1. Name Of The Medicinal Product
Monomil 20 mg Tablets
Carmil 20 mg Tablets
Isosorbide Mononitrate 20 mg tablets.
2. Qualitative And Quantitative Composition
Isosorbide-5-mononitrate Ph. Eur. 20 mg/tablet.
3. Pharmaceutical Form
Tablets
White to off-white, round flat tablets with 'I15' embossing on one side.
4.1 Therapeutic Indications
For the prophylaxis of angina pectoris
As adjunctive therapy in congestive heart failure not responding to cardiac glycosides or diuretics.
4.2 Posology And Method Of Administration
Adults: One tablet to be taken asymmetrically (to allow a nitrate low period) two or three times a day. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose of isosorbide mononitrate be 20mg twice a day. The dosage may be increased to 120mg per day. The lowest effective dose should be used.
Children: The safety and efficacy of Isosorbide Mononitrate 20mg tablets in children has not been established.
Elderly: There is no evidence to suggest that an adjustment of the dosage is necessary.
Treatment with Isosorbide mononitrate tablets, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4)
4.3 Contraindications
Isosorbide mononitrate tablets should not be used in cases of acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse), or very low blood pressure, hypertrophic obstructive cardiomyopathy (HOCM), constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/mitral valve stenosis and diseases associated with a raised intra-cranial pressure e.g. following a head trauma and including cerebral haemorrhage.
This product should not be given to patients with a known sensitivity to isosorbide mononitrate, the listed ingredients or other nitrates.
Isosorbide mononitrate Tablets should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.
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)
4.4 Special Warnings And Precautions For Use
Isosorbide mononitrate Tablets should be used with caution in patients who have recent history of myocardial infarction, or who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.
Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.
This product may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.
Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.
Isosorbide mononitrate 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.
In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate Tablets.
If the tablets are not taken as indicated (see section 4.2), tolerance to the medication could develop. The lowest effective dose should be used.
Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.2)
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists etc. and/or alcohol may potentiate the hypotensive effects of Isosorbide mononitrate Tablets. This may occur with neuroleptics and tricyclic antidepressants.
Any blood pressure lowering effect of Isosorbide mononitrate tablets will be increased if used together with phosphodiesterase type-5- inhibitors, which are used for erectile dysfunction (see special warning and contraindications). This may lead to life threatening cardiovascular complications. Patients who are on Isosorbide mononitrate therapy therefore must not use phosphodiesterase type-5 inhibitors.
Reports suggest that concomitant administration of Isosorbide mononitrate tablets may increase the blood levels of dihydroergotamine and its hypertensive effects.
4.6 Pregnancy And Lactation
There is inadequate evidence of safety in human pregnancy and lactation and use during pregnancy and lactation is not recommended unless considered essential by the patient's physician.
4.7 Effects On Ability To Drive And Use Machines
Dizziness, tiredness or blurred vision might occur at the start of the treatment. The patient should therefore be advised that if affected, they should not drive or operate machinery. This effect may be increased by alcohol.
4.8 Undesirable Effects
A very common (>10% of patients) adverse reaction to Isosorbide mononitrate Tablets is throbbing headache. The incidence of headache diminishes gradually with time and continued use.
At the start of therapy or when the dosage is increased, hypotension and/or light-headedness in the upright position are commonly observed (i.e. in 1-10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachycardia and a feeling of weakness.
Infrequently (i.e. in less than 1% patients) nausea, vomiting, flushing and allergic skin reactions (e. g. rash) may occur sometimes severely. In single cases exfoliative dermatitis may occur.
Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.
A few reports of heartburn most likely due to a nitrate induced sphincter relaxation have been reported.
Tachycardia and paroxysmal bradycardia have been reported.
4.9 Overdose
Symptoms and signs: Headache, hypotension, nausea, vomiting, sweating, tachycardia, vertigo, restlessness, warm flushed skin, blurred vision and syncope. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur. Methaemoglobinaemia (cyanosis, hypoxaemia, restlessness, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure) occurs rarely.
Management:
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. Correct hypotension by raising the foot of the bed and /or by expanding the intravascular volume. Other measures as indicated by the patient's clinical condition. If severe hypotension persists despite the above measures consider use of inotropes.
If methaemoglobinaemia (symptoms or >30% methaemoglobin), IV administration of methylene blue 1-2mg/kg body-weight. If therapy fails with second dose after 1 hour or contraindicated, consider red blood cell concentrates or exchange transfusion. In case of cerebral convulsions, diazepam or clonazepam IV, or if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.
5.1 Pharmacodynamic Properties
ATC code: C01D A14 Vasodilatator used in cardiac diseases
Isosorbide mononitrate is an organic nitrate, which, in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.
Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.
It reduces the requirements of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.
5.2 Pharmacokinetic Properties
Isosorbide 5—mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.
Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.
Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosrbide-5-mn-2-glucoronide, which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.
After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.
5.3 Preclinical Safety Data
Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, oncogenicity and toxicity to reproduction.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Microcrystalline cellulose Ph. Eur., Lactose Monohydrate Ph. Eur., Colloidal Anhydrous Silica Ph. Eur., Maize starch Ph. Eur., Talc Ph. Eur., and Magnesium stearate Ph. Eur.
6.2 Incompatibilities
None known.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 25ºC.
6.5 Nature And Contents Of Container
PVC/Aluminium foil blisters on a cardboard carton.
Each sheet of blisters contains 10 tablets and there are six sheets of ten tablets per carton (60's pack).
Each strip of blister contains 14 tablets and there are four such strips per carton (56's pack).
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 16363/0001
9. Date Of First Authorisation/Renewal Of The Authorisation
21st September 1998
10. Date Of Revision Of The Text
16/10/2007
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