- Approval Id
- 618e7ea6002d0519
- Drug Approval Emc Name
- Glyceryl Trinitrate Spray 400 micrograms/metered dose, sublingual spray
- Drug Name
- Glyceryl Trinitrate Spray 400 micrograms/metered dose, sublingual spray
- Company Name
- Aspire Pharma Ltd
- Company Address
- 4 Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, UK
- Company Website
- http://www.aspirepharma.co.uk
- Company Telephone
- +44 (0)1730 231148
- Company Medical Info Direct Line
- +44 (0)1730 231148
- Company Customer Care Direct Line
- +44 (0)1730 231148
- Atc Code
- C01DA02
- Legal Category
- Pharmacy
- Authorisation Holder
- Ayrton Saunders Ltd
9 Arkwright Road
Astmoor Industrial Estate
Runcorn
Cheshire
WA7 1NU
United Kingdom
- Authorisation Number
- PL 16431/0018
- Authorisation Date
- 15/09/2005
- Instruction Authorisation Holder
- Ayrton Saunders Ltd
9 Arkwright Road
Astmoor Industrial Estate
Runcorn
Cheshire
WA7 1NU
United Kingdom
- Instruction Authorisation Number
- PL 16431/0018
- Instruction Authorisation Date
- 15/09/2005
- Instruction Composition
- Glyceryl Trinitrate: 400 micrograms per metered dose
\*\*Excipient(s) with known effect\*\*
Ethanol (alcohol) – 7.5mg per spray.
For the full list of excipients, see Section 6.1
- Instruction Dosage Form
- Sublingual spray, solution.
(Sublingual spray)
- Instruction 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 sprays (400 to 800 micrograms glyceryl trinitrate) to be sprayed under the tongue for the relief of anginal pain while the breath is held. If symptoms do not resolve, this may be repeated at five-minute intervals for a total of three sprays (maximum of 1.2 mg taken within 15 minutes). If symptoms have not resolved after a total of three sprays, immediate medical attention should be sought.
For the prevention of inducible angina (e.g. due to physical effort, emotional stress, exposure to cold) one or two metered sprays (400 to 800 micrograms glyceryl trinitrate) to be sprayed under the tongue 2 to 3 minutes prior to activity likely to cause angina.
\*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 the 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 90mm Hg).
- Hypotensive shock
- Severe anaemia
- Constrictive pericarditis
- Extreme bradycardia
- Cerebral haemorrhage and brain trauma
- Aortic and/or mitral stenosis
- Angina caused by hypertrophic obstructive cardiomyopathy.
- Circulatory collapse
- Cardiogenic shock, unless a sufficiently high left ventricular end diastolic pressure is assured by intra-aortic balloon pump counterpulsation therapy or positive inotropic drugs
- 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
Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms).
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 increase 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, ß-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:
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Very Common\*\* \*\*(≥ 1/10)\*\* | \*\*Common\*\* \*\*(≥ 1/100 to < 1/10)\*\* | \*\*Uncommon\*\* \*\*(≥ 1/1,000 to < 1/100)\*\* | \*\*Rare\*\* \*\*(≥ 1/10,000 to < 1/1,000)\*\* | \*\*Very Rare\*\* \*\*(< 1/10,000)\*\* |
| \*\*Nervous System Disorders\*\* | Headache | Vertigo Dizziness | | Syncope | |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | | | Allergic dermatitis \\* | Exfoliative dermatitis |
| \*\*Vascular Disorders\*\* | | Facial Flushing | | Orthostatic hypotension Circulatory collapse | |
| \*\*General Disorders and Administration Site Conditions\*\* | | Asthenia | Application site discomfort including Burning sensation and Stinging | | |
| \*\*Gastrointestinal Disorders\*\* | | Nausea | Tongue blistering | | |
| \*\*Cardiac Disorders\*\* | | | | Tachycardia Bradycardia Angina pectoris aggravated | |
| \*\*Investigations\*\* | | | | Blood pressure decreased | |
\\*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.
If methaemoglobinaemia is suspected, it should be confirmed, assessed and treated in accordance with local guidance and best practice. Treatment includes supplemental oxygen and intravenous methylthioninium chloride, as indicated. Symptomatic treatment should be given for respiratory and circulatory defects in more serious cases.
- Instruction Pharmacology
- 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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Peppermint oil
Propellant HFC 134A (1,1,1.2 Tetrafluoroethane)
Ethanol6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 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 either 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 10260.0 mg of solution and propellant) providing 180 metered doses.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Glyceryl Trinitrate: 400 micrograms per metered dose
\*\*Excipient(s) with known effect\*\*
Ethanol (alcohol) – 7.5mg per spray.
For the full list of excipients, see Section 6.1
## Pharmaceutical Form
Sublingual spray, solution.
(Sublingual spray)
## 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 sprays (400 to 800 micrograms glyceryl trinitrate) to be sprayed under the tongue for the relief of anginal pain while the breath is held. If symptoms do not resolve, this may be repeated at five-minute intervals for a total of three sprays (maximum of 1.2 mg taken within 15 minutes). If symptoms have not resolved after a total of three sprays, immediate medical attention should be sought.
For the prevention of inducible angina (e.g. due to physical effort, emotional stress, exposure to cold) one or two metered sprays (400 to 800 micrograms glyceryl trinitrate) to be sprayed under the tongue 2 to 3 minutes prior to activity likely to cause angina.
\*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 the 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 90mm Hg).
- Hypotensive shock
- Severe anaemia
- Constrictive pericarditis
- Extreme bradycardia
- Cerebral haemorrhage and brain trauma
- Aortic and/or mitral stenosis
- Angina caused by hypertrophic obstructive cardiomyopathy.
- Circulatory collapse
- Cardiogenic shock, unless a sufficiently high left ventricular end diastolic pressure is assured by intra-aortic balloon pump counterpulsation therapy or positive inotropic drugs
- 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
Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms).
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 increase 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, ß-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:
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Very Common\*\* \*\*(≥ 1/10)\*\* | \*\*Common\*\* \*\*(≥ 1/100 to < 1/10)\*\* | \*\*Uncommon\*\* \*\*(≥ 1/1,000 to < 1/100)\*\* | \*\*Rare\*\* \*\*(≥ 1/10,000 to < 1/1,000)\*\* | \*\*Very Rare\*\* \*\*(< 1/10,000)\*\* |
| \*\*Nervous System Disorders\*\* | Headache | Vertigo Dizziness | | Syncope | |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | | | Allergic dermatitis \\* | Exfoliative dermatitis |
| \*\*Vascular Disorders\*\* | | Facial Flushing | | Orthostatic hypotension Circulatory collapse | |
| \*\*General Disorders and Administration Site Conditions\*\* | | Asthenia | Application site discomfort including Burning sensation and Stinging | | |
| \*\*Gastrointestinal Disorders\*\* | | Nausea | Tongue blistering | | |
| \*\*Cardiac Disorders\*\* | | | | Tachycardia Bradycardia Angina pectoris aggravated | |
| \*\*Investigations\*\* | | | | Blood pressure decreased | |
\\*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.
If methaemoglobinaemia is suspected, it should be confirmed, assessed and treated in accordance with local guidance and best practice. Treatment includes supplemental oxygen and intravenous methylthioninium chloride, as indicated. Symptomatic treatment should be given for respiratory and circulatory defects in more serious cases.
## 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.
## Pharmaceutical Particulars
6.1 List of excipients
Peppermint oil
Propellant HFC 134A (1,1,1.2 Tetrafluoroethane)
Ethanol6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 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 either 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 10260.0 mg of solution and propellant) providing 180 metered doses.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
