This information is intended for use by health professionals

1. Name of the medicinal product

Monomil XL Tablets

Carmil XL Tablets

2. Qualitative and quantitative composition

Isosorbide – 5 – mononitrate: 60mg/tablet. Also contains lactose.

For full list of excipients, see Section 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

Posology

Adults: One tablet to be taken once daily 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 the treatment with 30mg (half tablet) for the first 2 – 4 days.

Paediatric population: The safety and efficacy of Monomil XL/Carmil XL tablets in children has not been established.

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.

Method of administration

Monomil XL/Carmil XL tablets must not be chewed or crushed. They should be swallowed whole with a small amount 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.

Severe cerebrovascular insufficiency or hypotension are relative contraindications to the use of Monomil XL/Carmil XL tablets.

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 contraindicated (see section 4.5)

Monomil XL/Carmil XL is contraindicated in diseases associated with a raised intra-cranial pressure e.g. following a head trauma and including a cerebral haemorrhage, and in patients with closed angle glaucoma.

4.4 Special warnings and precautions for use

Monomil XL/Carmil XL tablets are not indicated for the relief of acute angina attacks; in the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.

Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol. Consumption of alcohol should be avoided during the treatment with Carmil/Monomil XL tablets as the vasodilator activity of isosorbide mononitrate may be enhanced.

Monomil XL/ Carmil XL 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.

Monomil XL/Carmil XL 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.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of Monomil XL/Carmil XL tablets and Phosphodiesterase Type 5 Inhibitors can potentiate the vasodilatory effect of Monomil XL/Carmil XL tablets with the potential result of serious side effects such as syncope or myocardial infarction. Therefore, Monomil XL/Carmil XL 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 Monomil XL/Carmil XL 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 Monomil XL/Carmil XL tablets. Patients should be advised to determine how they react to Monomil XL/Carmil XL tablets before they drive or operate machinery.

4.8 Undesirable effects

The adverse reactions which follow have been reported in studies with isosorbide mononitrate. 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. 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).

Nervous system disorders

Common: Headache, Dizziness

Rare: Fainting.

Cardiac and vascular disorders

Common: Tachycardia, Hypotension

Gastrointestinal disorders

Common: Nausea

Uncommon: Vomiting, Diarrhoea.

Skin and subcutaneous tissue disorders

Rare: Rash and pruritus

Musculoskeletal and connective tissue disorders

Very rare: Myalgia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal products 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 or search for MHRA Yellow Card in thr 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 the 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.

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 elimination half-life of isosorbide mononitrate is about 5 hours. The plasma protein binding is less than 5%. The volume of distribution for isosorbide mononitrate is about 0.6 l/kg and the 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 has no major influence on the pharmacokinetic properties.

Monomil XL/Carmil XL Tablets are prolonged release formulations. 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 isosorbide mononitrate in extended 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 in extended release 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, once daily extended release tablets containing isosorbide mononitrate have 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).

Monomil XL/Carmil XL Tablets are 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. Extended release tablets containing isosorbide mononitrate, when administered once daily in the morning, produce a plasma profile of high levels during the day and low levels during the night. With the 60mg or 120mg once daily tablet, 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 this formulation.

5.3 Preclinical safety data

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate, hypromellose, maize starch, glyceryl palmitostearate and magnesium stearate.

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months

6.4 Special precautions for storage

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

6.5 Nature and contents of container

PVC/Aluminium blisters in a cardboard carton. Each strip of blister contains 14 tablets and there are two strips of blisters per carton.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Milpharm Limited

Ares, Odyssey Business Park

West End Road

South Ruislip, HA4 6QD

United Kingdom

8. Marketing authorisation number(s)

PL 16363/0003

9. Date of first authorisation/renewal of the authorisation

12/05/2005

10. Date of revision of the text

20/04/2018