This information is intended for use by health professionals

1. Name of the medicinal product

Zemon 40 XL

2. Qualitative and quantitative composition

Isosorbide-5-mononitrate 40 mg

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

3. Pharmaceutical form

Tablets (Prolonged Release)

Round, cream coloured tablets, marked 'IM40' on one side.

4. Clinical particulars
4.1 Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2 Posology and method of administration

Dosage

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.

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

Children: The safety and efficacy of Zemon 40 XL 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.

Treatment with Zemon 40XL, 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

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

Zemon 40XL should not be used in cases of acute myocardial infarction with low filling pressure, acute circulatory failure (shock, vascular collapse), or very low blood pressure, hypertrophic obstructive cardiomyopathy (HOCM), constrictive 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 and including cerebral haemorrhage and cerebrovascular insufficiency.

This product should not be given to patients with a known sensitivity to isosorbide mononitrate, the listed ingredients or other nitrates.

Zemon 40XL 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 their co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5).

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

Zemon 40XL 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 first 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.

Zemon 40XL 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.

Zemon 40 XL tablets are not indicated for relief of acute anginal attacks; in the event of an acute attack, a sublingual treatment such as a GTN spray or buccal glyceryl trinitrate tablets should be used instead of Zemon 40 XL tablets.

If the tablets are not taken as indicated (see section 4.2.) tolerance to the medication could develop. In some patients being treated with prolonged release preparations, attenuation of effect is observed. In such patients, intermittent therapy may be more appropriate.

The lowest effective dose should be used.

Treatment with Zemon, as with any other nitrate, should not be stopped suddenly. Both the 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.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, ACE-inhibitors, calcium channel blockers, vasodilators (hydralazine), alprostadil, aldesleukin, angiotensin II receptor antagonists, antihypertensives, diuretics etc and/or alcohol may potentiate the hypotensive effect of Zemon 40XL prolonged release tablets. This may also occur with neuroleptics and tricyclic antidepressants.

Any blood pressure lowering effect of Zemon 40XL will be increased if used together with phosphodiesterase type-5 inhibitors (e.g. sildenafil) which are used for erectile dysfunction (see Special Warnings and Contraindications). This might lead to life threatening cardiovascular complications. Patients who are on Zemon 40XL therapy therefore must not use phosphodiesterase type-5 inhibitors

Reports suggest that concomitant administration of Zemon 40XL may increase the blood level 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 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 Zemon 40 XL prolonged release tablets during pregnancy or 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.

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.

Breastfeeding

The safety and efficacy of Zemon 40 XL modified 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, dizziness, tiredness or blurred vision occurs.

These effects may be increased by alcohol.

4.8 Undesirable effects

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

A very common (>10% pf patients) adverse reaction to Zemon 40XL is throbbing headache. The incidence of headache may occur when treatment is initiated, but usually disappears after 1-2 weeks of treatment.

At the start of therapy or when the dosage is increased, hypotension and/or light headedness (postural hypotension)_ in the upright position are commonly observed (i.e. in 1 – 10% of patients). These symptoms may be associated with dizziness, nausea, fatigue, drowsiness, reflex tachycardia and a feeling of weakness.Infrequently (i.e. in less than 1% of patients) flushing and allergic skin reaction (e.g. rash) may occur sometimes severely. These symptoms usually disappear during long-term treatment.

Cases of exfoliative dermatitis have been reported.

Drowsiness, diarrhoea or vomiting 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, bradycardia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.

There have been isolated reports of myalgia.

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

Tachycardia and paroxysmal bradycardia 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 Yellow Card Scheme at: www.mhra.go.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 and signs:

Headache, excitation, cold perspiration, hypotension, palpitations, 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, changes in mental status, 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 (intravenous fluids should be administered and ionotropes considered). Other measures as indicated by the patient's clinical condition.

If methaemoglobinaemia (symptoms or > 30% methaemoglobin) treat with supplemental oxygen and 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.

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:G04BD

Mechanism of action

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.

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-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.

Metabolism:

ISMN 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 ISMN is excreted unchanged in the urine. An elimination half-life of about 4-5 hours has been reported.

5.3 Preclinical safety data

Not applicable

6. Pharmaceutical particulars
6.1 List of excipients

Stearic acid

Carnauba wax

Hydroxypropylmethylcellulose

Lactose

Magnesium Stearate

Talc

Silica colloidal anhydrous

Polyethylene glycol 4000

Titanium dioxide (E171)

Yellow iron oxide (E172)

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

The tablets are packed in blisters which consist of 250µm PVC with a 25µm PVdC coating which is sealed to 25µm aluminium foil with 20µm PVdC sealing laquer.

Pack sizes: 28, 30, 56, 60, and 100 tablets

6.6 Special precautions for disposal and other handling

Not applicable.

Administrative Data

7. Marketing authorisation holder

Fannin (UK) Limited

42-46 Booth Drive

Park Farm South

Wellingborough

NN8 6GT

United Kingdom

8. Marketing authorisation number(s)

20417/0091

9. Date of first authorisation/renewal of the authorisation

20 December 2001

10. Date of revision of the text

23rd August 2018