Data Sheet
CORANGIN®
Isosorbide-5-mononitrate
Qualitative and quantitative composition
Tablets 40mg: A white capsule shaped divisible slow-release tablet with convex faces containing 40mg isosorbide-5-mononitrate.
Length: 15mm
Imprints: 1st side CG/CG with score
2nd side EDE/EDE, with score
Pharmaceutical form
Slow release tablets for oral administration
Clinical particulars
Vasodilator.
Therapeutic indications
- Chronic treatment for disorders of blood flow in the coronary vessels (coronary heart disease), and for the prevention of angina pectoris attacks, and also in cases where symptoms of angina pectoris persist after myocardial infarction. Corangin may be used either as monotherapy or in combination with other antianginal agents (e.g. β-blockers or calcium antagonists).
- Treatment for chronic heart failure, in combination with digitalis or other positive-inotropic agents and/or diuretics.
Dosageand method of administration
General rules
Corangin is not intended for the immediate relief of acute attacks of angina pectoris; if they occur, the additional use of rapid-acting nitrate preparations is indicated.
Corangin is presented in the form of Divitabs. These are divisible slow-release tablets, which allow the dosage to be increased or decreased stepwise, so that it can be more closely adapted to individual requirements. Even if the two halves of the tablet are ingested separately, the prolonged duration of action remains undiminished.
Development of tolerance or attenuation of effect may occur with all long-acting nitrates in individual patients on continuous treatment. There are indications that intervals with low-nitrate blood levels (such as are observed with Corangin at the end of the dosing interval) may counteract an attenuation of effect in patients who do not show an adequate clinical response.
Angina pectoris
Treatment should be commenced with 1 tablet of Corangin 40 mg once daily and increased as required, by adding ½ of a 40 mg tablet. Depending on the time of day at which the angina pectoris attacks occur in the individual patient, the slow-release tablet can be taken either in the morning or in the evening.
If treatment with Corangin in angina pectoris patients is to be ended, an abrupt cessation should be avoided: if a change to another product is envisaged, a period of overlapping treatment should be resorted to.
Chronic heart failure
In chronic heart failure it is recommended that treatment be started in hospital and the patient's hemodynamic status monitored; treatment should also be continued in hospital until the requisite maintenance dosage has been established. The optimal dosage should be determined in the light of the clinical response and the side effects encountered, with careful monitoring for signs of overdosage such as a fall in blood pressure and tachycardia.
Children
No information is available on the use of Corangin in children.
Contraindications
Known hypersensitivity to nitrates. Acute circulatory failure associated with marked hypotension (shock, states of collapse). Conditions associated with elevated intracranial pressure. Myocardial insufficiency due to obstruction (e.g. in the presence of aortic or mitral stenosis or of constrictive pericarditis).
Concomitant use of Corangin and Viagra® (sildenafil) is contraindicated, because sildenafil may amplify the vasodilatory effects of Corangin resulting in severe hypotension.
Special warnings and special precautions for use
So as not to expose the patient to the risk of attacks of angina pectoris, abrupt withdrawal of Corangin should be avoided and overlapping treatment resorted to when transferring the patient to another form of medication.
In cases of recent myocardial infarction or acute heart failure, Corangin should only be used cautiously under strict medical surveillance and/or hemodynamic monitoring.
Patients with angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, isosorbide-5-mononitrate could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
Interaction with other medicinal products and other forms of interaction
Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, β-blockers, diuretics, antihypertensives, tricyclic antidepressants, or major tranquilizers, as well as the consumption of alcohol, may potentiate the blood-pressure-lowering effect of Corangin.
Concurrent administration of Corangin with dihydroergotamine may increase the bioavailability of dihydroergotamine. Special attention should be paid to this point in patients with coronary artery disease, because dihydroergotamine antagonizes the effects of nitrates and may lead to coronary vasoconstriction.
The possibility that acetylsalicylic acid and non-steroidal antiinflammatory drugs might diminish the therapeutic response to Corangin cannot be excluded.
Use during pregnancy and lactation
As a general rule no drugs should be taken during the first 3 months of pregnancy, and the benefits and risks of taking drugs should be carefully considered throughout the whole of pregnancy.
Experience with Corangin is limited, but no adverse effects in human pregnancy have been reported. Use Corangin only if drug therapy in pregnancy is essential.
It is not known whether the active substance passes into the breast milk. The benefits for the mother must be weighed against the risks for the child.
Effects on ability to drive and use machines
Even when taken as directed, Corangin can impair the patient's ability to respond appropriately to road traffic and to operate machinery. This may happen especially at the start of treatment, or when a concomitant medicament is introduced, or if alcohol is ingested.
