at night.
The use of any form of glyceryl trinitrate during the early days of acute myocardial infarction requires particular attention to haemodynamic monitoring and clinica status.
Because GLYTRIN Spray is more stable than glyceryl trinitrate tablets, it is possible that some patients transferred to the spray will receive a larger dose of the drug than usual. This may increase possible side effects, eg. headache ( see Adverse Reactions ).
General: Severe hypotension, particularly with upright posture, may occur even with small doses of glyceryl trinitrate. The drug, therefore, should be used with caution in subjects with may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (eg. below 90 mmHg). Paradoxical bradycardia and increased angina pectoris may accompany glyceryl trinitrate induced hypotension. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Tolerance: Tolerance to this drug and cross tolerance to other nitrates and nitrites may occur. Tolerance to the vascular and antianginal effects of nitrates has been demonstrated in clinical trials, experience through occupational exposure, and in isolated tissue experiments in the laboratory.
Intermittent therapy, such as with GLYTRIN Spray, will reduce the likelihood of tolerance developing to glyceryl trinitrate.
Withdrawal: Various clinical trials in angina patients indicate that withdrawal of glyceryl trinitrate may cause rebound of haemodynamic effect and a more ready provocation of anginal attack.
Hypoxaemia: Arterial oxygen tension decreases after administration of glyceryl trinitrate in normal subjects and in patients with coronary artery disease.
Caution should be observed in patients with severe ischaemic heart disease as a decrease in available oxygen may oppose its antianginal effect.
Methaemoglobinaemia: Methaemoglobinaemia has been reported in association with high doses of glyceryl trinitrate therapy. This may be clinically significant, especially in the presence of methaemoglobin reductase deficiencies or in congenital methaemoglobin variants.
Use in Pregnancy: [(Category B2) 3rd edition "Medicines in Pregnancy"{Australia}]
The safety of glyceryl trinitrate administered to women who are or who may become pregnant has not been established. Therefore, GLYTRIN Spray should not be given to pregnant women unless, in the judgment of the doctor, the expected benefit outweighs any potential risk.
Use in lactation: It is not known whether glyceryl trinitrate is excreted in human milk. Caution is advised when glyceryl trinitrate is administered to a breastfeeding mother.
Use in children: The safety and effectiveness of glyceryl trinitrate in children have not been established.
Generally dose related, particularly headache and hypotension. Headache, which may be severe and persistent, is the most commonly reported side effect. The following adverse events observed on occasion during treatment with organic nitrates but not necessarily GLYTRIN Spray are as follows.
Nervous system. The most frequent adverse reaction in patients treated with glyceryl trinitrate is headache, which is dose dependent. The individual sensitivity to headache varies greatly. Dizziness and fainting, especially on standing, have also been reported.
Biochemical. Decreased arterial oxygen tension.
Cardiovascular. Tachycardia, bradycardia, hypotension, palpitations.
Dermatological. Cutaneous flushing, exfoliative dermatitis.
Gastrointestinal. Nausea and vomiting are both uncommon.
Haematological. Methaemoglobinaemia.
Musculoskeletal. Muscle twitching, weakness
Nervous system. Apprehension, restlessness.
Abrupt withdrawal may precipitate angina. Withdrawal may also exacerbate
Raynaud's phenomenon in susceptible patients.
Alcohol may enhance sensitivity to the hypotensive effects of nitrates. Glyceryl trinitrate acts directly on vascular muscle. Therefore, any other agent that directly or indirectly acts on vascular smooth muscle can be expected to have decreased or increased effect depending upon the agent. 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.
Glyceryl trinitrate may potentiate the hypotensive and anticholinergic effects of tricyclic antidepressants.
Concomitant use of GLYTRIN Spray and sildenafil (Viagra®) enhances the hypotensive effect. Therefore, the concomitant administration of GLYTRIN Spray and sildenafil is contraindicated. If a patient treated with sildenafil needs a rapidly effective nitrate (eg in the case of an acute angina pectoris attack) he/she must be hospitalised immediately.
Symptoms: Nitrate overdosage may result in severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhoea), syncope (especially in the upright posture), methaemoglobinaemia with cyanosis and anorexia, initial hyperpnoea, dyspnoea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse.
Treatment: Keep the patient recumbent and comfortably warm. Hypotension and reflex tachycardia caused by overdosage can be treated by elevating the legs.
Since the duration of the haemodynamic effects following overdosage with glyceryl trinitrate is quite short (because of its short half-life) additional measures are usually not required.
Administer oxygen and artificial ventilation if necessary.
In cases of severe overdose apply the general guidelines for treating overdose and/or shock therapy. For pronounced hypotension, volume expansion can be performed.
However, if further therapy is indicated, administration of an intravenous a-adrenergic agonist (eg. metaraminol) should be considered.
Warning: Adrenaline is ineffective in reversing the severe hypotensive events associated with overdose. It and related compounds are contraindicated in this situation.
Methaemoglobin: Case reports of clinically significant methaemoglobinaemia are rare at conventional doses of organic nitrates. The formation of methaemoglobin is dose related and in the case of genetic abnormalities of haemoglobin that favour methaemoglobin formation, even conventional doses of organic nitrates could produce harmful concentrations of methaemoglobin. If methaemoglobinaemia is present, administration of methylene blue (1% solution), 1 to 2mg/kg bodyweight intravenously, may be required.
Store at temperature below 25°C. Protect from frost, heat and sunlight. GLYTRIN Spray is a pressurised aluminium canister which must not be pierced or burnt even after use. Patients, especially those who smoke should be warned not to use GLYTRIN Spray near a naked flame.
Pharmacy only medicine
Metered dose spray containing 200 doses per aluminium container.
The propellant is CFC free.
Distributed by:
AFT Pharmaceuticals Ltd
PO Box 87-266, Meadowbank
AUCKLAND
E:mail hartley.atkinson@aftpharm.co.nz
For Bioglan Pharma Plc, Hitchin, SG4 0AP, United Kingdom
3 March 2001