For the prophylaxis of angina pectoris

Posology

Adults: One capsule to be taken daily, or two capsules daily, in the morning.

Dosage regime should be designed according to the clinical response of the patient. The lowest effective dose should be used.

Elderly: There is no evidence to suggest an adjustment of the dosage in elderly patients is necessary.

Paediatric population

The safety and efficacy of Elantan LA has yet to be established in children.

Method of administration

For oral administration

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

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

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

The capsules 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 a cerebral haemorrhage.

Elantan LA should not be used in patients with severe anaemia, closed angle glaucoma, severe hypotension 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).

The capsules should be used with caution in patients who have a recent history of myocardial infarction or 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, severe liver or severe renal disease.

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

This product may give rise to symptoms of 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.

Elantan LA capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Due to the presence of sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Elantan LA capsules.

The development of tolerance (decrease of efficacy) as well as cross tolerance towards other nitrate-type drugs (decrease in effect in case of a prior therapy with another nitrate drug) has been described. Continuously high dosages should be avoided.

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 of Elantan LA, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (See section 4.2).

In patients with decreased gastrointestinal transit time, and using prolonged-release formulation of isosorbide mononitrate, a decrease in release of the active ingredient may occur.

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

Elantan 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).

Hypoxaemia

Caution should be exercised in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure. As a potent vasodilator, isosorbide mononitrate (ISMN) could result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.

During treatment with ISMN alcohol should be avoided as it may potentiate the hypotensive and vasodilating effect of ISMN (see section 4.5).

Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists, ACE-inhibitors, monoamine oxidase inhibitors etc and/or alcohol may potentiate the hypotensive effect of Elantan LA. This may also occur with neuroleptics and tricyclic antidepressants.

The concurrent intake of ISMN with ACE-inhibitors or arterial vasodilators could be a desirable interaction unless the antihypertensive effects are excessive in which case consider reducing the dose of one or both drugs.

Any blood pressure lowering effect of Elantan LA will be increased if used together with phosphodiesterase type-5 inhibitors which are used for erectile dysfunction (seesections 4.3 and 4.4). This might lead to life threatening cardiovascular complications. Patients who are on Elantan LA therapy therefore must not use phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Reports suggest that concomitant administration of Elantan LA may increase the blood level of dihydroergotamine and its hypertensive effect.

Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide sythetase. 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.

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 outweigh the possible 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.

Dizziness, tiredness or blurred vision may 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.

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 Elantan LA 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 Elantan LA, 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 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.

Animal experience:

In rats and mice, significant lethality at oral doses of 1965 mg/kg and 2581 mg/kg, respectively, was observed.

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

Special procedure:

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

• Treatment of methaemoglobinaemia

• Resuscitation measures

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

Pharmacotherapeutic group: vasodilators used in cardiac diseases, ATC code: C01DA14

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 preload of the heart.

Isosorbide mononitrate influences the oxygen supply to the 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.

Isosorbide mononitrate is a vasodilator, which is rapidly absorbed following oral administration. These capsules have a bioavailability of 84 (± 7)% when compared to the immediate release isosorbide mononitrate tablets. There is no effect of food on bioavailability.

The capsules contain pellets which are formulated to release 30% of the dose immediately whilst 70% of the dose is released slowly.

Time to peak plasma levels (T_max) is 5.0 (± 3) hrs; with a half life (T_½ ) of 5.02 (± 0.68) hrs.

Isosorbide mononitrate is extensively metabolised to nitric oxide (NO-which is the active ingredient) and isosorbide (inactive). In patients with cirrhotic disease or cardiac failure or renal failure, parameters were similar to those obtained in healthy volunteers.

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

Core:

Lactose monohydrate

Purified Talc

Ethyl cellulose

Macrogol 20000

Hydroxypropyl cellulose

Sucrose

Corn starch

Capsule shell:

Gelatin

Titanium dioxide

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable

5 years

Do not store above 30° C.

Cartons of blister strips of PVC and aluminium or of PP and aluminium.

Aluminium foil thickness 20 µ m or 16 µ m.

Pack size: 28 capsules.

No special requirements