MODISAL XL 40 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Modisal XL 40mg Prolonged Release Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 40mg isosorbide mononitrate.

Excipient with known effect

Lactose monohydrate – 25.46mg per tablet

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged Release Tablets.

Round, cream-coloured tablet, with the marking ‚IM40‘ on one side of the tablet. The dimensions of the tablets are 8 mm x 4.58 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Adults

One tablet (40mg) once daily given in the morning. The dose may be increased to two tablets (80mg), the whole dose to be given together (dose range 30mg to

120mg). The dose can be titrated to minimise the possibility of headache by initiating treatment with a lesser dose for the first two to four days.

Paediatric population

The safety and efficacy of Modisal XL 40mg Prolonged 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.

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 4.4).

As with other drugs for the treatment of angina pectoris, therapy should not be discontinued suddenly, as this 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).

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

Method of administration

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe cerebrovascular insufficiency.

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

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

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

Modisal XL 40mg Prolonged Release Tablets should not be given to patients with a known sensitivity to nitrates.

Concomitant use with the soluble guanylate cyclase stimulator, riociguat, can

cause hypotension and is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Modisal XL 40mg Prolonged Release Tablets are not indicated for the relief of acute anginal attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

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

The lowest effective dose should be used.

Attenuation of effect (tolerance) 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.

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.

Modisal XL 40mg Prolonged Release Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The hypotensive effects of nitrates are potentiated by the concomitant administration of phosphodiesterase type-5 inhibitors (e.g. sildenafil) (see section 4.3). This might lead to life-threatening cardiovascular complications.

Any medication which may cause hypotension may have its hypotensive effects potentiated by concurrent administration of Modisal XL 40mg Prolonged Release Tablets (e.g. beta-blockers, ACE-inhibitors, alcohol, vasodilators (hydralazine), alprostadil, aldesleukin, angiotensin II receptor antagonists, calcium channel blockers, antihypertensives and diuretics).

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

Concomitant use with the soluble guanylate cyclase stimulator, riociguat, can cause hypotension and is contraindicated (see section 4.3).

4.6 Fertility, pregnancy and lactation

Pregnancy

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 Modisal XL 40mg Prolonged Release Tablets during pregnancy 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 possible hazards.

Breast-feeding

The safety and efficacy of Modisal XL 40mg Prolonged Release Tablets during lactation 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 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, blurred vision or dizziness occurs.

4.8 Undesirable effects

Most of the adverse reactions are pharmacologically mediated and are 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 and 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 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. 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.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

Symptoms

Headache, 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 of the bed and/or by expanding the intravascular volume (intravenous fluids should be administered, and inotropes 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

Pharmacotherapeutic group: Vasodilators used in Cardiac Diseases/Organic nitrates, ATC code: C01DA14

Mechanism of action

Organic nitrates (including glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN) and isosorbide mononitrate (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. 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 sulfhydryl groups, which apparently come from the amino acid cysteine. Nitric oxide undergoes further reduction to nitrosothiol by further interaction with sulfhydryl 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, isosorbide mononitrate does not undergo first-pass hepatic metabolism and bioavailability is 100%. Isosorbide mononitrate has a volume of distribution of about 40 litres and is not significantly protein bound.

Metabolism

Isosorbide mononitrate is metabolised to inactive metabolites including isosorbide and isosorbide glucuronide.

Elimination

The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic insufficiency. Only 20% of isosorbide mononitrate 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 monohydrate, magnesium stearate, talc, purified siliceous earth, macrogol 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

Do not store above 25°C. Store in the original container.

6.5 Nature and contents of container

The tablets are packed in blisters which consist of 250jim PVC with a 25gm

PVdC coating which is sealed to 25jim aluminium foil coated with 20jim PVdC sealing lacquer. This medicine is available in packs containing 28, 30, 56, 60 or 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable.