1.    NAME OF THE MEDICINAL PRODUCT

TRINTEK 10 Glyceryl Trinitrate Transdermal Patches.

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each 16 cm² patch contains 44.8 mg glyceryl trinitrate as the active substance. The average amount of glyceryl trinitrate released per patch is 0.4 mg/hr or 10 mg/24 hours.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Transdermal patch.

TRINTEK 10 Glyceryl Trinitrate Transdermal Patch is a translucent rectangular patch with rounded corners, affixed to a clear peelable liner, and is supplied in a foil-lined sachet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The prophylactic treatment of attacks of angina pectoris.

4.2    Posology and method of administration

Posology

Adults including elderly patients:

For adults and the elderly treatment should be initiated with one TRINTEK 5 (5mg/24hr) transdermal patch.

If higher doses are required a TRINTEK 10 (10mg/24hr) transdermal patch and if necessary a TRINTEK 15 (15mg/24hr) transdermal patch may be substituted.

The maximum daily dose in resistant cases is one TRINTEK 15 (15mg/24hr) transdermal patch.

The effective dosage must be obtained progressively because of the risk of hypotension and severe headache in some patients except when transdermal form is used after intravenous form of nitrates.

Transdermal glyceryl trinitrate should be given intermittently with the patch removed for at least 8 hours in each 24 hour period. The intermittent usage is required to prevent the development of tolerance or attenuation of therapeutic effect.

The glyceryl trinitrate free interval should be established during the period when the patient does not have anginal attacks. The time of administration of the existing combined therapy (beta-blocker and/or calcium antagonist therapy) should be chosen accordingly to assure a therapeutic efficacy.

Paediatric patients:

Transdermal glyceryl trinitrate patches are not recommended for use in children. Method of administration

The patch should be applied to the lateral chest wall over a hairless area.

Replacement patches should be applied to a new area of skin allowing a week to elapse before reapplying a patch to the same area of skin.

The patches should not be cut or torn.

4.3    Contraindications

Hypersensitivity to the active substance, and related organic nitrates or to any of the excipients listed in section 6.1.

Severe hypotension (systolic blood pressure less than 90 mmHg).

Myocardial insufficiency due to mitral stenosis, constrictive pericarditis or any cause of outflow obstruction, in particular aortic stenosis and hypertrophic cardiomyopathy or pericardial tamponade.

Acute circulatory failure associated with marked hypotension (shock).

Cerebral haemorrhage, head trauma, closed-angle glaucoma.

Severe anaemia.

Severe hypovolaemia.

Concomitant administration of TRINTEK and phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil is contraindicated because PDE5 inhibitors may amplify the vasodilatory effect of TRINTEK resulting in severe hypotension.

Conditions associated with increased intracranial pressure.

4.4    Special warnings and precautions for use

The lowest effective dose should be used. TRINTEK transdermal patch is not indicated for the treatment of acute anginal attacks, unstable angina and myocardial infarction.

TRINTEK transdermal patch should be used cautiously under strict medical surveillance and/or haemodynamic monitoring in patients with low filling pressure e.g. in recent myocardial infarction or (acute) heart failure. A reduction of blood pressure below 90mmHg should be avoided (see also section 4.3).

As with other nitrate preparations, when transferring the patient on long-term therapy to another form of medication, glyceryl trinitrate should be gradually withdrawn and overlapping treatment started.

Withdrawal of long-term treatment should be gradual as chest pain and myocardial infarction have been associated with the sudden withdrawal of nitrates.

If an anginal attack occurs during the period of withdrawal, a re-evaluation of the coronary disease is crucial and an adaptation of the treatment should be considered (medical treatment or revascularisation).

Hypoxaemia:

Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of glyceryl trinitrate is reduced. Similarly, caution is called for in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure. In patients with alveolar hypoventilation a vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (Euler-Liljestrand mechanism). Patients with angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, glyceryl trinitrate could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.

Caution should be exercised in patients suffering from hypothyroidism, malnutrition, severe renal or hepatic impairment and hypothermia.

