This information is intended for use by health professionals

1. Name of the medicinal product

Chemydur 60XL

Mitrate 60XL

2. Qualitative and quantitative composition

Each tablet contains 60 mg of isosorbide-5-mononitrate.

International non-proprietary name (INN): Isosorbide mononitrate.

Chemical name: 1,4 : 3,6 dianhydro-D-glucitol-5-nitrate.

Excipients with known effect:

Lactose

(38.167 mg/ tablet)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets (modified release).

Oval, cream coloured tablets, half scored on both sides and marked with a crown and 60 on one side.

4. Clinical particulars
4.1 Therapeutic indications

Chemydur 60XL Tablets are indicated in adults for the prophylactic treatment of angina pectoris

4.2 Posology and method of administration

Posology

Adults:

One tablet (60 mg) once daily given in the morning. The dose may be increased to two tablets (120 mg), to be taken together.

The dose can be titrated to minimise the possibility of headache by initiating treatment with half a tablet (30 mg) for the first two to four days.

The tablets should not be chewed or crushed and should be swallowed with half a glass of fluid.

Paediatric population

The safety and efficacy of Chemydur 60XL Tablets in children have not been established.

Elderly:

There is no need for routine dose adjustment in the elderly, but care may be needed in those patients with increased susceptibility to hypotension, and in those with marked hepatic or renal insufficiency.

The lowest effective dose should be used.

There is a risk of tolerance developing to modified release preparations. In such patients intermittent therapy may be more appropriate.

As with other drugs for the treatment of angina pectoris, abrupt discontinuation of therapy may lead to exacerbation of symptoms. When discontinuing long-term treatment, the dosage should be reduced gradually over several days, and the patient carefully monitored (see section 4.4).

Method of administration

Oral.

4.3 Contraindications

Hypersensitivity to isosorbide mononitrate or to any of the excipients listed in section 6.1.

Acute myocardial infarction with low filling pressures, hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral stenosis and severe anaemia, hypovolaemia, conditions causing raised intracranial pressure (e.g. cerebral haemorrhage, head trauma) and closed-angle glaucoma. Severe cerebrovascular insufficiency or hypotension are contraindications to use.

Phosphodiesterase type-5 inhibitors (e.g. sildenafil) have been shown to potentiate the hypotensive effects of nitrates, their co-administration with nitrates or nitric oxide donors is therefore contraindicated.

4.4 Special warnings and precautions for use

The lowest effective dose should be used.

There is a risk of tolerance developing to modified release preparations. In such patients intermittent therapy may be more appropriate.

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

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

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 consumption of alcohol.

Chemydur 60XL Tablets are not indicated for relief of acute anginal attacks: in the event of an acute attack, glyceryl trinitrate should be used.

The administration of isosorbide mononitrate causes a decrease of) effective renal plasma flow (eRPF) in cirrhotic patients and should be used with caution.

Caution should be used in patients who have a recent history of myocardial infarction and in patients suffering from hypothyroidism, hypothermia, malnutrition, and severe liver or renal disease. Oral nitrates should also be used with caution in patients with angina due to other causes, or pre-existing hyperdynamic conditions.

Since oral nitrates can cause venous dilatation, they should not be used in patients with increased intracranial pressure.

Chemydur 60XL Tablets contain lactose,

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The hypotensive effect of nitrates will be increased if used together with phosphodiesterase type-5 inhibitors (e.g. sildenafil). This might lead to life threatening cardiovascular complications.

Any medication which may cause hypotension may have its hypotensive effects potentiated by concurrent administration of Chemydur 60XL Tablets (e.g. alcohol, antihypertensives, vasodilators, calcium channel blockers, and diuretics).

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

Alcohol can attenuate cerebral ischaemia associated with postural hypotension.

Isosorbide mononitrate can act as a physiological antagonist to noradrenaline, acetylcholine and histamine.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety and efficacy of 1Chemydur 60XL Tablets/Mitrate 60XL Tablets during pregnancy in humans has not been established. Animal studies have shown reproductive toxicity (see section 5.3). Isosorbide mononitrate should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

Breast-feeding

The safety and efficacy of 2Chemydur 60XL Tablets/Mitrate 60XL Tablets during lactation in humans 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 during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

1 PL 06464/0506-0020; 11/12/2009

2 PL 06464/0506-0020; 11/12/2009

4.7 Effects on ability to drive and use machines

The patient should be warned not to drive or operate machinery if hypotension or dizziness occurs.

4.8 Undesirable effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependent.

Headache is very common (>10%). The incidence of headache usually disappears after 1-2 weeks of treatment. (see section 4.2)

Immune system disorders

Allergic dermatitis, exfoliative dermatitis.

Nervous system disorders

Headache, restlessness, somnolence, pituitary haemorrhage.

