SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Menisor XL 60 mg Prolonged-Release Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 60 mg isosorbide mononitrate.

Excipient with known effect:

Each tablet also contains 215 mg of lactose (as monohydrate), for the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet

White capsule-shaped tablets with MP86 imprinted on one side and reverse scored.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Isosorbide mononitrate is indicated in adults for the prophylactic treatment of angina pectoris

4.2    Posology and method of administration

Posology:

Adults

60 mg (one tablet) daily in the morning. The dose may be increased to 120mg (two tablets) daily, both to be taken in the morning. The dose can be titrated to minimise the possibility of headache by starting treatment with 30 mg (half a tablet) for the first 2-4 days.

Elderly

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

Children

The safety and efficacy of isosorbide mononitrate in children have not been established.

Method of administration: Oral Swallow whole, do not chew or crush

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Constrictive cardiomyopathy and pericarditis, aortic stenosis, cardiac tamponade, mitral stenosis and severe anaemia

Relative contraindications to the use of isosorbide mononitrate are severe cerebrovascular insufficiency and hypotension.

Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil) potentiate the effects of nitrates; therefore co-administration with nitrates or nitric oxide donors is contraindicated.

4.4    Special warnings and precautions for use

Isosorbide Mononitrate 60 mg Prolonged-release Tablets should not be used for the relief of acute angina attacks. In the event of an acute angina attack, sublingual or buccal glyceryl trinitrate tablets should be taken.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5    Interaction with other medicinal products and other forms of interaction

Concomitant administration of Isosorbide Mononitrate and Phosphodiesterase Type 5 Inhibitors can potentiate the vasodilatory effect of Isosorbide Mononitrate with the potential result of serious side effects such as syncope or myocardial infarction. Therefore, Isosorbide Mononitrate and Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil) must not be given concomitantly.

Fertility, pregnancy and lactation

The safety and efficacy of isosorbide mononitrate during pregnancy or lactation has not been established.

4.7    Effects on ability to drive and use machines

Patients may develop dizziness when first using Isosorbide Mononitrate. Patients should be advised to determine how they react to Isosorbide Mononitrate before they drive or operate machinery.

4.8    Undesirable effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependant. Headache may occur on initiation of treatment but this usually disappears after 1-2 weeks of treatment. The dose can be titrated to minimise the possibility of headache, by initiating treatment with 30 mg. Hypotension with symptoms such as dizziness and nausea, have occasionally been reported but these symptoms generally disappear during continued treatment. On rare occasions rash and pruritus have been reported. Myalgia has been reported very rarely.

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 Symptoms:

The symptoms of overdose include pulsing headache, excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure.

Management:

In the event of overdosage emesis should be induced and activated charcoal should be given. In case of pronounced hypotension the patient should be placed in the supine position with legs raised. If necessary, fluids should be administered intravenously.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: C01D A14

Pharmacotherapeutic group: Vasodilators used in cardiovascular disease (organic nitrates)

The principal pharmacological action of isosorbide mononitrate, an active metabolite of isosorbide dinitrate, is relaxation of vascular smooth muscle, producing vasodilation of both arteries and veins with the latter effect predominating. The effect of the treatment is dependent on the dose. Low plasma concentrations lead to venous dilatation, resulting in peripheral pooling of blood, decreased venous return and reduction in left ventricular end-diastolic pressure (preload). High plasma concentrations also dilate the arteries reducing systemic vascular resistance and arterial pressure leading to a reduction in cardiac after-load. Isosorbide mononitrate may also have a direct dilatory effect on the coronary arteries. By reducing the end diastolic pressure and volume, the preparation lowers the intramural pressure, thereby leading to an improvement in the sub-endocardial blood flow.

The net effect when administering isosorbide mononitrate is therefore a reduced workload of the heart and an improved oxygen supply/demand balance in the myocardium.

5.2 Pharmacokinetic properties

Isosorbide mononitrate is rapidly and completely absorbed following oral administration. As it is not subject to first pass metabolism by the liver, this reduces the intra- and inter-individual variations in plasma levels and leads to predictable and reproducible clinical effects.

Compared with an immediate release dosage form Isosorbide Mononitrate 60 mg Prolonged-release Tablets produce a lower peak plasma concentration, which occurs later but with the apparent elimination half-life unchanged. Compared to ordinary tablets the absorption phase is prolonged and the duration of effect is extended.

The extent of bioavailability of isosorbide mononitrate prolonged-release tablets is about 90% compared to immediate release tablets. Absorption is not significantly affected by food intake and there is no accumulation during steady state. Isosorbide Mononitrate 60 mg Prolonged-release Tablets produces dose proportional kinetics up to 120 mg. After repeated peroral administration with 60 mg once daily, maximal plasma concentration (around 3000 nmol/l) is achieved after around 4 hours. The plasma concentration then gradually falls to under 500 nmol/l at the end of the dosage interval (24 hours after dosage intake). The tablets are divisible.

In placebo-controlled studies, isosorbide mononitrate prolonged-release tablets once daily has been shown to effectively control angina pectoris both in terms of exercise capacity and symptoms, and also in reducing signs of myocardial ischaemia. The duration of the effect is at least 12 hours; at this point the plasma concentration is at the same level as at around 1 hour after dose intake (around 1300 nmol/l).

The elimination half-life of isosorbide mononitrate is about 5 hours. The protein plasma binding is less than 5%. The volume of distribution for isosorbide mononitrate is about 0.6 l/kg and total clearance around 115 ml/minute. Elimination is primarily by denitration and conjugation in the liver. The metabolites are excreted mainly via the kidneys with about 2% of the dose excreted intact.

Impaired liver or kidney function have no major influences on pharmacokinetic properties.

Isosorbide is effective as monotherapy as well as in combination with longterm beta-blocker therapy.

The clinical effects of organic nitrates may be attenuated during repeated administration owing to high and/or even plasma levels. This can be avoided by allowing low plasma levels for a certain period of the dosage interval in order to restore responsiveness and prevent development of tolerance. Isosorbide mononitrate, when administered once daily in the morning, produces a plasma profile of high levels during the day and low levels during the night. With isosorbide mononitrate 60 mg or 120 mg once daily no development of tolerance with respect to antianginal effect has been observed. Rebound phenomenon between doses as described with intermittent nitrate patch therapy has not been seen with isosorbide mononitrate. The lowest effective dosage schedule should be utilised in long-term treatment.

5.3 Preclinical safety data

The accessible data indicate that isosorbide mononitrate has expected pharmacodynamic properties of an organic nitrate ester, has simple pharmacokinetic properties, and is devoid of toxic, mutagenic or oncogenic effects.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate

Hydroxypropylmethylcellulose (Methocel K4M) Glyceryl palmitostearate Maize starch Magnesium stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Blister packs (PVC film 250 pm / aluminium foil 25 pm) of 28 tablets

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Metwest Pharmaceuticals Limited

15 Runnelfield

Harrow on the Hill

Middlesex

HA1 3NY

8    MARKETING AUTHORISATION NUMBER(S)

PL 17521/0086

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/07/2014

10    DATE OF REVISION OF THE TEXT

17/07/2014