Use with caution in patients with known postural hypotension.

Hypertrophic cardiomyopathy:

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. Increased angina:

The possibility of increased frequency of angina during patch free periods should be considered. In such cases a supplementary oral anti-anginal therapy with drugs not containing organic nitrates may be required.

The patch should be removed before applying magnetic or electrical fields to the body during procedures such as MRI (Magnetic Resonance Imaging), cardioversion or DC defibrillation in order to avoid the possibility of arcing between the patch and the electrodes. The system should also be removed before diathermy treatment.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

Removal of the patch should be considered as part of the management of patients who develop significant hypotension. The patch should also be removed if collapse or shock occurs.

Concomitant administration of organic nitrates and sildenafil may result in severe hypotension (see sections 4.3 and 4.5).

Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants, neuroleptics and dihydroergotamine, as well as the consumption of alcohol, may potentiate the hypotensive effects of glyceryl trinitrate.

Tolerance to sublingual glyceryl trinitrate:

As tolerance to glyceryl trinitrate patches develops, the effect of sublingual glyceryl trinitrate on exercise tolerance may be partially diminished.

4.5    Interaction with other medicinal products and other forms of interaction

Interactions resulting in a concomitant use contraindicated:

Concomitant administration of TRINTEK transdermal patch and other vasodilators (e.g. PDE5 inhibitors such as sildenafil) potentiates the blood-pressure-lowering effect of TRINTEK.

Concomitant administration of nitrates and sildenafil may result in severe hypotension due to a synergic effect (see also section 4.3). This may increase myocardial ischaemia and induce, particularly, an acute coronary event.

Interactions to be considered:

Concomitant treatment with calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers may potentiate the blood-pressure-lowering effect of TRINTEK transdermal patch, as may alcohol.

The non-steroidal anti-inflammatory drugs, with the exception of acetyl salicylic acid, may diminish the therapeutic response of TRINTEK transdermal patch.

Concurrent administration of TRINTEK transdermal patch with amifostine and acetyl salicylic acid may potentiate the blood pressure lowering effects of TRINTEK.

Concurrent administration of TRINTEK transdermal patch with dihydroergotamine may increase the bioavailability of dihydroergotamine. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises the effect of glyceryl trinitrate and may lead to coronary vasoconstriction.

4.6    Fertility, pregnancy and lactation

Fertility:

There is no data available on the effect of TRINTEK transdermal patch on fertility in humans.

Pregnancy:

Studies performed with glyceryl trinitrate in rats (intraperitoneal route) and rabbits (intravenous route) showed no evidence of embryotoxicity or teratogenicity in these species. However, since there are no adequate studies in pregnant women the product should only be administered during pregnancy if the potential benefits outweigh any possible risk to the foetus.

Caution should be advised during pregnancy, especially in the first 3 months. Breast-feeding:

There is limited information on the excretion of the active substance in human or animal breast milk. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from TRINTEK transdermal patch therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7    Effects on ability to drive and use machines

TRINTEK transdermal patch, especially at the start of treatment or dose adjustments, may impair the reactions or might rarely cause orthostatic hypotension and dizziness (as well as exceptionally syncope after overdosing). Patients experiencing these effects should refrain from driving or using machines.

4.8    Undesirable effects

Adverse drug reactions are listed by MedDRA System-Organ Class (SOC). Within each System-Organ Class the adverse drug reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse drug reactions are ranked in order of decreasing seriousness. In addition, the corresponding frequency category, using the following convention (CIOMS III: Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to <1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data)

System Organ Class	Very Common	Common	Uncommon	Rare	Very Rare	not known
Nervous system disorders		Headache1			Dizziness
Cardiac disorders				Tachycardia2		Palpitation4
Vascular disorders				Orthostatic hypotension flushing2
Gastrointestinal disorders	Nausea, vomiting
Skin and subcutaneous tissue disorders			Contact dermatitis			Rash generalized4
General disorders and administration site conditions			Application site erythema, pruritus, burning, 3 irritation
Investigations				Heart rate increase

¹ Like other nitrate preparations, TRINTEK transdermal patch commonly causes dose-dependent headaches due to cerebral vasodilatation. These often regress after a few days despite the maintenance of therapy. If headaches persist during intermittent therapy, they should be treated with mild analgesics. Unresponsive headaches are an indication for reducing the dosage of glyceryl trinitrate or discontinuing treatment.

