This information is intended for use by health professionals

1. Name of the medicinal product

Imdur ® Tablets 60mg.

2. Qualitative and quantitative composition

Isosorbide mononitrate 60mg

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Extended release film coated tablet (Durules®)

4. Clinical particulars
4.1 Therapeutic indications

Prophylactic treatment of angina pectoris.

4.2 Posology and method of administration

Posology

Adults

Imdur 60mg (one tablet) once daily given in the morning. The dose 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 Imdur in children has not yet been established.

Older people

No evidence of a need for routine dosage adjustment in older people 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

Imdur 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 Imdur must not be given Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil).

Severe cerebrovascular insufficiency or hypotension are relative contraindications to the use of Imdur.

4.4 Special warnings and precautions for use

Imdur is not indicated for relief of acute angina 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

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

4.6 Fertility, pregnancy and lactation

The safety and efficacy of Imdur 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 Imdur. Patients should be advised to determine how they react to Imdur 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)

System Organ Class

Frequency

Reaction

Nervous system disorders

Common

Headache, dizziness

Rare

Fainting

Cardiac and vascular disorders

Common

Hypotension, tachycardia

Gastrointestinal disorders

Common

Nausea

Uncommon

Vomiting, diarrhoea

Skin and subcutaneous tissue disorders

Rare

Rash, pruritus

Musculoskeletal and connective tissue disorders

Very rare

Myalgia

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.

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.

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 administered intravenously.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vasodilators used in cardiovascular disease (organic nitrates). ATC Code: C01D A.

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

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 elimination half-life of isosorbide mononitrate is around 5 hours. The plasma protein 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. Only about 2% of the dose given is excreted intact via the kidneys.

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

Imdur is an extended release formulation (Durules). 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.

The extent of bioavailability of Imdur is about 90% compared to immediate release tablets. Absorption is not significantly affected by food intake and there is no accumulation during steady state. Imdur 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, Imdur 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).

Imdur is effective as monotherapy as well as in combination with chronic β-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. Imdur, when administered once daily in the morning, produces a plasma profile of high levels during the day and low levels during the night. With Imdur 60mg or 120mg 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 Imdur.

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

Aluminium silicate

Paraffin special

Hydroxypropylcellulose LF

Magnesium stearate

Colloidal anhydrous silica

Hypromellose 6cps

Macrogol 6000

Titanium dioxide E171

Iron oxide yellow E172.

6.2 Incompatibilities

Not applicable for extended release products.

6.3 Shelf life

Glass bottle: 3 years

Blister pack: 3 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Amber glass bottles with a LD-polyethylene cap in a pack of 100 tablets.

Press-through package of thermoformed PVC, in packs of 7, 14, 28 and 98 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Do not crush or chew tablets. The tablets should be taken with half a glass of water.

7. Marketing authorisation holder

TopRidge Pharma (Ireland) Limited

6-9 Trinity Street, Dublin 2

Ireland

8. Marketing authorisation number(s)

PL 46500/0002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 21st July 1987

Date of latest renewal: 18th May 2004

10. Date of revision of the text

11th August 2017