SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

TRANGINA XL 60mg TABLETS

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 60mg Isosorbide-5-mononitrate.

3    PHARMACEUTICAL FORM

Prolonged release tablets

White, oval-shaped tablets impressed “C” on one face and the identifying letters “CY” on either side of a central division line on the reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2    Posology and method of administration

Posology

Adults: Isosorbide mononitrate (one tablet) once daily to be taken in the morning. The dose of 60mg may be increased to 120mg (two tablets) daily, both to be taken once daily in the morning. The dose can be titrated to minimise the possibility of headache, by initiating treatment with 30mg (half a tablet) for the first 2-4 days.

Isosorbide mononitrate tablets must not be chewed or crushed. They should be swallowed whole with half a glass of water.

Children: The safety and efficacy of isosorbide mononitrate in children has not been established.

Elderly: No evidence of a need for routine dosage adjustment in the elderly has been found, but special care may be needed in those with increased susceptibility to hypotension or marked hepatic or renal insufficiency.

The core of the tablet is insoluble in the digestive juices but disintegrates into small particles when all active substance has been released. Very occasionally the matrix may pass through the gastrointestinal tract without disintegrating and be found visible in the stool, but all active substance has been released.

Method of Administration For oral use.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral valve stenosis, severe anaemia, closed-angle glaucoma, toxic pulmonary oedema, conditions associated with raised intracerebral pressure e.g. following head trauma, cerebral haemorrhage.

Acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse) or very low blood pressure. Phosphodiesterase type-5 inhibitors e.g. sildenafil, tadalafil and vardenafil have been shown to potentiate the hypotensive effects of nitrates, and their coadministration with nitrates or nitric oxide donors is therefore contra-indicated (see section 4.5). Trangina XL should not be given to patients with a known sensitivity to nitrates.

4.4    Special warnings and precautions for use

Trangina XL is not indicated for relief of acute anginal attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

Trangina XL should be used with caution in patients who have a recent history of myocardial infarction, or who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.

The lowest effective dose should be used.

Attenuation of effect (tolerance) has occurred in some patients being treated with prolonged release preparations. In such patients intermittent therapy may be more appropriate (see Section 4.2).

Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see Section 4.2).

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

Severe postural hypotension with light-headedness and dizziness is frequently observed after the concomitant consumption of alcohol.

Trangina XL contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

4.5    Interaction with other medicinal products and other forms of interaction

Isosorbide dinitrate can act as a physiological antagonist to noradrenaline, acetylcholine, histamine and other agents.

Alcohol can accentuate cerebral ischaemia associated with postural hypotension. Beta-blocking drugs have a different pharmacological action in angina and may have a complimentary effect when co-administered with isosorbide mononitrate.

The hypotensive effects of nitrates are potentiated by concurrent administration of ACE inhibitors. The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors (eg sildenafil, tadalafil and vardenafil).

4.6    Fertility, pregnancy and lactation

For isosorbide-5-mononitrate no clinical data on exposed pregnancies is available. Studies in animals have shown reproductive toxicity (see section 5.3). The relevance of these data for humans is unknown. Trangina XL 60mg Tablets should not be used during pregnancy unless clearly necessary.

Isosorbide mononitrate should only be used in pregnancy and during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.

4.7    Effects on ability to drive and use machines

Isosorbide-5-mononitrate has a moderate influence on the ability of an individual to drive and use machines. Isosorbide mononitrate may cause dizziness. Patients should make sure they are not affected before driving or operating machinery.

Undesirable effects

Throbbing headache may occur when treatment is initiated, but usually disappears after 1-2 weeks of treatment. Hypotension, including postural hypotension, with symptoms such as dizziness, nausea, vomiting and fatigue has occasionally been reported. Infrequently, flushing, allergic reactions (including rashes), syncope, temporary hypoxaemia and heartburn can occur. These symptoms generally disappear during long-term treatment.

Tachycardia and paroxysmal bradycardia have been reported.

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

4.9 Overdose

Symptoms: Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure.

Treatment: Induction of emesis, activated charcoal. In case of pronounced hypotension the patient should first be placed in the supine position with legs raised. If necessary intravenous administration of fluid.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Isosorbide mononitrate is an active metabolite of the vasodilator isosorbide dinitrate.

Isosorbide-5-mononitrate is a potent venodilator and to a lesser extent an arterial dilator. Both intravenous and oral formulations reduce systemic arterial pressure and venous return, thereby lowering cardiac volume, dimensions and work. While the precise mechanism of action remains unclear, it is probably due to nitric oxide (NO) release which activates guanylate cyclase and increases the synthesis of cyclic GMP. It is possible that NO combines with sulphydryl groups in the endothelium and produces S-nitrosothiols that stimulate guanylate cyclase production. This is enhanced by N-acetylcysteine, which provides a source of sulphydryl groups. How cyclic GMP produces vascular relaxation is not exactly known.

5.2 Pharmacokinetic properties

Isosorbide mononitrate is readily absorbed from the gastro-intestinal tract. Following oral administration of conventional tablets, peak plasma levels are reached in about 1 hour. Unlike isosorbide dinitrate, isosorbide mononitrate does not undergo first-pass hepatic metabolism and bioavailability is nearly 100%. Isosorbide mononitrate is widely distributed with a large apparent volume of distribution. It is taken up by smooth muscle cells of blood vessels and the nitrate group is cleaved to inorganic nitrite and then to nitric oxide. Isosorbide mononitrate is metabolised to inactive metabolites, including isosorbide and isosorbide glucuronide. Only 2% of isosorbide mononitrate is excreted unchanged in the urine. An elimination half-life of about 4 to 5 hours has been reported.

5.3 Preclinical safety data

High concentrations of isosorbide-5-mononitrate in rats are associated with prolonged gestation and parturition, stillbirths and neonatal death.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The tablets also contain: lactose, hypromellose (E464), glyceryl palmitostearate, maize starch, magnesium stearate.

Incompatibilities

Not applicable.

6.3    Shelf life

Shelf-life

Two years from date of manufacture.

Shelf-life after dilution/reconstitution Not applicable.

Shelf-life after first opening Not applicable.

6.4    Special precautions for storage

Do not store above 25^oC.

Keep container in the outer carton.

6.5    Nature and contents of container

Aluminium (25pm)/PVC (250pm) strips in a carton box. Pack sizes: 28, 56 (Al/PVC)

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS

8    MARKETING AUTHORISATION NUMBER(S)

PL 00142/0462

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/03/2009

10 DATE OF REVISION OF THE TEXT

20/04/2015