²A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.

³Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.

⁴The following adverse drug reactions have been derived from post-marketing experience with TRINTEK transdermal patch via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Within each System-Organ Class, adverse reactions are presented in order of decreasing seriousness.

4.9 Overdose

High doses of glyceryl trinitrate are known to cause pronounced systemic undesirable effects including nausea, vomiting, restlessness, warm flushed skin, blurred vision, headache, fainting, tachycardia, hypotension and palpitations resulting in syncope and collapse. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur.

The nitrate effect of TRINTEK transdermal patch can be rapidly terminated simply by removing the system(s). Observe for at least 4 hours after the overdose or 12 hours if a sustained release preparation has been taken. Monitor blood pressure and pulse.

Correct hypotension by elevation e.g. raising the foot of the bed, or, if necessary, compression bandaging of the patient’s legs and/or by expanding the intravascular volume. Other general resuscitative measures as indicated by the patient’s clinical condition.

Methaemoglobinaemia has been reported following accidental overdosage. When methaemoglobinaemia is diagnosed the treatment of choice is methylene blue 1 to 2mg/kg intravenously.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Vasodilators used in cardiac disease, ATC Code: C01D A02

Glyceryl trinitrate relaxes vascular smooth muscle causing peripheral venodilatation, and to a lesser degree, arteriolar-dilatation. Thus preload is reduced as a result of decreased venous return to the heart and thereby reduced left ventricular filling pressure and pulmonary capillary wedge pressure. Afterload is also reduced since arteriolar dilatation reduces peripheral vascular resistance and hence decreases left ventricular outflow impedance. Both these effects reduce myocardial oxygen consumption.

Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction and coronary dilatation remains undefined.

5.2    Pharmacokinetic properties

In healthy volunteers, steady state plasma concentrations of glyceryl trinitrate are achieved approximately two hours after application of the patch and are maintained for the duration of wearing the patch (up to 24 hours). Upon removal of the patch, the plasma concentration of glyceryl trinitrate and its metabolites rapidly declines.

Glyceryl trinitrate is widely distributed with a large apparent volume of distribution (3 L/kg). Due to extensive first pass metabolism in the liver, bloavailability is reduced, with a resulting serum half-life of approximately three minutes. Glyceryl trinitrate is metabolised to two active metabolites, 1,2-glyceryl dinitrate and 1 ,3-glyceryl dinitrate. The serum half-life of these metabolites is approximately 40 minutes. The dinitrates are further metabolised to the inactive mononitrate and, ultimately to glycerol and carbon dioxide.

Preclinical safety data

In a primary dermal irritation study in rabbits with the 24 cm transdermal patch applied for 12 hours, on removal of the patch there was slight to well defined erythema which was absent by the 14th day post-application. There was no evidence of glyceryl trinitrate induced delayed skin sensitisation when the 24 cm² glyceryl trinitrate transdermal patch was applied to guinea-pigs.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Release liner consisting of a polyester layer coated on one side with silicone. Impermeable backing film made from a patented blend of polyethylene resins.

Acrylic pressure sensitive adhesive made from a random copolymer of 2-ethylhexylacrylate, vinyl acetate and acrylic acid.

White ink containing: titanium dioxide (pigment), acrylic polymer resin, styrenated acrylic polymer emulsion, triethanolamine, propylene glycol, polyethylene wax, polytetrafluorethylene, poly dimethyl siloxane and sodium dioctyl sulphosuccinate.

6.2    Incompatibilities

Not applicable

6.3    Shelf life

24 months

6.4    Special precautions for storage

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

6.5    Nature and contents of container

The patches are packed into cardboard cartons containing 15 or 30 individual patches.

The sachet consists of paper/PE/aluminium/PE layers.