SUMMARY OF PRODUCT CHARACTERISTICS 1    NAME OF THE MEDICINAL PRODUCT

ISIB® 50XL Capsules/Isotard 50XL Capsules/Isodur 50XL Capsules/Dynamin XL50 Capsules

2.    Qualitative and Quantitative Composition

Isosorbide-5-mononitrate 50mg.

Excipient(s) with known effect: Not more than 112mg of sucrose per capsule.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Modified release capsules, hard.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2    Posology and method of administration

Adults:    One capsule (50mg) once daily, to be taken in the morning. The dose

may be increased to two capsules if required.

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.

Children:    This product is not recommended for use in children.

4.3

pressure. They should not be used in patients with a known sensitivity to nitrates , marked anaemia, head trauma, cerebral haemorrhage, severe hypotension or hypovolaemia. Sildenafil has been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contra-indicated.

4.4. Special Warnings and Precautions for Use

This product should be used with caution in patients who are predisposed to closed angle glaucoma, or who are suffering from hypothyroidism, hypothermia, malnutrition or severe liver or renal disease. Symptoms of circulatory collapse may arise after the first dose, particularly in patients with labile circulation. A headache may occur at the start of treatment, but this usually disappears with continued treatment.

This product is not indicated for the relief of acute angina attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets/sprays should be used.

This product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Some of the effects of alcohol and the action of hypotensive agents may be potentiated by isosorbide -5 - mononitrate. The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil.

4.6 Pregnancy and lactation

Nitrates have been used widely in the treatment of angina for many years without apparent ill consequence and animal studies have shown no hazard. However, safety in human pregnancy has not been established. This drug should therefore not be used in pregnancy and lactation unless considered essential by the physician.

4.7 Effects on ability to drive and use machines

Since postural hypotension with symptoms such as dizziness has been reported during use of isosorbide - 5- mononitrate , patients should be advised to be careful when driving or operating machinery if they suffer from these symptoms.

4.8 Undesirable Effects

Headache, nausea, tachycardia, palpitations, postural hypotension, dizziness,

flushing and fatigue may occur during administration of isosorbide-5-mononitrate. Headache may be minimised by starting with the lower dose and gradually increasing the dose. Other side-effects include vomiting and abdominal discomfort.

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.

4.9 Overdose

The main symptom of overdosage is likely to be hypotension. Measures to support the circulation are recommended (e.g. elevating the legs and / or treatment with hypertensive agents). Gastric lavage is indicated in severe cases.

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 dilation 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 vasodilation , 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

The rationale for the product is based on the drug reaching relatively high plasma concentrations (~ 500ng.ml-') rapidly, sustaining the concentration for a period of 1216 hours and then, concentrations falling to give relatively low drug concentration for the remaining period before the next dose. Such a profile is achieved by the use of immediate and sustained release drug within the formulation, which is then taken once a day.

Absorption

Isosorbide - 5- mononitrate is readily absorbed from the gastro - intestinal tract, and absorption is essentially complete ; bioavailability approaching 100%. The rate of absorption is slowed by food but overall bioavailability is unchanged.

Distribution

The determination of volumes of distribution suggest that isosorbide-5-mononitrate is distributed in a volume which approximates to that of total body water.

Metabolism

Isosorbide-5-mononitrate does not undergo first-pass hepatic metabolism.

Metabolism occurs primarily in the liver by denitration to isosorbide and by glucuronidation in the kidney as well as the liver to the 2-glucuronide.

Elimination

ISMN is metabolised to inactive metabolites with a half life of approximately 7 hours. Only 2% 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

Sucrose

Sugar spheres Maize starch Shellac Polyvidone

Poly (- o - ethyl) cellulose

Talc

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Erythrosin (E127)

Ethyl alcohol Isopropyl alcohol Propylene glycol N-butyl alcohol

The printing inks may also contain:

Sodium hydroxide or ammonium hydroxide potassium hydroxide purified water

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

No special precautions for storage.