Summary of medicine characteristics - ISMO 10
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 10 mg isosorbide-5-mononitrate.
Excipient with known effect: lactose
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet for oral use.
White round tablets marked “ISMO” on one face and “10” on the reverse.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
ISMO products 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 administration
Posology
Paediatric Population
The safety and efficacy of ISMO in children has not been established.
Adults
The recommended dosage is from 20 to 120 mg isosorbide-5-mononitrate daily in divided doses. The majority of patients will require a dosage in the range of 40 to 60 mg daily in divided doses. The tablets should be taken with fluid and swallowed whole without chewing.
The lowest effective dose should be used.
For patients who have not previously received prophylactic nitrate therapy it is recommended that the ISMO Starter Pack be employed. This provides an initial dosage of 10 mg isosorbide-5-mononitrate (1 tablet) daily for 2 days followed by a dosage of 20 mg daily (1 tablet morning and evening) for a further 3 days. Subsequently the daily dosage may be increased to the normal prophylactic level using the ISMO 20 tablets also included in the Starter Pack. Patients already accustomed to chronic nitrate therapy normally may be transferred directly to a therapeutic dose of ISMO.
For those previously treated with isosorbide dinitrate in conventional form the dosage of ISMO should be the same initially. ISMO is effectively twice as potent as sustained release forms of isosorbide dinitrate and patients transferred from such treatment should receive ISMO at half the previous dosage.
Therapy should not be discontinued suddenly. Both dosage and frequency should be tapered gradually (see section 4.4).
Elderly
There is no evidence to suggest an adjustment of dose is necessary. However, caution may be required in elderly patients who are known to be susceptible to the effects of hypotensive medication.
Renal and hepatic impairment
No dosage reduction is necessary.
Method of administration
Oral.
4.3 Contraindications
hypersensitivity to the active substance, or to any of the excipients listed in section 6.1
hypersensitivity to isosorbide dinitrate
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
ISMO is 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose 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. ACE-inhibitors, angiotensin-II-receptor antagonists, beta-blockers, calcium antagonists, diuretics), neuroleptics, sapropterin, alprostadil, aldesleukin and alcohol can potentiate the hypotensive effect of ISMO 10.
In particular, the hypotensive effects of nitrates are potentiated by concurrent co-administration 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
Pregnancy
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.
Lactation
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.
Fertility
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)
Nervous system disorders
Very common: Particularly at the start of treatment, a transient “nitrate headache” may occur which normally subsides after some days of continued treatment.
Vascular disorders
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
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
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
ISMO 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 ISMO.
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
No special findings.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
ISMO 10 tablets also contain anhydrous lactose, colloidal silicon dioxide and magnesium stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
ISMO Starter Pack: 8 tablets of ISMO 10 and 60 tablets of ISMO 20 in calendarised blister strips.
ISMO 10 – packs of 100 tablets.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements.
7 MARKETING AUTHORISATION HOLDER
RIEMSER Pharma GmbH,
An der Wiek 7,
17493 Greifswald – Insel Riems,
Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 42336/0003