Cardiac disorders

Tachycardia, bradycardia - these symptoms generally disappear during long-term treatment.

Vascular disorders

Flushing, dizziness, orthostatic hypotension - these symptoms generally disappear during long-term treatment. Pallor. Circulatory collapse (sometimes accompanied by bradyarrhythmia, bradycardia and syncope). Severe hypotension may lead to enhanced angina pectoris symptoms.

Respiratory, thoracic and mediastinal disorders

Hypoxia.

Gastrointestinal disorders

Nausea, vomiting, diarrhoea

Skin and subcutaneous tissue disorders

Hyperhidrosis, pruritus.

Musculoskeletal and connective tissue disorders

Myalgia.

General disorders and administration site conditions

Asthenia.

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 and signs

Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur.

Methaemoglobinaemia (cyanosis, hypoxaemia, change in mental status, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure and raised intracranial pressure) occurs rarely.

Management

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, fluids should be administrated intravenously.

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.

If methaemoglobinaemia occurs seek expert advice. Treat with supplemental oxygen and methylene blue. In cases not responding to methylene blue or where methylene blue is contraindicated consider exchange transfusion or red blood cell concentrates. In case of cerebral convulsions, consider diazepam or clonazepam IV or, if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: organic nitrate

ATC code: C01DA14

Mechanism of action

Organic nitrates (including glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate) are potent relaxers of smooth muscle. They have a powerful effect on vascular smooth muscle with less effect on bronchiolar, gastrointestinal, ureteral and uterine smooth muscle. Low concentrations dilate both arteries and veins.

Venous dilatation pools blood in the periphery leading to a decrease in venous return, central blood volume, and ventricular filling volumes and pressures. Cardiac output may remain unchanged or it may decline as a result of the decrease in venous return. Arterial blood pressure usually declines secondary to a decrease in cardiac output or arteriolar vasodilatation, or both. A modest reflex increase in heart rate results from the decrease in arterial blood pressure. Nitrates can dilate epicardial coronary arteries including atherosclerotic stenoses.

Pharmacodynamic effects

The cellular mechanism of nitrate-induced smooth muscle relaxation has become apparent in recent years. Nitrates enter the smooth muscle cell and are cleaved to inorganic nitrate and eventually to nitric oxide. This cleavage requires the presence of sulphydryl groups, which apparently come from the amino acid cysteine. Nitric oxide undergoes further reduction to nitrosothiol by further interaction with sulphydryl groups. Nitrosothiol activates guanylate cyclase in the vascular smooth muscle cells, thereby generating cyclic guanosine monophosphate (cGMP). It is this latter compound, cGMP,that produces smooth muscle relaxation by accelerating the release of calcium from these cells.

5.2 Pharmacokinetic properties

Absorption

Isosorbide mononitrate is readily absorbed from the gastro-intestinal tract. After oral administration of extended release tablets, Isosorbide mononitrate is slowly and completely absorbed as compared to Isosorbide dinitrate.

Distribution

Following oral administration of extended release tablet formulation of Isosorbide mononitrate, peak plasma levels are reached in approximately 3 hours. Isosorbide mononitrate are distributed throughout the whole body fluid. Unlike isosorbide dinitrate, isosorbide mononitrate does not undergo first pass hepatic metabolism and bioavailability is 77-80%.

Elimination

The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic insufficiency. Isosorbide mononitrate is excreted mainly in the urine; compounds recovered in urine after isosorbide mononitrate administration have included isosorbide, sorbitol, and conjugates; only 2% of a dose is excreted as unchanged drug. About 96% of an administered dose of isosorbide mononitrate is excreted in urine and about 1% in feces within 5 days; most excretion (about 93%) occurs within 48 hours. An elimination half-life of about 4-5 hours has been reported.

5.3 Preclinical safety data

3High concentrations of isosorbide mononitrate in rats is associated with prolonged gestation and parturition, stillbirths and deaths.

3 PL 06464/0506-0020; 11/12/2009

6. Pharmaceutical particulars
6.1 List of excipients

Stearic acid, carnauba wax, hydroxypropylmethylcellulose, lactose, magnesium stearate, talc, purified siliceous earth, polyethylene glycol 4000, titanium dioxide E171, yellow iron oxide E172.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in a dry place at or below 25°C. Protect from sunlight.

6.5 Nature and contents of container

The tablets are packed in aluminium foil/PVC blisters packed in boxes of 28, 30, 56, 60 and 100 oval, cream-coloured tablets, half-scored on both sides and marked with a crown and 60 on one side.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Amdipharm UK Limited

Capital House, 85 King William Street,

London EC4N 7BL, UK

8. Marketing authorisation number(s)

PL 20072/0220

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 12 March 1998

10. Date of revision of the text

29/12/2014