Summary of medicine characteristics - ISOSORBIDE MONONITRATE TABLETS 40 MG
1 NAME OF THE MEDICINAL PRODUCT
1 NAME OF THE MEDICINAL PRODUCTISOSORBIDE MONONITRATE TABLETS 40mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 40mg Isosorbide mononitrate.
3. Pharmaceutical Form
3. Pharmaceutical FormWhite to off-white, uncoated tablets.
White to off-white, circular, biconvex uncoated tablets impressed “C” on one face and the identifying letters “IV”on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Isosorbide mononitrate tablets are indicated for use in the treatment and prophylaxis of angina pectoris and as adjunctive therapy in congestive heart failure which does not respond adequately to cardiac glycosides and/or diuretics.
4.2 Posology and method of administrationPosology
Adults
Angina
Usually 20mg, two or three times daily. Patients already accustomed to prophylactic nitrate therapy may normally be transferred directly to a therapeutic dose of isosorbide mononitrate. For patients not already receiving prophylactic nitrate therapy, it is recommended that the initial dosage should be 20mg twice daily.
The maintenance dose in individual patients is usually between 20–120mg daily.
Congestive cardiac failure
In severe congestive cardiac failure doses of 20mg, two or three times daily may be employed depending on individual requirements. The optimum dosage is best determined by continuous haemodynamic monitoring. The use of isosorbide mononitrate tablets in severe congestive cardiac failure should be regarded as an adjunctive therapy to more conventional treatment (e.g. cardiac glycosides, diuretics).
For those previously treated with isosorbide dinitrate in conventional form, the dosage of isosorbide mononitrate should be the same initially. Isosorbide mononitrate is effectively twice as potent as sustained release forms of isosorbide dinitrate and patients transferred from such treatment should receive isosorbide mononitrate at half the previous dosage.
Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see section 4.4).
Elderly
Dosage requirements may be reduced especially when hepatic or renal function is impaired. Also, particular care should be taken due to susceptibility to hypotension.
Renal and hepatic impairment
Dosage should be reduced in patients with renal or hepatic impairment.
Paediatric population
Safety and efficacy has not been established.
For oral administration.
It is recommended that the tablets should be swallowed whole with a little fluid after meals.
4.3 Contraindications
Hypersensitivity to isosorbide dinitrate or mononitrate; to other nitrates, or to any of the excipients listed in section 6.1
In cases of marked low blood pressure (BP < 90 mm Hg systolic)
Circulatory collapse
Shock
Cardiogenic shock
Acute myocardial infarction with low left ventricular filling pressure
Hypertrophic obstructive cardiomyopathy
Constrictive pericarditis
Cardiac tamponade
Aortic/mitral valve stenosis
Severe anaemia
Closed-angle glaucoma and conditions associated with raised intracerebral pressure e.g. following head trauma and cerebral haemorrhage
Severe hypovolaemia
Phosphodiesterase-5 inhibitors, e.g. sildenafil, vardenafil and tadalafil have been shown to potentiate the hypotensive effects of nitrates (see section 4.8), and their co-administration with nitrates or nitric oxide donors is therefore contraindicated.
4.4 Special warnings and precautions for use
Isosorbide mononitrate tablets are not indicated for relief of an acute attack, sublingual or buccal glyceryl trinitrate tablets or spray should be used.
The lowest effective dose should be used (see section 4.2).
Since a rebound phenomenon cannot be excluded, therapy with isosorbide-5-mononitrate should be terminated gradually rather than stopping abruptly (see section 4.2).
Caution should be exercised in patients suffering from hypothyroidism, malnutrition, severe renal or hepatic impairment, hypothermia and recent history of myocardial infarction and in patients already taking medicine to lower blood pressure or taking any other medication (see section 4.5).
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 consumption of alcohol.
Tolerance development and occurrence of cross-tolerance with other nitrate compounds have been described. In order to avoid any attenuation or loss of effect, high continuous dosing regimens should be avoided.
Administration of isosorbide-5-nitrate may produce transient hypoxaemia as a result of redistribution of blood flow with a relative increase in perfusion of poorly ventilated areas of the lung.
This may cause ischaemia in patients with coronary heart disease.
Dose escalation and/or changes in the dosing interval can lead to an attenuation or loss of the effect.
This product 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 other vasodilatators, antihypertensives (e.g. ACEinhibitors, angiotensin-II-receptor antagonists, beta-blockers, calcium antagonists, diuretics), neuroleptics, sapropterin, alprostadil, aldesleukin and alcohol can potentiate the hypotensive effect of isosorbide mononitrate tablets.
In particular, the hypotensive effects of nitrates are potentiated by concurrent coadministration of phosphodiesterase type-5 inhibitors e.g. sildenafil, vardenafil and tadalafil (see section 4.3); these effects are potentially life threatening.
4.6 Fertility, pregnancy and lactation
There is inadequate evidence of safety of isosorbide-5-mononitrate in human pregnancy although nitrates have been in wide use for many years without ill consequence, animal studies having shown no adverse effects on the foetus. Use in pregnancy is not recommended unless considered essential by the patient's physician.
There is no information on excretion of isosorbide-5-mononitrate in breast milk. Use in lactation is not recommended unless considered essential by the patient's physician.
