SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Eumon 60 XL

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Isosorbide-5-mononitrate 60 mg

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

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

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

Children:    The safety and efficacy of Eumon 60 XL modified release tablets

has 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.

Attenuation of effect has occurred in some patients being treated with sustained release preparations. In such patients intermittent therapy may be more appropriate (see Section 4.4.).

As with other drugs for the treatment of angina pectoris, therapy should not be discontinued suddenly, as may lead to exacerbation of symptoms. Both dosage and frequency should be tapered gradually over several days, and the patient carefully monitored ( (see Section 4.4.).

4.3 Contraindications

Severe cerebrovascular insufficiency. Phosphodiesterase type-5 inhibitors e.g Sildenafil, tadalafil and vardenafil has been shown to potentiate the hypotensive effects of nitrates and its co-administration with nitrate or nitric oxide donors is therefore contraindicated.

Known hypersensitivity to active substance or any of the excipients. .

Acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse) or very low blood pressure.

Hyperthrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral valve stenosis, severe anaemia and hypovolaemia, conditions causing raised intracranial pressure e.g cerebral haemorrhage, head trauma, closed-angle glaucoma.

Eumon 60 XL should not be given to patients with a known sensitivity to nitrates.

4.4 Special warnings and precautions for use

Eumon 60 XL modified release tablets are not indicated for relief of acute anginal attacks; in the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

The lowest effective dose should be used.

Attenuation of effect has occurred in some patients being treated with sustained release preparations (prolonged release). 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.).

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 exercised in patients suffering from hypothyroidism, malnutrition, severe renal or hepatic impairment, hypothermia and recent history of myocardial infarction.

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.

Eumon 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

There is a possibility that ISMN may enhance the hypotensive effect of hydralazine.

The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 (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 Eumon (e.g. beta-blockers, , ACE-inhibitors, alcohol, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists,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 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.The safety and efficacy of Eumon 60 XL modified release tablets during pregnancy or lactation 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 possible hazards.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

Headache is very common (>10%). 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, fatigue or nausea has occasionally been reported. Infrequently, flushing and allergic reactions (including rashes can occur). These symptoms generally disappear during long-term treatment.

Severe hypotensive responses have been reported for organic nitrates and include 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.

Dizziness, nausea, tachycardia and paroxysmal bradycardia have been reported. There have been isolated reports of myalgia.

Drowsiness, diarrhoea or vomiting may occur. Cases of exfoliative dermatitis have been reported.

4.9 Overdose

Treatment should be symptomatic. The main symptom is likely to be hypotension.

Symptoms:    Headache . More serious symptoms include Excitation, cold

perspiration, vertigo, nausea, vomiting, restlessness, warm flushed skin, blurred vision, fainting, tachycardia, hypotension and palpitations. 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, raised intracranial pressure).

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 on the bed and/or by expanding the intravascular volume (intravenous fluids should be administrated and ionotropes considered.). Other measures as indicated by the patient’s clinical condition.

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.

If severe hypotension persists despite the above measures consider use of inotropes such as dopamine or dobutamine.

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 dilatation pools blood in the periphery leading to a decrease in venous return, central blood volume, and ventricular filling volumes and pressures. Cardiat 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 been 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 is 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, hypromellose, lactose, magnesium stearate, talc, anhydrous colloidal silica, polyethylene glycol 4000, titanium dioxide (E171) and iron oxide (E172).

6.2 Incompatibilities

None known.

Shelf life

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots

Cambs. PE19 8ET

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0457

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 08/05/2003

10 DATE OF REVISION OF THE TEXT

14/08/2012