Summary of medicine characteristics - EUMON 40XL
1 NAME OF THE MEDICINAL PRODUCT
Eumon 40 XL
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 40 mg isosorbide-5-mononitrate
Excipients with known effect: Each tablet contains 25.46mg of lactose.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Modified Release Tablets
Round biconvex cream coloured tablets, with an approximate diameter of 8mm x 4.5mm, marked ‚IM40‘ on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Prophylactic treatment of angina pectoris.
4.2 Posology and method of administration
Posology
Adults
One tablet (40 mg) once daily given in the morning. The dose may be increased to two tablets (80 mg), the whole dose to be given together (dose range 30mg to 120mg.) The dose can be titrated to minimise the possibility of headache by initiating treatment with lesser dose for the first two to four days.
Paediatric population
The safety and efficacy of Eumon 40 XL modified release tablets has not been established.
Older people
No 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 lowest effective dose should be used.
Attenuation of effect (tolerance) has occurred in some patients being treated with sustained release preparations. In such patients intermittent therapy may be more appropriate (see section 4.4).
As with other drugs for the treatment of angina pectoris, therapy should not be discontinued suddenly, as may lead to exacerbation of symptoms. Both dosage and frequency should be tapered gradually over several days, and the patient carefully monitored (see section 4.4).
The core of the tablet is insoluble in the digestive juices but disintegrates into small particles when all the active substance has been released. Very occasionally the matrix may pass through the gastrointestinal tract without disintegrating and be found inside the stool, but all active substance has been released
Method of administration
The tablets should not be chewed or crushed and should be swallowed with half a glass of fluid.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe cerebrovascular insufficiency.
Phosphodiesterase type-5 inhibitors e.g sildenafil, tadalafil and vardenafil has been shown to potentiate the hypotensive effects of nitrates, and its coadministration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5).
Acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse) or very low blood pressure.
Hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral valve stenosis, hypovolaemia closed-angle glaucoma, severe anaemia, conditions causing raised intracranial pressure e.g following head trauma, cerebral haemorrhage.
Eumon 40 XL should not be given to patients with a known sensitivity to nitrates.
Concomitant use with the soluble guanylate cyclase stimulator, riociguat, can cause hypotension and is contraindicated (see section 4.5).
4.4 Special warnings and precautions for use
Eumon 40 XL modified release tablets are not indicated for relief of acute anginal attacks. In the event of an acute attack, sublingual or buccal glyceryl trinitrate tablets should be used.
Caution should be exercised in patients suffering from hypothyroidism, malnutrition, severe renal or hepatic impairment, hypothermia and recent history of myocardial infarction.
The lowest effective dose should be used.
Attenuation of effect (tolerance) has occurred in some patients being treated with sustained release preparations (prolonged release). In such patients intermittent therapy may be more appropriate (see section 4.2).
Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see section 4.2).
The administration of Isosorbide mononitrate causes a decrease of ERPF (Effective Renal Plasma Flow) in cirrhotic patients and should be used with caution.
Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.
Severe postural hypotension with light-headedness and dizziness is frequently observed after the concomitant consumption of alcohol.
Eumon 40XL tablets contain lactose, and therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors (e.g. sildenafil) (see section 4.3). This might lead to life threatening cardiovascular complications.
Any medication which may cause hypotension may have its hypotensive effects potentiated by concurrent administration of Eumon 40 XL (e.g. beta-blockers, ACEinhibitors, alcohol, vasodilators (hydralazine), alprostadil, aldesleukin, angiotensin II receptor antagonists, calcium channel blockers, antihypertensives and diuretics).
Reports suggest that concomitant administration of Isosorbide Mononitrate may increase the blood level of dihydroergotamine and its hypertensive effect.
Concomitant use with the soluble guanylate cyclase stimulator, riociguat, can cause hypotension and is contraindicated (see section 4.3).
4.6 Fertility, pregnancy and lactation
Pregnancy
No data have been reported which would indicate the possibility of adverse effects resulting from the use of isosorbide mononitrate in pregnancy.The safety and efficacy of Eumon 40 XL modified release tablets during pregnancy has not been established. Animal studies have shown reproductive toxicity (see section 5.3).
Isosorbide mononitrate should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards
Breastfeeding
The safety and efficacy of Eumon 40 XL modified release tablets during lactation has not been established.
It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing women.
Isosorbide mononitrate should only be used during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.
4.7 Effects on ability to drive and use machines
The patient should be warned not to drive or operate machinery if hypotension, blurred vision or dizziness occurs.
4.8 Undesirable effects
Most of the adverse reactions are pharmacodynamically mediated and dose dependent.
