Chemydur 60XL

1. Name Of The Medicinal Product

Chemydur 60XL or Mitrate 60XL

2. Qualitative And Quantitative Composition

Isosorbide-5-Mononitrate 60mg.

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

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

For excipients, see 6.1.

3. Pharmaceutical Form

Tablets (modified release).

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylactic treatment of angina pectoris

4.2 Posology And Method Of Administration

Adults: one tablet (60mg) once daily given in the morning. The dose may be increased to two tablets (120mg), the whole doses to be given together.

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

Children: The safety and efficacy of Isosorbide mononitrate modified release tablets have not been established.

Elderly: No 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 lowest effective dose should be used.

There is a risk of tolerance developing to sustained 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).

4.3 Contraindications

Hypersensitivity to Isosorbide Mononitrate or to any of the excipients.

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.

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

Severe cerebrovascular insufficiency or hypotension are contra-indications to use.

4.4 Special Warnings And Precautions For Use

The lowest effective dose should be used.

There is a risk of tolerance developing to sustained 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).

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.

Isosorbide mononitrate modified release 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 ERPF (Effective Renal Plasma Flow) 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.

Chemydur 60XL tablets contain lactose, and therefore 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 (e.g. alcohol, vasodilators, calcium channel blockers, antihypertensives and diuretics).

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

4.6 Pregnancy And Lactation

The safety and efficacy of isosorbide mononitrate modified release tablets during pregnancy or lactation in humans has not been established. Animal studies have shown reproductive toxicity (see section 5.3).

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

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)

Flushing, dizziness, postural hypotension, tachycardia and paradoxical bradycardia have been reported. These symptoms generally disappear during long-term treatment.

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, bradycardia and syncope).

Uncommonly severe hypotension may lead to enhanced angina symptoms.

Allergic skin reaction, pruritus, myalgia and, drowsiness, diarrhoea or vomiting may occur.

Cases of exfoliative dermatitis have been reported.

4.9 Overdose

Symptoms and signs

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

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

Management

In case of pronounced hypotension the patient should first be placed in the supine position with legs raised. If necessary, intravenous fluids should be administrated and ionotropes considered.

Consider oral activated charcoal if ingestion of a potentially toxic amount has occurred within one hour. Observe for at least 12 hours after the overdose. Monitor blood pressure and pulse.

If methaemoglobinaemia occurs, 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

Organic nitrates (including GTN, ISDN and ISMN) 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 dilation 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.

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-5-Mononitrate is readily absorbed from the gastro-intestinal tract.

Distribution

Following oral administration of conventional tablets, peak plasma levels are reached in about 1 hour. Unlike isosorbide dinitrate, ISMN does not undergo first pass hepatic metabolism and bioavailability is 100%. ISMN has a volume of distribution of about 40 litres and is not significantly protein bound.

Elimination

ISMN is metabolised to inactive metabolites including isosorbide and isosorbide glucuronide. The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic insufficiency. Only 20% of ISMN are excreted unchanged in the urine. An elimination half-life of about 4-5 hours has been reported.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Stearic acid, carnauba wax, hydroxypropylmethylcellulose, lactose, magnesium stearate, talc, purified siliceous earth, polyethylene glycol 4000, E171, E172.

6.2 Incompatibilities

Not known.

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 ISMN on one side.

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.

Administrative Data

7. Marketing Authorisation Holder

Waymade PLC

t/a Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex, SS14 3FR

8. Marketing Authorisation Number(S)

PL 06464/0506

9. Date Of First Authorisation/Renewal Of The Authorisation

12 March 1998

10. Date Of Revision Of The Text

August 2010