This information is intended for use by health professionals

1. Name of the medicinal product

Monomil 40 mg Tablets

Carmil 40 mg Tablets

Isosorbide Mononitrate 40 mg Tablets.

2. Qualitative and quantitative composition

Isosorbide-5-mononitrate Ph. Eur. 40 mg/tablet.

3. Pharmaceutical form

Tablet.

White to off-white, round flat tablets with 'I16' embossing on one side.

4. Clinical particulars
4.1 Therapeutic indications

For the prophylaxis of angina pectoris

As adjunctive therapy in congestive heart failure not responding to cardiac glycosides or diuretics.

4.2 Posology and method of administration

Adults: One tablet to be taken asymmetrically (to allow a nitrate low period) two or three times a day. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose of isosorbide mononitrate be 40mg twice a day. The dosage may be increased to 120mg per day.

The lowest effective dose should be used.

Paediatric population: The safety and efficacy of Isosorbide Mononitrate 40mg tablets in children has not been established.

Elderly: There is no evidence to suggest that an adjustment of the dosage is necessary.

Treatment with Isosorbide mononitrate tablets, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4)

Method of administration

The tablet should be swallowed whole, and not chewed or crushed.

4.3 Contraindications

Isosorbide mononitrate tablets should not be used in cases of acute myocardial infarction with low filling pressures, 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.

Hypersensitivity to the active substance, other nitrates or to any of the excipients listed in section 6.1

Isosorbide mononitrate Tablets should not be used in patients with severe 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)

During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).

4.4 Special warnings and precautions for use

Isosorbide mononitrate Tablets should be used with caution in patients who have recent history of myocardial infarction, low filling pressures e.g. in acute myocardial infarction, impaired left ventricular function (left ventricular failure). Reducing systolic blood-pressure below 90 mmHg must be avoided. Also in patients who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.

Symptoms of circulatory collapse may arise after the initial 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.

Isosorbide mononitrate 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.

In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate Tablets.

If the tablets are not taken as indicated (see section 4.2), tolerance to the medication could develop. The lowest effective dose should be used.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.2)

Patients who undergo a maintenance treatment with Isosorbide mononitrate tablets would be informed that they must not use phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil).

Isosorbide mononitrate tablets therapy should not be interrupted to take phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil), because the risk of inducing an attack of angina pectoris could increase by doing so (see section 4.3 and 4.5).

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, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists etc. and/or alcohol may potentiate the hypotensive effects of Isosorbide mononitrate Tablets. This may occur with neuroleptics and tricyclic antidepressants.

The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5- inhibitors, which are used for erectile dysfunction (see special warning and contraindications). This may lead to life threatening cardiovascular complications. Patients who are on Isosorbide mononitrate therapy therefore must not use phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Reports suggest that concomitant administration of Isosorbide mononitrate tablets may increase the blood levels of dihydroergotamine and its hypertensive effects.

Saproterine (Tetrahydropterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of saproterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).

The use of isosorbide mononitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.

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. Safety in pregnancy however has not been established, 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.

Breast-feeding

It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing women.

Fertility

There is no data available on the effect of isosorbide mononitrate on fertility in humans.

4.7 Effects on ability to drive and use machines

Dizziness, tiredness or blurred vision might occur at the start of the treatment. The patient should therefore be advised that if affected, they should not drive or operate machinery. This effect may be increased by alcohol.

4.8 Undesirable effects

Undesirable effects frequencies are defined as: very common (≥1/10), common (≥1/100<1/10), uncommon (≥1/1,000<1/100), rare (≥1/10,000<1/1,000), very rare (<10,000), not known (cannot be estimated from the available data).

Nervous system disorders:

• very common: headache,

• common: dizziness (including dizziness postural), somnolence.

Cardiac disorders:

• common: tachycardia,

• uncommon: angina pectoris aggravated.

Vascular disorders:

• common: orthostatic hypotension,

• uncommon: circulatory collapse (sometimes accompanied by bradyarrhythmia and syncope).

• not known: hypotension

Gastrointestinal disorders:

• uncommon: nausea, vomiting,

• very rare: heartburn.

Skin and subcutaneous tissue disorders:

• uncommon: allergic skin reactions (e.g. rash), flushing

• not known: dermatitis exfoliative.

Immune system disorders:

• not known: angioedema

General disorders and administration site conditions:

common: asthenia.

A very common (>10% of patients) adverse reaction to Isosorbide mononitrate Tablets is throbbing headache. The incidence of headache diminishes gradually with time and continued use.

At the start of therapy or when the dosage is increased, hypotension and/or light-headedness in the upright position are commonly observed (i.e. in 1-10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachycardia and a feeling of weakness.

Infrequently (i.e. in less than 1% patients) nausea, vomiting, flushing and allergic skin reactions (e. g. rash) may occur sometimes severely.

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness pallor and excessive perspiration. During treatment with Isosorbide Mononitrate Tablets, a temporary hypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease, this may lead to a myocardial hypoxia. Uncommonly severe hypotension may lead to enhanced angina symptoms.

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

Tachycardia and paroxysmal bradycardia have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal products 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

Symptoms and signs: Fall of blood pressure ≤ 90 mmHg, headache, paleness, weak pulse, light headedness on standing, weakness, dizziness, diarrhoea, hypotension, 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, restlessness, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure) has been reported in patients receiving other organic nitrates. During isosorbide mononitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of isosorbide mononitrate may cause this adverse reaction.

In very high doses the intracranial pressure may be increased. Yhis might lead to cerebral symptoms.

Management:

General Procedure:

• Stop intake of the drug

• General procedures in the event of nitrate-related hypotension:

o 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. Other measures as indicated by the patient's clinical condition. If severe hypotension persists despite the above measures consider use of inotropes.

o Supply oxygen

o Expand plasma volume (i.v. fluids)

o Specific treatment for shock (admit patient to intensive care unit)

Special Procedure:

• Raising the blood pressure if the blood pressure is very low.

o Treatment with methaemoglobinaemia:If methaemoglobinaemia (symptoms or >30% methaemoglobin), IV administration of methylene blue or toluidine-blue 1-2mg/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.

o Reduction therapy of choice with vitamin C

o Administer oxygen (if necessary)

o Initiate artificial ventilation

o Haemodialysis (if necessary)

• Resuscitation measures

In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC code: C01D A14

Pharmacotherapeutic group: Vasodilator used in cardiac diseases

Isosorbide mononitrate is an organic nitrate, which, in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.

Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.

It reduces the requirements of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.

5.2 Pharmacokinetic properties

Isosorbide 5—mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.

Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.

Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosrbide-5-mn-2-glucoronide, which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.

After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, oncogenicity and toxicity to reproduction.

6. Pharmaceutical particulars
6.1 List of excipients

Microcrystalline cellulose Ph. Eur., Lactose Monohydrate Ph. Eur., Colloidal Anhydrous Silica Ph. Eur., Maize starch Ph. Eur., Talc Ph. Eur. and Magnesium stearate Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC/Aluminium foil blisters on a cardboard carton.

Each sheet of blisters contains 10 tablets and there are six sheets of ten tablets per carton (60's pack).

Each strip of blister contains 14 tablets and there are four such strips per carton (56's pack).

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing authorisation number(s)

PL 16363/0002

9. Date of first authorisation/renewal of the authorisation

21/09/2008

10. Date of revision of the text

22/03/2019