Adverse effects
Central nervous system
Like other nitrate preparations, Corangin may frequently give rise to headache, which is due to cerebral vasodilatation and is dose dependent. Such headaches, however, usually regress after a few days despite continuation of the therapy. If they do not disappear, they should be treated with mild analgesics. In cases where the headaches are unresponsive to treatment, the dosage of Corangin should be reduced or use of the product discontinued.
Cardiovascular system
Facial flushing, faintness, dizziness, and postural hypotension, which may be associated with reflex-induced tachycardia, have rarely been reported. A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a β-blocker.
Gastrointestinal tract
Rare: nausea, vomiting.
Overdose
Signs and symptoms
High doses of isosorbide-5-mononitrate may lead to more pronounced systemic side effects, e.g. to a marked fall in blood pressure or to collapse. Excessive dosage of all nitrates may, on rare occasions, provoke methemoglobinemia.
Treatment
Overdosage should be treated symptomatically. The main symptom is likely to be hypotension, which may be treated by elevation of the legs and passive exercise of the extremities to promote venous return. Gastric lavage may also be useful.
Pharmacological properties
Pharmacodynamic properties
Pharmaco therapeutic group: Vasodilator
Like other nitrates, isosorbide-5-mononitrate is suitable for the chronic treatment of coronary heart disease and heart failure. In angina pectoris its fundamental mechanism of action is primarily based on an increase in venous capacitance (venous pooling) leading to a decreased return of blood to the heart. Owing to this phenomenon, left-ventricular end-diastolic pressure (preload) and hence filling volume diminishes, resulting in a decreased myocardial oxygen requirement at rest and especially during exercise, with an improvement in exercise capacity in patients with angina pectoris. In the coronary arterial circulation isosorbide-5-mononitrate dilates both extramural conductance and small resistance vessels. The drug appears to cause a redistribution of coronary blood flow to the ischemic subendocardium by selectively dilating large epicardial vessels. It also produces relaxation of vasospasm, whether spontaneous or induced by ergometrine.
In addition, isosorbide-5-mononitrate exerts a dose-dependent dilating effect on the arteriolar vascular bed, as a result of which systemic vascular resistance (afterload) and left-ventricular systolic wall tension decrease, leading to a reduction in myocardial oxygen consumption.
In chronic heart failure the dilating action exerted by isosorbide-5-mononitrate on the veins lowers the elevated left-ventricular filling pressure, while at the same time cardiac output either remains unchanged or increases slightly.
Isosorbide-5-mononitrate proves especially effective in patients with severe heart failure showing prominent signs and symptoms of venous pulmonary congestion due to a pronounced increase in left-ventricular filling pressure. If an increase in cardiac output is desired, combined treatment with an arterial vasodilator is recommended.
The duration of action of isosorbide-5-mononitrate is longer than that of its parent compound. A therapeutic efficacy similar to that of isosorbide dinitrate may be achieved with approximately half the dose.
Pharmacokinetic properties
Isosorbide-5-mononitrate is rapidly and completely absorbed from the conventional dosage forms. Unlike isosorbide dinitrate, isosorbide-5-mononitrate is free from first-pass metabolism in the liver, and its bioavailability therefore shows lower interindividual variability.
AUC values assessed by reference to the plasma levels increase linearly with the dose. Mean half-lives of isosorbide-5-mononitrate calculated after administration of conventional formulations range between 4.0 and 4.8 hours.
With Corangin the peak concentrations attained are approx. 60% lower than after administration of the same dose in conventional dosage forms. Peak concentrations are reached 4-8 hours after ingestion of Corangin and in less than 1 hour after administration of conventional formulations. The amount absorbed from sustained-release formulations such as Corangin is slightly reduced (by 10-20%) in comparison with conventional formulations.
No accumulation of isosorbide-5-mononitrate was seen after repeated once-daily administration in normal volunteers or in patients. The results of pharmacokinetic studies suggest that no alterations of the dosage should be necessary in patients with coronary heart disease, renal failure, or liver cirrhosis. Ingestion of food has been reported to have only a negligible effect on the absorption of isosorbide-5-mononitrate.
Pharmaceutical particulars
List of excipients
Tablets (40 mg,): silicagel, aerosil 200, lactose, magnesium stearate,
Methocel
K 100 M premium (hydroxypropyl-methylcellulose), polyethylenglycol 4000,
polyvinylpyrrolidon K 30.
Incompatibilities
None known.
Shelf life
5 years.
Special precautions for storage
Store at below 25°C. Protect from moisture.
Corangin should be kept out of the reach of children.
Nature and content of container
PVC/PE/PVDC blisters of 30 tablet packs.
Medicines classification
Prescription Medicine
Name and address
Novartis New Zealand Limited
Private Bag 65904
Mairangi Bay
Auckland 0754
Building G, 5 Orbit Drive
Rosedale
Auckland 0632
Telephone: 09 361 8100
Date of preparation
8 June 2009
(Ref: BPI 27 November 98)