This information is intended for use by health professionals

1. Name of the medicinal product

Isosorbide Mononitrate 20 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 20 mg isosorbide mononitrate.

Each tablets contains 151.7 mg lactose monohydrate.

For full list of excipients see Section 6.1.

3. Pharmaceutical form

Tablets

Isosorbide Mononitrate 20 mg Tablets, round tablet, flat with bevelled edge, score and engraving (E/20) on the upper side and rounded on the lower 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

For oral 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 be one tablet of Isosorbide Mononitrate 20 mg Tablets twice a day.

The dosage may be increased up to 120 mg per day.

The lowest effective dose should be used.

Older people

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

Paediatric population

The safety and efficacy of Isosorbide Mononitrate 20 mg Tablets has yet to be established in children.

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)

4.3 Contraindications

Isosorbide Mononitrate 20 mg Tablets 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.

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

Isosorbide Mononitrate 20 mg Tablets should not be used in patients with severe anaemia, severe hypotension, closed angle glaucoma or severe 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 4.4 and 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 20 mg Tablets should be used with caution in patients who have a 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 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.

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 Tablets, 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 should 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 sections 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 effect of Isosorbide Mononitrate Tablets. This may also occur with neuroleptics and tricyclic antidepressants.

Any blood pressure lowering effect of Isosorbide Mononitrate Tablets will be increased if used together with phosphodiesterase type-5 inhibitors which are used for erectile dysfunction (see sections 4.3 and 4.4). This might lead to life threatening cardiovascular complications. Patients who are on Isosorbide Mononitrate Tablets 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 level of dihydroergotamine and its hypertensive effect.

Sapropterine (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

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 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 (<1/10,000), not known (cannot be estimated from the available data).

During administration of Isosorbide Mononitrate Tablets the following undesirable effects may be observed:

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.

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.

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.

4.9 Overdose

Human experience:

Symptoms:

- Fall of blood pressure ≤ 90 mmHg

- Paleness

- Sweating

- Weak pulse

- Tachycardia

- Light-headedness on standing

- Headache

- Weakness

- Dizziness

- Nausea

- Vomiting

- Diarrhoea

Methaemoglobinaemia 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. This might lead to cerebral symptoms.

General procedure:

• Stop intake of the drug

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

o Patients should be kept horizontal with the head lowered and legs raised

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.

• Treatment of methaemoglobinaemia:

o Reduction therapy of choice with vitamin C, methylene-blue or toluidine-blue

o Administer oxygen (if necessary)

o Initiate artificial ventilation

o Hemodialysis (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 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 requirement 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 Isosorbide-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

Lactose monohydrate

Purified talc

Colloidal silicon dioxide

Potato starch

Microcrystalline cellulose

Aluminium stearate

6.2 Incompatibilities

None Known

6.3 Shelf life

5 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Cartons of blister strips of PP/aluminium or of PP/PP.

Aluminium foil thickness 16 μm or 20 μm.

Pack sizes: 50, 56, 60, 84, 90 and 100 tablets.

6.6 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

Merus Labs Luxco II S.à r.l.

26-28, rue Edward Steichen

L-2540 Luxembourg

8. Marketing authorisation number(s)

PL 44374/0013

9. Date of first authorisation/renewal of the authorisation

28/02/2008

10. Date of revision of the text

August 2016