GLYCERYL TRINITRATE SPRAY 400 MICROGRAMS PER METERED DOSE SUBLINGUAL SPRAY - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Glyceryl Trinitrate Spray 400 microgram­s/metered dose, sublingual spray.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Glyceryl Trinitrate: 400 micrograms per metered dose

Excipient(s) with known effect

Ethanol (alcohol) – 7.5 mg per spray.

For the full list of excipients, see Section 6.1

3 PHARMACEUTICAL FORM

Sublingual spray, solution.

(Sublingual spray)

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of acute angina pectoris.

Prevention of inducible angina (e.g. physical effort, emotional stress, exposure to cold).

4.2 Posology and method of administration

Posology

Oromucosal Dosage

Adults including the elderly

At the onset of an attack, one or two metered doses (400 to 800 micrograms glyceryl trinitrate) to be sprayed under the tongue for the relief of anginal pain while breath is held. No more than three doses are recommended at any one time.

For the prevention of inducible angina (e.g. physical effort, emotional stress, exposure to cold), one or two 400 microgram metered doses sprayed under the tongue within 2 – 3 minutes of the event starting.

Paediatric population

Glyceryl Trinitrate Spray should not be used in children and adolescents under 18 years.

Method of administration

Before using Glyceryl Trinitrate Spray for the first time, the patient should check that the spray is working by pressing the pump button a few times until it produces a fine mist of liquid. The patient should practice aiming the spray onto a tissue or similar item so that they will be able to aim it correctly under the tongue when they need to use it. If the patient does not need to use Glyceryl Trinitrate Spray very often, the spray should be checked regularly to see that it still works properly.

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.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

– Severe hypotension (systolic blood pressure lower than 90 mm Hg)

– Hypotensive shock

– Severe anaemia

– Constrictive pericarditis

– Extreme bradycardia

– Glucose-6-phosphate-dehydrogenase-deficiency

– Cerebral haemorrhage and brain trauma

– Aortic and/or mitral stenosis

– Angina caused by hypertrophic obstructive cardiomyopathy

– Circulatory collapse

– Cardiogenic shock

– Toxic pulmonary oedema

– Concomitant use with phosphodiesterase inhibitors, such as sildenafil, tadalafil, or vardenafil

– Concomitant use with the soluble guanylate cyclase stimulator riociguat (see section 4.5).

4.4 Special warnings and precautions for use

Tolerance to this drug and cross-tolerance to other nitrates may occur.

Glyceryl Trinitrate Spray should be administered with particular caution in:

– Pericardial tamponade

– Low filling pressures (e.g. acute myocardial infarction, left ventricular failure)

– Tendency to dysregulation of orthostatic blood pressure

– Diseases accompanied by an increase in intracranial pressure (so far further pressure has been observed solely in high doses of glyceryl trinitrate).

Alcohol should be avoided because of the hypotensive effect.

Medical controls of the intraocular pressure of glaucoma patients are advisable.

Particular caution should also be exercised when using Glyceryl Trinitrate Spray in patients with volume depletion from diuretic therapy, severe hepatic or renal impairment and hypothyroidism.

This medicine contains 7.5 mg of alcohol (ethanol) in each spray. The amount in one spray of this medicine is equivalent to less than 1 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

4.5 Interaction with other medicinal products and other forms of interaction

– Alcohol may potentiate the hypotensive effect.

– Vasodilators, antihypertensives, B-blockers, calcium antagonists, neuroleptics, tricyclic antidepressants and diuretics can increase nitrate induced hypotension.

– The hypotensive effects of nitrates are potentiated by the concurrent administration of phosphodiesterase inhibitors, such as Sildenafil, Tadalafil or Vardenafil.

– The use of a soluble guanylate cyclase stimulator such as riociguat is contraindicated (see section 4.3) since concomitant use can cause hypotension.

– The bioavailability of dihydroergotamine may be increased by concomitant use of Glyceryl Trinitrate Spray, which can result in vasoconstriction since dihydroergotamine can antagonise the effects of glyceryl trinitrate.

– The concomitant administration of Glyceryl Trinitrate Spray and heparin can reduce the antithrombotic effect of heparin. Regular monitoring of coagulation parameters and adjustments of the heparin dose may be necessary.

– In patients pretreated with organic nitrates a higher dose of glyceryl trinitrate may be necessary to achieve the desired haemodynamic effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of glyceryl trinitrate in human pregnancy, especially during the first trimester has not been established.

Breastfeeding

It is not known whether glyceryl trinitrate is excreted into human breast milk. Glyceryl Trinitrate Spray should only be used after weighing the benefit for the mother against possible risks for the child. Nursing should be discontinued during treatment with this product.

Fertility

Preclinical data reveal no special hazard for humans based on conventional studies of toxicity to reproduction (see section 5.3).

4.7 Effects on ability to drive and use machines

The ability to react may be diminished because of the side effects or interactions due to the nitrates. This effect is potentiated by alcohol consumption. Therefore, driving and/or using machines should be avoided during treatment with Glyceryl Trinitrate Spray.

4.8 Undesirable effects

The following adverse reactions have been reported:

*symptoms which are known in conjunction with hypersensitivity reactions

Use of Glyceryl Trinitrate Spray may give rise to transient hypoxaemia and, in patients with coronary heart disease, ischaemia as a result of a relative redistribution of the bloodstream, which is to hypoventilated alveolar areas.

Tolerance development and the occurrence of crossed tolerance of other nitro compounds have been found in chronic, continuous treatment using high doses. To avoid a decrease in efficacy or a loss of efficacy, high continuous doses should be avoided.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow

Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Signs and symptoms

Flushing, severe headache, vertigo, tachycardia, a feeling of suffocation, hypotension, fainting and rarely cyanosis and methaemoglobinaemia may occur. In a few patients, there may be a reaction comparable to shock with nausea, vomiting, weakness, sweating and syncope.

Treatment

Recovery often occurs without special treatment. Hypotension may be corrected by elevation of the legs to promote venous return.

Methaemoglobinaemia should be treated by intravenous methylthioninium chloride and/or toluidine blue. Symptomatic treatment should be given for respiratory and circulatory defects in more serious cases.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vasodilators used in cardiac diseases, organic nitrates. ATC-Code: C01DA02

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.

5.2. Pharmacokinetic Properties

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or toxicity to reproduction.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Peppermint oil

Propellant HFC 134A (1,1,1.2 Tetra­fluoroethane)

Ethanol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

Glyceryl Trinitrate Spray is an aerosol spray and contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the aluminium container (canister), even when empty.

It should not be sprayed at a naked flame or any incandescent material.

Patients, especially those who smoke should be warned not to use Glyceryl Trinitrate Spray near a naked flame.

6.5 Nature and contents of container

Internally lacquered monobloc aluminium pressurised container (canister), sealed with a metered spray valve. The product is presented in packs with one container.

Each container contains 1760.0 mg of solution (according to 11400.0 mg of solution and propellant) providing 200 single metered doses, or 1584.0 mg of solution (according to 10260.0mg of solution and propellant) providing 180 metered doses.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Ayrton Saunders Ltd

9 Arkwright Road

Astmoor Industrial Estate

Runcorn

Cheshire

WA7 1NU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 16431/0018

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

15/09/2005