This information is intended for use by health professionals

1. Name of the medicinal product

Elantan LA 25 mg prolonged release capsules

2. Qualitative and quantitative composition

Each prolonged release capsule contains 25 mg isosorbide mononitrate.

Excipients: Each prolonged release hard capsule contains 6.71 mg lactose monohydrate and approximately 8-12 mg sucrose.

For a full excipient list, see section 6.1.

3. Pharmaceutical form

Prolonged release capsules.

Hard capsule with brown cap and white body, containing white to off-white pellets.

4. Clinical particulars
4.1 Therapeutic indications

For the prophylaxis of angina pectoris

4.2 Posology and method of administration

For oral administration

Adults

One capsule to be taken in the morning.

For patients with higher nitrate requirements the dose may be increased to two capsules taken simultaneously. Dosage regime should be designed according to the clinical response of the patient. The lowest effective dose should be used.

Older people

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

Paediatric population

The safety and efficacy of these capsules has yet to be established in children.

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).

4.3 Contraindications

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.

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

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).

4.4 Special warnings and precautions for use

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 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 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 Elantan LA capsules.

If these capsules 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 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, 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).

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 Elantan LA. This may also occur with neuroleptics and tricyclic antidepressants.

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.

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 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.

4.7 Effects on ability to drive and use machines

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.

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 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 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

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

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 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.

5.2 Pharmacokinetic properties

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 (Tmax) is 5.0 (±3) hrs; with a half life (T½) 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.

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

Core:

Lactose monohydrate

Purified Talc

Ethyl cellulose

Macrogol 20000

Hydroxypropyl cellulose

Sucrose

Corn starch

Capule shell:

Gelatin

Titanium dioxide

Iron oxide red (E172)

Iron oxide black (E172)

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 PVC and aluminium or of PP and aluminium.

Aluminium foil thickness 20 μm or 16 μm.

Pack size: 28 capsules.

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 44374/0015

9. Date of first authorisation/renewal of the authorisation

28 February 2008

10. Date of revision of the text

August 2016