There are no fertility data.
4.7 Effects on ability to drive and use machines
In theory, the ability to drive or to operate machinery may be impaired in patients experiencing hypotensive side effects such as dizziness or blurred vision.
4.8 Undesirable effects
The following categories are used when stating the frequency of undesirable effects:
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), Very rare (< 1/10,000), Not known (frequency cannot be estimated from the available data).
Very common:
Particularly at the start of treatment, a transient “nitrate headache” may occur which normally subsides after some days of continued treatment.
Common:
Especially at the beginning of treatment, hypotension (including postural hypotension) has been observed which may be accompanied by tachycardia and slight states of dizziness or feeling weakness, which normally improves on continuation of therapy.
Uncommon:
A significant drop in blood pressure with exacerbation of angina pectoris symptoms has been observed as well as states of collapse, sometimes accompanied by bradyarrhythmias and syncope.
Not known:
Severe hypotensive responses including nausea, vomiting, restlessness, pallor, and hyperhidrosis have been reported for organic nitrates.
Skin and subcutaneous tissue disorders Uncommon:
| Flushing Not known: Exfoliative dermatitis Immune system disorders Uncommon: Allergic skin reactions. Blood and lymphatic system disorders Not known: Formation of methaemoglobin, in particular in susceptible patients such as those with methaemoglobin reductase deficiency or in patients with diaphorase deficiency and abnormal haemoglobin structure. Gastrointestinal disorders Common: Especially when first used, gastro-intestinal symptoms, e.g. nausea and/or vomiting may occur. Not known: Heartburn Reporting of suspected adverse reactions 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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. | |
| 4.9 | Overdose Symptoms of an overdose nausea, vomiting, restlessness, warm flushed skin, blurred vision, headache, fainting, tachycardia, hypotension and palpitations. At high doses (more than 20 mg/kg body weight), methaemoglobin formation, cyanosis, dyspnoea and tachypnoea can be expected, as a result of the nitrite ion formed when isosorbide-5-mononitrate is degraded. At very high doses, increased intracranial pressure with cerebral symptoms may occur. In cases of chronic overdose, increased methaemoglobin levels have been measured, the clinical relevance of which is debated. Measures to treat overdose In addition to general procedures, such as gastric lavage and keeping the patient horizontal with the legs raised, vital parameters must be monitored under intensive care conditions and corrected where necessary. In the event of marked hypotension and/or shock, volume replacement should be given; in exceptional cases, norepinephrine and/or dopamine can be infused as circulatory therapy. Administration of epinephrine and related substances is contraindicated. For methaemoglobinaemia, the following antidote is available: |
Methylene blue: Up to 50 ml of a 1% methylene blue solution IV.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: isosorbide mononitrate, ATC code: C01DA14
Isosorbide mononitrate provides long-term nitrate treatment of angina pectoris and heart failure in a form with complete biological availability due to lack of any significant hepatic first-pass metabolism. This provides consistently uniform blood levels of drug substance and a predictable clinical response.
The onset of activity occurs within 20 minutes, and, depending on dosage, is maintained for up to 10 hours.
Beta-blocking drugs have a different pharmacological action in angina and may have a complementary effect when co-administered with isosorbide mononitrate.
The main effect of isosorbide-5-mononitrate is to produce a marked venous vasodilation without a significant effect on the systemic arteries. The venous dilation leads to an accumulation of blood in the capacitance vessels resulting in a reduction of venous return to the heart. This results in a reduction of the ventricular diastolic volume, which produces a reduction in intramural tension (afterload) as well as reductions of filling pressures and pulmonary capillary pressure (preload) and as a result, a reduction in myocardial oxygen requirements from which arises the antianginal effect.
5.2 Pharmacokinetic properties
Isosorbide-5-mononitrate displays 100% bioavailability on oral administration. Consequently, serum levels are predictable, isosorbide-5-mononitrate is rapidly absorbed – peak serum concentrations occurring 1 hour after oral administration. Elimination half life is approximately 5 hours. The drug is eliminated solely by the liver and therefore can be used in renal insufficiency.
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Also contains:
Crospovidone
Lactose
Magnesium stearate
Maize starch
Microcrystalline cellulose (E460) Povidone.
6.2 Incompatibilities
None known.
6.3 Shelf life
Shelf-life
Two years from the date of manufacture.
Shelf-life after dilution/reconstitution
Not applicable.
Shelf-life after first opening
Not applicable.
6.4 Special precautions for storage
Store below 25°C in a dry place.
6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps, with polyfoam wad or cotton wool.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250^m white rigid PVC. (ii) Surface printed 20^m hard temper aluminium foil with 5–7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 1000s
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.
Maximum size of bulk packs: 50,000
6.6 Instructions for use, handling and disposal
6.6 Instructions for use, handling and disposalNot applicable.
7 MARKETING AUTHORISATION HOLDER
7 MARKETING AUTHORISATION HOLDERAccord-UK Ltd
(Trading style: Accord)
Whiddon Valley
Barnstaple
Devon
EX32 8NS
8. MARKETING AUTHORISATION NUMBER
8. MARKETING AUTHORISATION NUMBERPL 00142/0352
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
27/01/2009