This information is intended for use by health professionals

1. Name of the medicinal product

Nyzamac SR 40 mg Capsules

Nyzamac SR 50 mg Capsules

Nyzamac SR 60 mg Capsules

2. Qualitative and quantitative composition

Each 40 mg prolonged-release capsule contains 40 mg of isosorbide mononitrate.

Each 50 mg prolonged-release capsule contains 50 mg of isosorbide mononitrate.

Each 60 mg prolonged-release capsule contains 60 mg of isosorbide mononitrate.

Excipients with known effect:

Each 40mg capsule contains:

Lactose (120 mg/ capsule)

Sucrose (38.5mg/capsule)

Each 50mg capsule contains:

Lactose (150mg/capsule)

Sucrose (48.15 mg/capsule)

Each 60mg capsule contains:

Lactose (180mg/capsule)

Sucrose (57.75 mg/capsule)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged-release capsule, hard.

The 40mg capsule is a size 2 capsules and has an opaque white cap printed with « ISMN SR » in black ink and an opaque white body printed with « 40 » in black ink, containing off-white to yellowish microgranules.

The 50mg capsule is a size 1 capsule and has an opaque white cap printed with « ISMN SR » in black ink and an opaque white body printed with « 50 » in black ink, containing off-white to yellowish microgranules.

The 60mg capsule is a size 1 capsule and has an opaque white cap printed with « ISMN SR » in black ink and an opaque white body printed with « 60 » in black ink, containing off-white to yellowish microgranules.

4. Clinical particulars
4.1 Therapeutic indications

Nyzamac SR capsules are indicated in adults for the prophylactic treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Adults:

One capsule once daily given in the morning. The dose may be increased up to 120 mg.

The product must not be given in divided doses as a daily nitrate free period is required in order to prevent the development of tolerance. Thus, if more than one capsule is needed they must be taken simultaneously.

The dose can be titrated to minimise the possibility of headache by initiating treatment by a lower dose for the first two to four days.

Paediatric population

The safety and efficacy of Nyzamac SR Capsules in children have not been established.

Elderly:

There is no need for routine dose adjustment in the elderly, but care may be needed in those patients with increased susceptibility to hypotension, and in those with marked hepatic or renal insufficiency.

The lowest effective dose should be used.

There is a risk of tolerance developing to prolonged-release preparations. In such patients, intermittent therapy may be more appropriate (see section 4.4).

As with other drugs for the treatment of angina pectoris, abrupt discontinuation of therapy may lead to exacerbation of symptoms. When discontinuing long-term treatment, the dosage should be reduced gradually over several days, and the patient carefully monitored (see section 4.4).

Method of administration

For oral administration

The capsules may be taken with or without food.

The capsules should be swallowed whole with half a glass of fluid and they should not be chewed or crushed to avoid damage to the prolonged-release characteristics of the microgranules.

4.3 Contraindications

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

This product should not be given to patients with a known sensitivity to nitrates.

Acute myocardial infarction with low filling pressures, hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral stenosis and severe anaemia, hypovolaemia, conditions causing raised intracranial pressure (e.g. cerebral haemorrhage, head trauma) and closed-angle glaucoma. Severe cerebrovascular insufficiency or hypotension are contraindications to use.

Phosphodiesterase type-5 inhibitors (e.g. sildenafil) have been shown to potentiate the hypotensive effects of nitrates, their co-administration with nitrates or nitric oxide donors is therefore contraindicated.

4.4 Special warnings and precautions for use

The lowest effective dose should be used.

There is a risk of tolerance developing to modified release preparations. In such patients intermittent therapy may be more appropriate.

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

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

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.

Nyzamac SR Capsules are not indicated for relief of acute anginal attacks: in the event of an acute attack, glyceryl trinitrate should be used.

The administration of isosorbide mononitrate causes a decrease of effective renal plasma flow (eRPF) in cirrhotic patients and should be used with caution.

Caution should be used in patients who have a recent history of myocardial infarction and in patients suffering from hypothyroidism, hypothermia, malnutrition, and severe liver or renal disease. Oral nitrates should also be used with caution in patients with angina due to other causes, or pre-existing hyperdynamic conditions.

Since oral nitrates can cause venous dilatation, they should not be used in patients with increased intracranial pressure.

Nyzamac SR Capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Nyzamac SR Capsules contain sucrose. 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

The hypotensive effect of nitrates will be increased if used together with phosphodiesterase type-5 inhibitors (e.g. sildenafil). This might lead to life threatening cardiovascular complications.

Any medication which may cause hypotension may have its hypotensive effects potentiated by concurrent administration of Nyzamac SR Capsules (e.g. alcohol, antihypertensives, vasodilators, calcium channel blockers, and diuretics).

Reports suggest that concomitant administration of isosorbide mononitrate may increase the blood level of dihydroergotamine and its hypertensive effect.

Alcohol can attenuate cerebral ischaemia associated with postural hypotension.

Isosorbide mononitrate can act as a physiological antagonist to noradrenaline, acetylcholine and histamine.

Nyzamac SR Capsules should not be taken at the same time as alcohol. In vitro data suggests that in combination with Nyzamac SR Capsules, alcohol may increase the rate of in vivo release of the product from the prolonged release preparation. Alcohol may increase dose-dependent effects and lead to potential adverse pharmacodynamic interactions.

Alcohol use could therefore increase the rate and seriousness of isosorbide mononitrate adverse drug reactions such as vasodilatory related events.

