SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Angitate Tablets 20mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 20mg of the active ingredient Isosorbide 5- Mononitrate.

Each tablet contains 5mg Lactose monohydrate (Ph.Eur)

For full list of excipients see section 6.1

3    PHARMACEUTICAL FORM

Each tablet contains 20mg of the active ingredient Isosorbide 5- Mononitrate.

White to off- white, biconvex tablets, marked with 'IMN and 20' on one side with a scoreline in between and the other side with 'BL'

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the prophylaxis of angina pectoris

As adjunctive therapy in congestive heart failure not responding to cardiac glycosides or diuretics

4.2    Posology and method of administration

Adults:

One tablet to be taken asymmetrically (to allow a nitrate low period) two or three times daily. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose be one tablet of Angitate 20mg twice a day.

The dosage may be increased up to 120 mg per day.

The lowest effective dose should be used.

Elderly

There is no evidence to suggest that an adjustment of the dosage is necessary

Children:

The safety and efficacy of Angitate 20mg has yet to be established in children. Route of Administration:

The tablet should be swallowed whole, and not chewed or crushed.

Treatment with Angitate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually. (see Section 4.4)

4.3 Contraindications

Acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse), severe hypotension(very low blood pressure), hypertrophic obstructive cardiomyopathy (HOCM), cardiac pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/mitral valve stenosis, and diseases associated with a raised intra-cranial pressure e.g. following a head trauma, including cerebral haemorrhage.

Angitate should not be given to patients with a known sensitivity to isosorbide mononitrate, the listed ingredient or other nitrates.

Angitate 20mg should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.

Phosphodiesterase type-5 inhibitors (e.g. Sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contraindicated. (see section 4.5)

4.4 Special warnings and precautions for use

Angitate 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.

Symptoms of circulatory collapse may arise after the initial dose, particularly in patients with labile circulation.

This product may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

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

Angitate tablets 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.

In the event of acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Angitate tablets

If the tablets are not taken as indicated (see section 4.2), tolerance to the medication could develop. The lowest effective dose should be used.

Treatment with Angitate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually. (see Section 4.2)

4.5 Interaction with other medicinal products and other forms of interaction

Nitrate preparations may act as a physiological antagonist to noradrenalin, acetylcholine, histamine and other agents.

Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists etc may potentiate the hypotensive effect of Angitate. This may also occur with neuroleptics and tricyclic antidepressants.

Interaction with alcohol-reaction capacity may be reduced and vasodilator activity enhanced.

The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors, such as sildenafil(used for erectile dysfunction, see section 4.4) which may lead to life threatening cardiovascular complications. Patients who are on Angitate therapy therefore must not use phosphodiesterase type-5 inhibitors.

Reports suggest that concomitant administration of Angitate may increase the blood level of dihydroergotamine and its hypertensive effect.

4.6 Fertility, pregnancy and lactation

No data have been reported which would indicate the possibility of adverse effects resulting from the use of isosorbide mononitrate in pregnancy. Safety in pregnancy, however, has not been established. It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing women.

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 hazards.

4.7 Effects on ability to drive and use machines

Dizziness, tiredness or blurred vision might occur at the start of treatment. The patient should be advised that, if affected, they should not drive or operate machinery. This effect may be increased by alcohol.

4.8 Undesirable effects

A very common (>10% of patients) adverse reaction to Angitate is throbbing headache. The incidence of headache diminishes gradually with time and continued use. At the start of therapy or when the dosage is increased, hypotension and/or light headedness in the upright position are commonly observed (i.e. in 1 - 10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachychardia and a feeling of weakness.

Infrequently (i.e. in less than 1% of patients) nausea, vomiting, flushing and allergic skin reaction (e.g. rash) may occur severely. In single cases exfoliative dermatitis may occur.

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.

A few reports of heartburn have been recorded, most likely due to a nitrate induced sphincter relaxation.

Tachycardia and paroxysmal bradycardia have been reported.

4.9 Overdose

Symptoms and signs:

Headache, hypotension, nausea, vomiting, sweating, tachycardia, vertigo, restlessness, warm flushed skin, blurred vision and syncope. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur. Methaemoglobinaemia (cyanosis, hypoxaemia, restlessness, respiratory

depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure) occurs rarely.

Management:

Consider oral activated charcoal if ingestion of a potentially toxic amount has occurred within 1 hour.

Observe for at least 12 hours after the overdose. Monitor blood pressure and pulse. Correct hypotension by raising the foot of the bed and/or by expanding the intravascular volume. Other measures as indicated by the patient's clinical condition. If severe hypotension persists despite the above measures consider use of inotropes.

If methaemoglobinaemia (symptoms or > 30% methaemoglobin), IV administration of methylene blue 1- 2 mg/kg body weight. If therapy fails with second dose after 1 hour or contraindicated, consider red blood cell concentrates or exchange transfusion. In case of cerebral convulsions, diazepam or clonazepam IV, or if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC Code: C01D A14 Vasodilator used in cardiac diseases

Isosorbide mononitrate is an organic nitrate which, in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.

Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.

It reduces the requirement of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.

5.2 Pharmacokinetic properties

Isosorbide-5-mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.

Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.

Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosorbide-5-mn-2-glucoronide which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.

After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, oncogenicity and toxicity to reproduction

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Monohydrate Compressible Sugar Colloidal Silicon Dioxide Magnesium Stearate

6.2    Incompatibilities

None known

6.3    Shelf life

Plastic containers: 60 months Blister packs: 24 months

6.4 Special precautions for storage

Store below 25°C

6.5    Nature and contents of container

Plastic containers composed of either:

A: White or grey polypropylene body with white or grey low-density polyethylene closure.

OR

B: White or grey HDPE body with an LDPE white or grey closure.

Pack sizes: 56, 60, 100, 250 and 500 tablets.

Blister packed in PVC/PVDC or hard tempered aluminium foil in strips of 14 in an outer cardboard carton.

Pack sizes: 14, 28, 30, 56 and 60 tablets

6.6    Special precautions for disposal

Not stated.

7    MARKETING AUTHORISATION    HOLDER

Bristol Laboratories Limited

Unit 3, Canalside

Northbridge Road

Berkhamsted

Herts

HP4 1EG

United Kingdom

8    MARKETING AUTHORISATION    NUMBER(S)

PL 17907/0312

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/05/1986 / 13/06/2002

10 DATE OF REVISION OF THE TEXT

26/06/2012