- Approval Id
- b5a7cccd256d3775
- Drug Approval Emc Name
- Monomil XL 60mg Tablets
- Drug Name
- Monomil XL 60mg Tablets
- Company Name
- Aurobindo Pharma - Milpharm Ltd.
- Company Address
- Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
- Company Website
- http://www.aurobindo.com
- Company Telephone
- + 44 (0)208 845 8811
- Company Medical Info Email
- medinfo@aurobindo.com
- Company Customer Care Direct Line
- +44 (0)208 845 8811
- Company Medical Info Fax
- +44 (0)208 845 8795
- Atc Code
- C01DA14
- Legal Category
- Pharmacy
- Authorisation Holder
- Milpharm Limited
Ares, Odyssey Business Park
West End Road
South Ruislip, HA4 6QD
United Kingdom
- Authorisation Number
- PL 16363/0003
- Authorisation Date
- 12/05/2005
- Instruction Authorisation Holder
- Milpharm Limited
Ares, Odyssey Business Park
West End Road
South Ruislip, HA4 6QD
United Kingdom
- Instruction Authorisation Number
- PL 16363/0003
- Instruction Authorisation Date
- 12/05/2005
- Instruction Composition
- Each Tablet contains 60 mg of isosorbide – 5 – mononitrate.
\*\*Excipient(s) with known effect\*\*
Each tablet contains 215mg of lactose monohydrate.
For full list of excipients, see Section 6.1
- Instruction Dosage Form
- Prolonged release tablets.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Prophylactic treatment of angina pectoris.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*\*Adults\*\*\*\*\*:\*\* Monomil XL/Carmil XL tablets (one tablet) given 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 for the first 2 – 4 days.
The score line on the tablet is not intended to divide the tablet into equal halves.
\*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.
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\*\*
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.
Patients treated with Monomil XL/Carmil XL tablets must not be given Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil).
Severe cerebrovascular insufficiency or hypotension are relative contraindications to the use of Monomil XL/Carmil XL tablets.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.
\*\*Monomil XL/Carmil XL tablets contains lactose\*\*
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.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
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).
\*\*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 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.
\*\*Management\*\*
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.
- Instruction Pharmacology
- 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 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, Monomil XL/Carmil XL 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 h; 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. Monomil XL/Carmil XL Tablets, 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, 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
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.
- Instruction 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 months6.4 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.
- Instruction Content
- ## Composition
Each Tablet contains 60 mg of isosorbide – 5 – mononitrate.
\*\*Excipient(s) with known effect\*\*
Each tablet contains 215mg of lactose monohydrate.
For full list of excipients, see Section 6.1
## Pharmaceutical Form
Prolonged release tablets.
## Clinical Particulars
4.1 Therapeutic indications
Prophylactic treatment of angina pectoris.4.2 Posology and method of administration
\*\*Posology\*\*
\*\*\*Adults\*\*\*\*\*:\*\* Monomil XL/Carmil XL tablets (one tablet) given 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 for the first 2 – 4 days.
The score line on the tablet is not intended to divide the tablet into equal halves.
\*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.
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\*\*
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.
Patients treated with Monomil XL/Carmil XL tablets must not be given Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil).
Severe cerebrovascular insufficiency or hypotension are relative contraindications to the use of Monomil XL/Carmil XL tablets.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.
\*\*Monomil XL/Carmil XL tablets contains lactose\*\*
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.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
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).
\*\*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 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.
\*\*Management\*\*
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.
## 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 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, Monomil XL/Carmil XL 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 h; 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. Monomil XL/Carmil XL Tablets, 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, 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
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.
## 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 months6.4 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.
