Isotard XL

1. Name Of The Medicinal Product

Isotard 25XL, 40XL, 50XL and 60XL Tablets

2. Qualitative And Quantitative Composition

Isosorbide-5-mononitrate 25mg

Isosorbide-5-mononitrate 40mg

Isosorbide-5-mononitrate 50mg

Isosorbide-5-mononitrate 60mg

International non-proprietary name (INN): Isosorbide mononitrate.

Isosorbide mononitrate is also referred to as ISMN.

Chemical name: 1,4:3,6 dianhydro-D-glucitol-5-mononitrate.

3. Pharmaceutical Form

Tablets (modified release).

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylactic treatment of angina pectoris.

4.2 Posology And Method Of Administration

Adults

One tablet, once daily given in the morning. The dose may be increased to two tablets, the whole dose to be given together (dose range 25 to 120 mg).

For Isotard 60XL only, the dose can be titrated to minimise the possibility of headache by initiating treatment with half a tablet (30 mg) for the first two to four days.

The tablets should not be chewed or crushed and should be swallowed with half a glass of fluid.

Children

The safety and efficacy of Isotard XL ISMN modified release tablets has not been established.

Elderly

No need for routine dosage adjustment in the elderly has been found, but special care may be needed in those with increased susceptibility to hypotension or marked hepatic or renal insufficiency.

The lowest effective dose should be used.

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).

Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see Section 4.4).

4.3 Contraindications

Hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral valve stenosis, severe anaemia, closed-angle glaucoma, conditions associated with raised intracerebral pressure e.g. following head trauma, cerebral haemorrhage. Acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse) or very low blood pressure. 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 contra-indicated (see section 4.5). Isotard XL should not be given to patients with a known sensitivity to nitrates.

4.4 Special Warnings And Precautions For Use

Isotard XL ISMN modified release tablets are not indicated for relief of acute anginal attacks. In

the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

Isotard XL ISMN 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.

The lowest effective dose should be used.

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 4.2).

Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see Section 4.2).

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

Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Alprostadil, aldesleukin, angiotensin II receptor antagonists.

This product may potentiate some of the effects of alcohol and the action of hypotensive agents. The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors e.g. sildenafil (see section 4.3).

4.6 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. It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing women.

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 possible hazards.

4.7 Effects On Ability To Drive And Use Machines

The patient should be warned not to drive or operate machinery if hypotension, blurred vision or dizziness occurs.

4.8 Undesirable Effects

Throbbing headache may occur when treatment is initiated, but usually disappears after 1–2 weeks of treatment. Hypotension with symptoms such as dizziness, nausea and fatigue has occasionally been reported. Infrequently, flushing and allergic rashes can occur. These symptoms generally disappear during long-term treatment.

Tachycardia and paroxysmal bradycardia have been reported.

4.9 Overdose

4.10

Symptoms: Nausea, vomiting, restlessness, warm flushed skin, blurred vision, headache, fainting, tachycardia, hypotension and palpitations. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur.

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 use of inotropes such as dopamine or dobutamine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Organic nitrates (including GTN, ISDN, and ISMN) are potent relaxers of smooth muscle. They have a powerful effect on vascular smooth muscle with less effect on bronchiolar, gastrointestinal, ureteral and uterine smooth muscle. Low concentrations dilate both arteries and veins.

Venous dilatation pools blood in the periphery leading to a decrease in venous return, central blood volume, and ventricular filling volumes and pressures. Cardiac output may remain unchanged or it may decline as a result of the decrease in venous return. Arterial blood pressure usually declines secondary to a decrease in cardiac output or arteriolar vasodilatation, or both. A modest reflex increase in heart rate results from the decrease in arterial blood pressure. Nitrates can dilate epicardial coronary arteries including atherosclerotic stenoses.

The cellular mechanism of nitrate-induced smooth muscle relaxation has become apparent in recent years. Nitrates enter the smooth muscle cell and are cleaved to inorganic nitrate and eventually to nitric oxide. This cleavage requires the presence of sulphydryl groups, which apparently come from the amino acid cysteine. Nitric oxide undergoes further reduction to nitrosothiol by further interaction with sulphydryl groups. Nitrosothiol activates guanylate cyclase in the vascular smooth muscle cells, thereby generating cyclic guanosine monophosphate (cGMP). It is this latter compound, cGMP, that produces smooth muscle relaxation by accelerating the release of calcium from these cells.

5.2 Pharmacokinetic Properties

Absorption

Isosorbide-5-mononitrate is readily absorbed from the gastro-intestinal tract.

Distribution

Following oral administration of conventional tablets, peak plasma levels are reached in about 1 hour. Unlike isosorbide dinitrate, ISMN does not undergo first-pass hepatic metabolism and bioavailability is 100%. ISMN has a volume of distribution of about 40 litres and is not significantly protein bound.

Elimination

ISMN is metabolised to inactive metabolites including isosorbide and isosorbide glucuronide. The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic insufficiency. Only 20% of ISMN is excreted unchanged in the urine. An elimination half life of about 4-5 hours has been reported.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Stearic acid

Carnauba wax

Hydroxypropylmethylcellulose

Lactose

Magnesium stearate

Talc

Purified siliceous earth

Polyethylene glycol 4000

E171

E172.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package. Keep container in the outer carton

6.5 Nature And Contents Of Container

The tablets are packed in blisters which consist of 250µm PVC with a 25µm PVdC coating which is sealed to 25µm thick aluminium foil with 20µm PVdC sealing lacquer. The tablets are packaged in boxes of 28 tablets.

Isotard 25XL, 40XL and 50XL tablets are round, biconvex, cream coloured tablets marked IM25, 40 or 50 on one side, as appropriate. The Isotard 60XL tablets, only, are oval, cream coloured tablets scored on both sides but with '6 (score) 0' on one side.

6.6 Special Precautions For Disposal And Other Handling

The tablets should be swallowed whole with half a glass of water. They must not be chewed or crushed.

Administrative Data

7. Marketing Authorisation Holder

ProStrakan Limited

Galabank Business Park

Galashiels

TD1 1QH

UK

8. Marketing Authorisation Number(S)

Isotard 25XL: PL 16508/0018

Isotard 40XL: PL 16508/0020

Isotard 50XL: PL 16508/0021

Isotard 60XL: PL 16508/0022

9. Date Of First Authorisation/Renewal Of The Authorisation

08 April 2002

10. Date Of Revision Of The Text

February 2006

11. Legal Category

P