Elantan LA 25 mg Prolonged Release Capsules

Each prolonged release capsule contains 25 mg isosorbide mononitrate.

Excipients: Each prolonged release capsule contains 6.71mg lactose monohydrate and 8.17-11.96 mg sucrose

For a full list of excipients, see section 6.1.

Prolonged release capsule, hard.

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

For the prophylaxis and long term management of angina pectoris.

For oral administration

Elantan LA should be swallowed whole with water.

Elantan LA 25mg: one daily, or two capsules daily, together in the morning

Adults

One capsule to be taken in the morning.

The dose may be increased up to two capsules per day for patients with higher nitrate requirements.

The lowest effective dose should be used.

Elderly

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

Children

The safety and efficacy of Elantan LA 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).

Elantan LA 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 (systolic blood pressure below 90 mmHg), 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 hypersensitivity to isosorbide mononitrate, the listed ingredients or other nitrates.

Elantan LA 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 4.5).

Elantan LA 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), or orthostatic dysfunction. Reducing systolic blood-pressure below 90 mmHg must be avoided.

It should also be used with caution in patients who are suffering from hypothyroidism, hypothermia, malnutrition, severe liver or severe liver 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.

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.

Elantan LA capsules also contain sucrose and therefore 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 onset of action of Elantan LA is not sufficiently rapid to be useful to treat an acute anginal attack.

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 LA should be informed that they must not use phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil).

Elantan LA 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 & 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 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 (see special warnings and contraindications). 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 synthetase. Caution is recommended during concomitant use of sapropterine-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).

Safety in pregnancy has not been established for isosorbide mononitrate. There is data that nitrates are excreted in breast milk and may cause methemoglobinemia in infants. The extent of excretion of isosorbide mononitrate in human breast milk has not been determined. Therefore caution should be exercised when administered to nursing women. Therefore Elantan should only be used in pregnancy and during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

Dizziness, tiredness or blurred vision may occur at the start of treatment. If affected do 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 <Name> 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.

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, 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.

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.

ATC Code: C01D A 14 – 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.

Mechanism of action:

Like all organic nitrates, isosorbide mononitrate acts as a donor of nitric oxide (NO). NO causes a relaxation of vascular smooth muscle via the stimulation of guanylyl cyclase and the subsequent increase of intracellular cyclic guanosine monophosphate (cGMP) concentration. A cGMP-dependent protein kinase is thus stimulated, with resultant alteration of the phosphorylation of various proteins in the smooth muscle cell. This eventually leads to the dephosphorylation of the light chain of myosin and the lowering of smooth muscle tone.

Isosorbide mononitrate is a vasodilator, which is rapidly absorbed following oral administration. These capsules have a bioavailability of 80 – 90% when compared to the immediate release isosorbide mononitrate tablets.

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

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

Characteristics in patients:

Evidence was provided that the plasma profiles in healthy volunteers and patients suffering from chronic stable angina are similar.

Isosorbide mononitrate is dialysable.

Acute toxicity:

Studies on acute toxicity in mice and rats with different routes of administration indicate a low acute toxicity (LD50 oral approximately 2,000 - 2,500 mg/kg b.w.).

Chronic toxicity:

Long term toxicity has been tested in rats for 78 weeks and in dogs for 52 weeks. First toxic reactions occurred in dosages of 90 mg/kg (dog) and 405 mg/kg (rat), respectively. Thus taking into account the recommended dosage of 20 to 30 mg/d in humans, the therapeutic index can be stated as high.

Reproduction studies:

These studies included a fertility and breeding study over two generations in rats; teratology studies in rats and rabbits; and a rat peri-postnatal study. The dosage levels used were generally high and produced maternal toxic effects at the highest dose. No teratogenic effects of isosorbide mononitrate were observed.

Mutagenicity:

Isosorbide mononitrate was tested in different studies both in vitro and in vivo (Ames test, Human peripheral lymphocytes, Bone marrow of rats and hamsters, V 79 test, SCE test) on possible mutagenic effects. As all tests were negative the mutagenic risk in humans is considered low.

Carcinogenicity:

Neither the long term toxicity studies in rats and dogs nor a special carcinogenicity study, performed in rats over 125 weeks (males) and 138 weeks (females), indicated neoplastic properties of isosorbide mononitrate. Therefore, it can be concluded that the carcinogenic risk in humans is low.

Lactose monohydrate

Hydroxypropylcellulose

Ethylcellulose

Talc

Macrogol 20,000

Sucrose

Corn starch

Gelatin

Titanium dioxide (E171)

Iron oxide black and red (E172).

Not applicable.

5 years.

Do not store above 30°C.

Cartons of blister strips of PVC and aluminium or of polypropylene and aluminium. Aluminium foil thickness 16 µm or 20 µm.14 capsules per strip.

Pack sizes: calendar packs containing 28 capsules.

No special requirements.

UCB Pharma (Ireland) Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

PA 891/11/4

Date of first authorisation: 24 July 1987

Date of last renewal: 24 July 2007

September 2013