Headache is very common (>10%). Throbbing headache may occur when treatment is initiated, but usually disappears after 1–2 weeks of treatment. Hypotension including postural hypotension, with symptoms such as dizziness, fatigue and nausea has occasionally been reported. Infrequently, flushing and allergic reactions (including rashes) can occur. These symptoms generally disappear during long-term treatment.
Severe hypotensive responses have been reported for organic nitrates and include vomiting, restlessness, pallor and excessive perspiration. Uncommonly, collapse may occur (sometimes accompanied by bradyarrhythmia, bradycardia and syncope).
Uncommonly severe hypotension may lead to enhanced angina symptoms.
Dizziness, nausea, tachycardia and paroxysmal bradycardia have been reported. There have been isolated reports of myalgia.
Drowsiness, diarrhoea or vomiting may occur. Cases of exfoliative dermatitis have been reported.
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 Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9 Overdose
4.9 OverdoseTreatment should be symptomatic. The main symptom is likely to be hypotension.
Symptoms: Headache, excitation, cold perspiration, vertigo, nausea, vomiting,
restlessness, warm flushed skin, blurred vision, fainting, tachycardia, hypotension and palpitations. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur.
Methaemoglobinaemia (cyanosis, hypoxaemia, change in mental status, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure).
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 (intravenous fluids should be administrated and ionotropes considered.). Other measures as indicated by the patient’s clinical condition.
If methaemoglobinaemia occurs, treat with supplemental oxygen and methylene blue. In cases not responding to methylene blue or where methylene blue is contraindicated consider exchange transfusion or red blood cell concentrates. In case of cerebral convulsions, consider diazepam or clonazepam IV or, if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.
If severe hypotension persists despite the above measures consider use of inotropes such as dopamine or dobutamine.
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Vasodilators used in Cardiac Diseases/Organic Nitrates
ATC-Code: G04BD
Mechanism of action
Organic nitrates (including GTN, ISDN and ISMN) are potent relaxers of smooth muscle. They have a powerful effect on vascular smooth muscle with less effect on bronchiolar, gastrointestinal, ureteral and uterine smooth muscle. Low concentrations dilate both arteries and veins.
Venous dilatation pools blood in the periphery leading to a decrease in venous return, central blood volume, and ventricular filling volumes and pressures. Cardiac output may remain unchanged or it may decline as a result of the decrease in venous return. Arterial blood pressure usually declines secondary to a decrease in cardiac output or arteriolar vasodilatation, or both. A modest reflex increase in heart rate results from the decrease in arterial blood pressure. Nitrates can dilate epicardial coronary arteries including atherosclerotic stenoses.
Pharmacodynamic e ffects
The cellular mechanism of nitrate-induced smooth muscle relaxation has become apparent in recent years. Nitrates enter the smooth muscle cell and are cleaved to inorganic nitrate and eventually to nitric oxide. This cleavage requires the presence of sulphydryl groups, which apparently come from the amino acid cysteine. Nitric oxide undergoes further reduction to nitrosothiol by further interaction with sulphydryl groups. Nitrosothiol activates guanylate cyclase in the vascular smooth muscle cells, thereby generating cyclic guanosine monophosphate (cGMP). It is this latter compound, cGMP,that produces smooth muscle relaxation by accelerating the release of calcium from these cells.
5.2 Pharmacokinetic properties
Absorption
Isosorbide-5-mononitrate is readily absorbed from the gastro-intestinal tract.
Distribution
Following oral administration of conventional tablets, peak plasma levels are reached in about 1 hour. Unlike isosorbide dinitrate, ISMN does not undergo first-pass hepatic metabolism and bioavailability is 100%. ISMN has a volume of distribution of about 40 litres and is not significantly protein bound.
Metabolism
ISMN is metabolised to inactive metabolites including isosorbide and isosorbide glucuronide.
Elimination
The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic insufficiency. Only 20% of ISMN is excreted unchanged in the urine. An elimination half life of about 4–5 hours has been reported.
5.3 Preclinical safety data
5.3 Preclinical safety dataHigh concentrations of isosorbide mononitrate in rats is associated with prolonged gestation and parturition, stillbirths and deaths.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Stearic acid, carnauba wax, hypromellose, lactose, magnesium stearate, talc, silica colloidal anhydrous, macrogol 4000, E171 and E172.
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original container.
6.5 Nature and contents of container
The tablets are packed in blisters which consist of 250 ^m PVC with a 25 ^m PVdC coating which is sealed to 25 pm thick aluminium foil with 20 pm PVdC sealing lacquer. The tablets are packed in boxes of 28, 30, 56, 60 or 100 tablets
Not all packs sizes may be marketed.
6.6 Special precautions for disposal and other handling
6.6 Special precautions for disposal and other handlingNo special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd
220 Butterfield,
Great Marlings
Luton
LU2 8DL
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0455
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
Date of first authorisation: 13/08/2008