TRANGINA XL 60 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

TRANGINA XL 60mg TABLETS

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60mg isosorbide-5-mononitrate.

Excipients with known effect:

Each 60mg tablet contains 215.00mg lactose monohydrate

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Prolonged release tablets

White, oval-shaped tablets impressed “C” on one face and the identifying letters “CY” on either side of a central division line on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Adults:

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

Paediatric population:

The safety and efficacy of isosorbide mononitrate in children has not been establised.

Elderly:

No evidence of a 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 core of the tablet is insoluble in the digestive juices but disintegrates into small particles when all active substance has been released. Very occasionally the matrix may pass through the gastrointestinal tract without disintegrating and be found visible in the stool, but all active substance has been released.

Method of Administration

For oral use.

Trangina XL 60mg tablets must not be chewed or crushed. They should be swallowed whole with half a glass of water.

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.

– Patients treated with Trangina XL 60mg tablets must not be given Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil).

– Severe cerebrovascular insufficiency or hypotension are relative contraindications to the use of Trangina XL 60mg tablets.

4.4 Special warnings and precautions for use

Trangina XL 60mg tablets is not indicated for relief of acute anginal attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

Trangina XL 60mg tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of Trangina XL 60mg tablets and Phosphodiesterase Type 5 Inhibitors can potentiate the vasodilatory effect of Trangina XL 60mg tablets with the potential result of serious side effects such as syncope or myocardial infarction. Therefore, Trangina XL 60mg tablets and Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil) must not be given concomitantly.

4.6 Fertility, pregnancy and lactation

The safety and efficacy of Trangina XL 60mg tablets 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 Trangina XL 60mg tablets.

Patients should be advised to determine how they react to Trangina XL 60mg tablets before they drive or operate machinery.

4.8 Undesirable effects

Most of the adverse reactions are pharmacodynamically mediated and dose dependent. Headache may occur when treatment is initiated, but usually disappears after 1–2 weeks of treatment. The dose can be titrated to minimise the possibility of headache, by initiating treatment with 30mg. Hypotension, with symptoms such as dizziness and nausea with syncope in isolated cases, has occasionally been reported. These symptoms generally disappear during continued treatment.

The following definitions of frequencies are used: 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) and Very Rare (<1/10,000).

Adverse drug reactions by frequency and system organ class (SOC)

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: Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure.

Treatment: 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 administered intravenously.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

ATC code: C01DA14

Mechnanism of action

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 afterload. 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 subendocardial 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

Absorption

Isosorbide mononitrate is completely absorbed and 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.

The active substance is released independently of pH, over a 10-hour period. Compared to ordinary tablets the absorption phase is prolonged and the duration of effect is extended.

Absorption is not significantly affected by food intake and there is no accumulation during steady state.

Distribution

The extent of bioavailability of Trangina XL 60mg tablets is about 90% compared to immediate release tablets. The volume of distribution for isosorbide mononitrate is about 0.6 l/kg and total clearance around 115 ml/minute. The plasma protein binding is less than 5%. Trangina XL 60mg tablets exhibits dose proportional kinetics up to 120mg. After repeated peroral administration with 60mg 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 dose intake). The tablets are divisible.

In placebo-controlled studies, Trangina XL 60mg 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). Trangina XL 60mg tablets is effective as monotherapy as well as in combination with chronic P-blocker therapy.

The clinical effects of 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. Trangina XL 60mg tablets, when administered once daily in the morning, produces a plasma profile of high levels during the day and low levels during the night. With Trangina XL 60mg tablets 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 Trangina XL 60mg tablets.

Elimination

The elimination half-life of isosorbide mononitrate is around 5 hours. Elimination is primarily by denitration and conjugation in the liver. Impaired liver or kidney function have no major influence on the pharmacokinetic properties.

Trangina XL 60mg tablets is an extended release formulation (Durules). The metabolites are excreted mainly via the kidneys. Only about 2% of the dose given is excreted intact via the kidneys.

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

The tablets also contain: lactose, hypromellose (E464), glyceryl palmitostearate, maize starch, magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Shelf-life

Two years from date of manufacture.

Shelf-life after dilution/recon­stitution Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special precautions for storage

Do not store above 25oC.

Keep container in the outer carton.

6.5 Nature and contents of container

Aluminium (20^m)/PVC (250^m) strips in a carton box.

Pack sizes: 28, 56 (Al/PVC)

6.6 Special precautions for disposal and other handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Accord-UK Ltd (Trading style: Accord) Whiddon Valley Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 00142/0462