There is no evidence of interaction with food.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety and efficacy of Nyzamac SR Capsules during pregnancy in humans has not been established. Animal studies have shown reproductive toxicity (see section 5.3). Isosorbide mononitrate should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

Breast-feeding

The safety and efficacy of Nyzamac SR Capsules during lactation in humans 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 during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

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. These effects may be increased by alcohol.

4.8 Undesirable effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependent.

The frequency of possible side effects listed below is defined using the following convention:

Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1000), Not known (cannot be estimated from available data).

System Organ Class

Very common

Common

Uncommon

Rare

Not Known

Nervous system disorders

Headache1

 

 

 

Restlessness,

Somnolence,

Pituitary haemorrhage

Cardiac disorders

 

 

 

Tachycardia2

Paroxysmal bradycardia2

 

Vascular disorders

 

Hypotension3,

Light-headedness in the upright position (orthostatic hypotension)

(may be associated with flushing, dizziness, drowsiness, tachycardia, feeling of weakness).

Collapse4

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

Hypoxia

Gastrointestinal disorders

 

 

Nausea

Vomiting

Heartburn5

 

Diarrhoea

Skin and subcutaneous tissue disorders

 

 

Hyperhidrosis

 

Pruritus

Exfoliative dermatitis

Allergic skin reaction (e.g. rash)

Musculoskeletal and connective tissue disorders

 

 

 

 

Myalgia

General disorders and administration site conditions

 

 

 

 

Asthenia

1 The incidence of headache usually disappears after 1-2 weeks of treatment. (see section 4.2)

2 These symptoms generally disappear during long-term treatment.

3 Severe hypotensive responses have been reported with organic nitrates with nausea, vomiting, restlessness, pallor, and excessive perspiration. Uncommonly, severe hypotension may lead to enhanced angina pectoris symptom (see section 4.4)

4 Sometimes accompanied by bradyarrhythmia, bradycardia and syncope

5 Most likely due to a nitrate-induced sphincter relaxation.

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 (Website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms and signs

Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur.

Methaemoglobinaemia (cyanosis, hypoxaemia, change in mental status, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure and raised intracranial pressure) occurs rarely.

Management

Induction of emesis, activated charcoal.

In case of pronounced hypotension the patient should first be placed in the supine position with legs raised. If necessary, fluids should be administrated intravenously.

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.

If methaemoglobinaemia occurs seek expert advice. Treat with supplemental oxygen and methylene blue. In cases not responding to methylene blue or where methylene blue is contraindicated consider exchange transfusion or red blood cell concentrates. In case of cerebral convulsions, consider diazepam or clonazepam IV or, if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vasodilator used in cardiac diseases

ATC code: C01DA14

Mechanism of action

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

Pharmacodynamic effects

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

This product has all the pharmacokinetic characteristics of a true modified release dosage form.

Compared with an immediate-release dosage form, the peak plasma concentration obtained is lower and occurs later, while the apparent elimination half-life is unchanged. Thus, compared to ordinary capsules, the absorption phase is prolonged and the duration of effect is extended.

The clinical effects of nitrates may be reduced following repeated administration due to too high and / or constant plasma levels. This can be avoided by allowing low plasma levels for a certain period between doses.

The slow continuous diffusion of the active ingredient from the modified-release microgranules makes it possible, at steady state, to maintain plasma concentrations above the putative effective level of 100ng/ml for a period of about 16 hours for the 40mg capsules and 20 hours for the 60mg capsules. Thus, no development of tolerance should be seen with isosorbide mononitrate SR capsules when they are taken in accordance with the recommended dosage regime.

Absorption

In man, isosorbide mononitrate is absorbed completely and rapidly following oral administration. There is no effect of food on bioavailability.

Distribution

Isosorbide mononitrate has a volume of distribution of about 40 litres and is not significantly protein bound.

Biotransformation

Isosorbide mononitrate is extensively metabolised to nitric oxide (NO-which is the active ingredient) and isosorbide (inactive). Unlike isosorbide dinitrate, isosorbide mononitrate does not undergo first pass hepatic metabolism and provides a low degree of inter-individual variation of blood levels, leading to predictable and reproducible clinical effects.

Elimination

Most of isosorbide mononitrate is excreted unchanged in the urine.

In patients with cirrhotic disease or cardiac failure or renal failure, parameters were similar to those obtained in healthy volunteers.

5.3 Preclinical safety data

High concentrations of isosorbide mononitrate in rats is associated with prolonged gestation and parturition, stillbirths and deaths.

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
6.1 List of excipients

Capsule content:

Lactose monohydrate,

Sugar spheres (containing sucrose and maize starch),

Bleached dewaxed shellac,

Dewaxed shellac,

Copolymer of methacrylic acid and methyl methacrylate (1:1),

Copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (1:2:0.1),

Talc

Capsule shell (40, 50 and 60 mg):

Gelatin

Titanium dioxide (E 171)

Black printing ink:

Shellac, propylene glycol, ammonium hydroxide, potassium hydroxide, black iron oxide (E 172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

The capsules are packed in in blister packs (20 μm aluminium/250 μm PVC) and boxed in cardboard cartons containing 28, 30, 56 or 60 capsules.

Sample blister pack of 8 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Ethypharm

194, Bureaux de la Colline – Bâtiment D

92213 Saint-Cloud Cedex

France

8. Marketing authorisation number(s)

PL 06934/0200

PL 06934/0207

PL 06934/0201

9. Date of first authorisation/renewal of the authorisation

PL 06934/0200: 2nd April 1996, 1st August 2001

PL 06934/0207: 24th June 2002, 17th March 2009

PL 06934/0201: 2nd April 1996, 1st August 2001

10. Date of revision of the text

September 2018