SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

ETIMONIS XL 50 mg Capsules ZIOTAN XL 50 mg Capsules IMO LA 50 mg Capsules

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Isosorbide Mononitrate...................50 mg

For excipients, see 6.1

3    PHARMACEUTICAL FORM

Prolonged-release capsules, hard

White capsules containing prolonged release microgranules

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. The lowest effective dose should be used.

Children: Safety and efficacy in children have not been established.

Elderly: There is no evidence of a need for routine dosage adjustment in the elderly, but special care may be needed in those with increased susceptibility to hypotension or marked hepatic or renal insufficiency.

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 IMO 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

Isosorbide Mononitrate should not be used in patients with 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.

IMO LA should not be used in patients with marked anaemia, closed angle glaucoma, severe hypotension or hypovolaemia.

Phosphodiesterase type-5 inhibitors (e.g. Sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates and their coadministration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5 Interaction with other medicinal products and other forms of interaction)

4.4 Special warnings and precautions for use

Isosorbide Mononitrate should be used with caution in patients who have a recent history of myocardial infarction or 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.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

Isosorbide Mononitrate is not suitable for relief of acute angina attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate (GTN) tablets/sprays should be used.

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.

IMO LA capsules contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption.

If the capsules are not taken as directed (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 IMO LA, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.2).

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

Any blood pressure lowering effect of IMO LA will be increased, if used together with phosphodiesterase type-5 inhibitors, which are used for erectile dysfunction (see section 4.3 Contraindications). This might lead to life-threatening cardiovascular complications. Patients who are on IMO LA therapy therefore must not use phosphodiesterase type-5 inhibitors.

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

No data have been reported which would indicate the possibility of adverse effects from use of IMO LA in pregnancy. Safety in pregnancy however has not been established. It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing mothers. This product should therefore not be used during pregnancy or lactation unless considered essential by the physician and unless possible benefits outweigh the possible hazards.

4.7 Effects on ability to drive and use machines

Since postural hypotension with symptoms such as dizziness, tiredness or blurred vision have been reported at the start of the treatment patients should be advised to be careful when driving or operating machinery if they suffer from these symptoms. This effect may be increased by alcohol.

4.8 Undesirable effects

A very common (10% of patients) adverse reaction to IMO LA is throbbing headache. This may occur at the onset of treatment but may be minimised by commencing with low doses and gradually increasing the dose. The incidence of headache diminishes 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. in1-10% of patients).

These symptoms may be associated with dizziness, drowsiness, reflex tachycardia and a feeling of weakness.

Uncommonly (i.e. in less than 1% of patients) nausea, vomiting, flushing and allergic skin reaction (e.g.rash) may occur, sometimes severely. In single cases exfoliative dermatitis may occur.

Severe hypotensive responses have been reported for organic nitrates and including nausea, vomiting, restlessness pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). 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.

4.9 Overdose

Symptoms and signs:

Headache, hypotension, nausea, vomiting, sweating, tachycardia, vertigo, 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) occurs rarely.

Management:

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 the use of inotropes.

If Methaemoglobinaemia (symptoms or >30% methaemoglobin), IV administration of methylene 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.

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.Nitrate compounds relax smooth muscle causing dilatation of the veins and arteries. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure.The result is a very marked reduction of 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 and is absorbed completely and rapidly following oral administration.

I

This product has all the pharmacokinetic characteristics of a true modified release dosage form. Compared with an immediate-release dosage form, the bioavailability is approximately 84 (±7)%. There is no effect of food on bioavailability.

The capsules are formulated to release 30% of the dose immediately and 70% of the dose is released slowly.

Time to peak plasma levels (T _max) is 5.0 (±3) hours; with a half life (T/2) of

5.02 (±0.68) hours.

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 of reproduction.

6.1    List of excipients

Capsule contents :

Lactose monohydrate,

Sucrose and maize starch microgranules Bleached dewaxed shellac,

Dewaxed shellac,

Copolymer of methacrylic acid and methyl methacrylate (1:1),

Copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (1:2:0.1),

Talc,

Ethanol 96 %. (ND*)

Capsule shell :

Gelatin

• Titanium dioxide (E 171)

Black ink :

Shellac, propylene glycol, ammonium hydroxide, potassium hydroxide, black iron oxide (E 172)

*Not detected in the finished product

6.2    Incompatibilities

None Known.

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

Blister packs (20 pm aluminium/250 pm PVC) - boxed in cardboard cartons containing 28, 30, 56 or 60 capsules. Sample blister pack of 8 capsules.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Athlone Pharmaceuticals Limited,

Ballymurray,

Co.Roscommon,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 30464/0059

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/06/2002 / 17/03/2009

10    DATE OF REVISION OF THE TEXT

29/07/2009