Summary of medicine characteristics - ISOSORBIDE MONONITRATE 40 MG TABLETS, ANGITATE 40 MG TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Isosorbide Mononitrate 40 mg Tablets
Angitate 40 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 40 mg of the active ingredient isosorbide mononitrate.
Excipient with known effect: Each tablet contains 10 mg lactose monohydrate and 190 mg anhydrous lactose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
White to off- white, biconvex tablets, marked with ‚IMN and 40’ on one side with a scoreline in between and the other side with 'BL‘.
4 CLINICAL PARTICULARS
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 daily. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose be one tablet of Isosorbide Mononitrate 40mg twice a day.
The dosage may be increased up to 120 mg per day.
The lowest effective dose should be used.
Elderly
There is no evidence to suggest that an adjustment of the dosage is necessary
Paediatric population
The safety and efficacy of Isosorbide Mononitrate has yet to be established in children.
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 4.4)
Method of administration
The tablet should be swallowed whole, and not chewed or crushed.
4.3 Contraindications
Hypersensitivity to the active substance, other nitrates or to any of the excipients listed in section 6.1
Isosorbide Mononitrate should not be used in cases of acute myocardial infarction with low filling pressure, 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.
Isosorbide Mononitrate should not be used in patients with severe anaemia, severe hypotension, closed angle glaucoma or severe hypovolaemia.
Phosphodiesterase type-5 inhibitors (e.g. Sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5).
During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).
4.4 Special warnings and precautions for use
Isosorbide Mononitrate should be used with caution in patients who have a recent history of myocardial infarction, low filling pressures e.g. in acute myocardial infarction, impaired left ventricular function (left ventricular failure). Reducing systolic blood-pressure below 90 mmHg must be avoided. Also in patients who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.
Symptoms of circulatory collapse may arise after the initial 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 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).
Patients who undergo a maintenance treatment with Isosorbide Mononitrate Tablets should be informed that they must not use phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil).
Isosorbide Mononitrate Tablets therapy should not be interrupted to take phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil), because the risk of inducing an attack of angina pectoris could increase by doing so (see sections 4.3 and 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Concurrent administration of drugs with blood pressure lowering properties, e.g. betablockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin
II receptor antagonists etc may potentiate the hypotensive effect of Isosorbide Mononitrate. This may also occur with neuroleptics and tricyclic antidepressants.
The hypotensive effects of nitrates are potentiated by concurrent administration of phosphodiesterase type-5 inhibitors, which are used for erectile dysfunction (see sections 4.3 and 4.4) , which may lead to life threatening cardiovascular complications. Patients who are on Isosorbide Mononitrate therapy therefore must not use phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).
Reports suggest that concomitant administration of Isosorbide Mononitrate may increase the blood level of dihydroergotamine and its hypertensive effect.
Saproterine (Tetrahydropterine, BH4) is a cofactor for nitric oxide synthatase. Caution is recommended during concomitant use of saproterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).
The use of isosorbide mononitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.
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. Safety in pregnancy however has not been established. Isosorbide mononitrate should only be used in pregnancy and during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.
Breast-feeding
It is not known whether nitrates are excreted in human milk and therefore caution should be exercised when administered to nursing women.
Fertility
There is no data available on the effect of isosorbide mononitrate on fertility in humans.
4.7 Effects on ability to drive and use machines
Dizziness, tiredness or blurred vision might occur at the start of treatment. The patient should be advised that, if affected, they should not drive or operate machinery. This effect may be increased by alcohol
4.8 Undesirable effects
Undesirable effects frequencies are defined as: very common (>1/10), common (>1/100 <1/10), uncommon (>1/1,000 <1/100), rare (>1/10,000 <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
During administration of Isosorbide Mononitrate Tablets 10 mg the following undesirable effects may be observed:
Nervous system disorders:
very common: headache,
common: dizziness (including dizziness postural), somnolence.
Cardiac disorders:
common: tachycardia,
uncommon: angina pectoris aggravated.
Vascular disorders:
common: orthostatic hypotension,
uncommon: circulatory collapse (sometimes accompanied by bradyarrhythmia and syncope).
not known: hypotension
Gastrointestinal disorders:
uncommon: nausea, vomiting,
very rare: heartburn.
Skin and subcutaneous tissue disorders:
uncommon: allergic skin reactions (e.g. rash), flushing
not known: dermatitis exfoliative.
Immune system disorders:
not known: angioedema
General disorders and administration site conditions:
common: asthenia.
Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor and excessive perspiration. During treatment with Isosorbide Mononitrate Tablets, a temporary hypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease, this may lead to a myocardial hypoxia.
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.
4.9 OverdoseHuman experience:
Symptoms:
Fall of blood pressure < 90 mmHg
Paleness
Sweating
Weak pulse
Tachycardia
Light-headedness on standing
Headache
Weakness
Dizziness
Nausea
Vomiting
Diarrhoea
Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During isosorbide mononitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of isosorbide mononitrate may cause this adverse reaction.
In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms.
Stop intake of the drug
General procedures in the event of nitrate-related hypotension:
o Patients should be kept horizontal with the head lowered and legs raised
o Supply oxygen
o Expand plasma volume (i.v. fluids)
o Specific treatment for shock (admit patient to intensive care unit)
Raising the blood pressure if the blood pressure is very low.
Treatment of methaemoglobinaemia:
o Reduction therapy of choice with vitamin C, methylene-blue or toluidine-blue
o Administer oxygen (if necessary)
o Initiate artificial ventilation
o Hemodialysis (if necessary)
Resuscitation measures
In case of signs of respiratory and circulatory arrest, initiate resuscitation
measures immediately.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: C01D A14
Pharmacotherapeutic group: Vasodilator 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 requirement 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 Isosorbide-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
5.3 Preclinical safety dataPreclinical 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
Lactose monohydrate
Anhydrous lactose
Colloidal silicon dioxide
Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store below 25°C. Store in the original package in order to protect from moisture and light.
6.5 Nature and contents of container
Blisters packed in PVC / PVDC on hard tempered aluminium foil
Pack sizes: 14, 28, 30, 56 and 60 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd.,
Unit 3, Canalside,
Northbridge Road,
Berkhamsted,
Hertfordshire,
HP4 1EG,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0524
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
24/03/2017