Modisal 60mg XL Tablets

1. Name Of The Medicinal Product

Modisal 60 XL

2. Qualitative And Quantitative Composition

Isosorbide-5-Mononitrate 60mg.

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

Chemical name:

1,4:3,6 dianhydro-D-glucitol-5-nitrate.

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 (60mg) once daily given in the morning. The dose may be increased to 2 tablets (120mg), the whole dose to be given together. The dose can be titrated to minimise the possibility of headache by initiating treatment with half a tablet (30mg) 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 Modisal 60 XL Modified Release Tablets has not been established in children.

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 hypo-tension or marked hepatic or renal insufficiency.

4.3 Contraindications

Severe cerebrovascular insufficiency. Hypotension.

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

Modisal 60 XL 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is a possibility that ISMN may enhance the hypotensive effect of hydralazine.

The hypotensive effects of nitrates are potentiated by concurrent administration of sildenafil.

4.6 Pregnancy And Lactation

The safety and efficacy of Modisal 60 XL Modified Release Tablets during pregnancy or lactation has not been established.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Headache may occur when treatment is initiated, but usually disappears after 1 to 2 weeks of treatment. Hypotension with symptoms such as dizziness or nausea has occasionally been reported. These symptoms generally disappear during long-term treatment.

4.9 Overdose

Treatment should be symptomatic. The main symptom is likely to be hypotension.

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, hydroxypropyl methylcellulose, lactose, magnesium stearate, talc, purified siliceous earth, polyethylene glycol 4000, E171 and E172.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store in a dry place below 25ºC. Protect from light.

6.5 Nature And Contents Of Container

*The tablets are packed in aluminium foil/PVC blisters packed in boxes of 28, 30, 56, 60 and 100.

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

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0284

9. Date Of First Authorisation/Renewal Of The Authorisation

5^th March 1998

10. Date Of Revision Of The Text

9 September 2003

* Only marketed pack sizes to be included in the SPC printed for issue