SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Modisal XL 40mg Prolonged Release Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 40mg isosorbide mononitrate.

For excipients see 6.1

3    PHARMACEUTICAL FORM

Prolonged Release Tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Prophylactic treatment of angina pectoris

4.2 Posology and Method of Administration

Adults: One tablet (40mg) once daily given in the morning. The dose may be increased to two tablets (80mg), the whole dose to be given together. 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 XL 40mg Prolonged 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 (tolerance) 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).

The core of the tablet is insoluble in the digestive juices but disintegrates into small particles when all the active substance has been released. Very occasionally the matrix may pass through the gastrointestinal tract without disintegrating and be found inside the stool, but all active substance has been released.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

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).

Modisal XL 40mg Prolonged Release Tablets should not be given to patients with a known sensitivity to nitrates.

4.4 Special warnings and precautions for use

Modisal XL 40mg Prolonged Release Tablets are not indicated for the relief of acute anginal attacks; in the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

Modisal XL 40mg Prolonged Release Tablets 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 (tolerance) 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 concomitant consumption of alcohol.

Modisal XL 40mg Prolonged Release Tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Since oral nitrates cause venous dilatation they should not be used in patients with increased intracranial pressure. (With high dose i.v. administration of Glyceroltrinitrate a further increase in pressure was observed).

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually

4.5 Interaction with other medicinal products and other forms of interaction

The hypotensive effect of Modisal XL 40mg Prolonged Release Tablets may be potentiated by the concomitant administration of drugs with hypotensive effects e.g. beta-blockers, diuretics, ACE-inhibitors, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists and /or alcohol.

The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors, which are used in erectile dysfunction e.g. Sildenafil. This can lead to life-threatening vascular complications. Patients treated with isosorbide mononitrate must not use phosphodiesterase type 5 inhibitors. e.g. Sildenafil (see section 4.3).

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on the use of isosorbide mononitrate during pregnancy are insufficient to be able to assess the possible harmful effect. Limited data from animal studies indicate no adverse effects on the pregnancy or the unborn child. As precautionary measure, it is preferable to avoid the use of isosorbide mononitrate during pregnancy.

Breastfeeding

There are no data on passage of isosorbide mononitrate in human milk, but some excretion seems likely. The effects of this exposure on a nursing infant are unknown. As precautionary measure, breast-feeding should be discontinued during treatment with isosorbide mononitrate.

Animal data do not suggest an effect of the treatment of isosorbide mononitrate on male and female fertility. Human data are lacking.

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

Most undesirable effects are pharmacologically mediated and are dose dependent. Headache occurs in approximately 25% of patients at the start of treatment and can be attributed to the vasodilatory effect of the preparation; the headache usually disappears within about one week. Hypotension (with dizziness and nausea) has been reported, but this disappears with continued treatment

The frequencies of adverse events are ranked according to the following:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000),

Not known (cannot be estimated from the available data)

System Organ Class	Frequency	Adverse event
Nervous System Disorders	Very common	Headache
	Common	Dizziness, Somnolence
	Rare	Syncope
General disorders and administration site conditions	Common	Asthenia Fatigue

Vascular Disorders	Common	Hypotension Postural hypotension
	Uncommon	Collapse with worsening of symptoms of angina pectoris (sometimes accompanied by bradyarrhythmia and syncope); Transient hypoxemia with myocardial hypoxia in patients with coronary artery disease.
Cardiac disorders:	Common	Tachycardia
	Not known	Paroxysmal bradycardia
Gastrointestinal disorders	Common	Nausea
	Uncommon	Vomiting, diarrhoea
	Very rare	Dyspepsia*
Skin and subcutaneous tissue disorders	Rare	Rash, pruritus
	Not known	Exfoliative dermatitis, flushing, allergic skin reactions**

* Most likely due to a nitrate induced sphincter relaxation ** Sometimes severe

The frequency of headache can be reduced by starting treatment with 30 mg during the first 2-4 days and gradually titrating the dose upwards as necessary. A drop in blood pressure can lead to reflex tachycardia, dizziness and fainting.

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: 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.

Treatment for methemoglobinemia

•    Administration of antidote:

-    methylene blue: up to 50 ml of a 1% solution i.v.;

-    vitamin C: 1 g p.o. or as sodium salt i.v;

-    toluidine blue: initially 2 - 4 mg/kg body weight strictly i.v.; if necessary repeated several times with a time lag of one hour with 2 mg/kg body weight.

•    If necessary, apply artificial respiration.

•    In severe refractory methemoglobinemia (metHEB> 70%) consider hemodialysis, exchange transfusion.

In case of signals of a respiratory and circulatory arrest, start reanimation immediately.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Organic nitrates (including glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN) and isosorbide mononitrate (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 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

Absorption

Isosorbide 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, isosorbide mononitrate does not undergo first-pass hepatic metabolism and bioavailability is 100%. Isosorbide Mononitrate has a volume of distribution of about 40 litres and is not significantly protein bound.

Elimination

Isosorbide Mononitrate 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 Isosorbide Mononitrate is excreted unchanged in the urine. An elimination half life of about 4-5 hours has been reported.

5.3 Preclinical safety data

Isosorbide mononitrate produces very few toxic effects and is less toxic than isosorbide dinitrate. After chronic administration at high doses (60mg/kg), signs of toxicity have been detected in canine liver and kidneys. Tests conducted have shown no evidence of a teratogenic or mutagenic potential

6 PHARMACEUTICAL PARTICULARS

List of excipients

Stearic acid, carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, talc, purified siliceous earth, macrogol 4000, titanium dioxide (E171), yellow iron oxide (E172).

6.2    Incompatibilities

Not applicable.

6.3    Shelf Life

36 months

6.4    Special precautions for storage

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

6.5    Nature and contents of container

The tablets are packed in blisters which consist of 250pm PVC with a 25pm PVdC coating which is sealed to 25pm aluminium foil coated with 20pm PVdC sealing lacquer. The tablets are packed in boxes of 28, 30, 56, 60 or 100 round, cream-coloured tablets, with the marking 'IM40' on one side of the tablet.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited,

Unit G4, Riverside Industrial Estate, Riverside Way,

Dartford, DA1 5BS

MARKETING AUTHORISATION NUMBER(S)

PL 40147/0050

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/03/2009

10    DATE OF REVISION OF THE TEXT

23.05.2014