INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ISOPTIN®SR 240 mg

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ISOPTIN®SR 240 mg
Film coated tablets

COMPOSITION:
Each film coated tablet contains 240 mg
verapamil hydrochloride.

PHARMACOLOGICAL CLASSIFICATION:
7.1 Vasodilators, hypotensive medicines.

PHARMACOLOGICAL ACTION:
Verapamil is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacological effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Verapamil reduces myocardial oxygen consumption in vitro directly by intervening in the energy consuming metabolic process of the myocardial cell, and indirectly by diminishing the peripheral resistance (afterload). It prolongs impulse conduction in the AV node.

INDICATIONS:
Angina pectoris, mild to moderate hypertension, supraventricular tachydysrhythmia.
Prophylaxis of supraventricular relapses after electrocardioversion.

CONTRA-INDICATIONS:
Hypotension associated with cardiogenic shock. Heart failure. Retarded AV conduction (second and third degree AV block); acute stage of myocardial infarction; sick sinus syndrome.

WARNINGS
Pregnancy: Verapamil should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Heart failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4 954 patients 87 (1,8%) developed congestive heart failure or pulmonary oedema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g. ejection fraction less than 30%, pulmonary wedge pressure above 20 mm Hg, or severe symptoms of heart failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Patients with milder ventricular dysfunction should, should, if possible, be controlled with optimal doses of digitalis and/or diuretics before verapamil treatment.
Hypotension: Verapamil may occasionally produce symptomatic hypotension in normotensive patients. In hypertensive patients, decreases in blood pressure below normal values are unusual.
Elevated liver enzymes: Elevation of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations are normally transient and may disappear even in the face of continued verapamil treatment.
Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and coexisting accessory AV pathway have developed an increased anterograde conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk.
Atrioventricular block: The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of the drug.
Patients with hypertrophic cardiomyopathy (IHSS): A variety of serious adverse effects can occur in patients with hypertrophic cardiomyopathy - pulmonary oedema and/or severe hypotension, sinus bradycardia, AV block and sinus arrest. Most adverse effects respond well to dose reduction and discontinuation of therapy is rarely necessary.

DOSAGE AND DIRECTIONS FOR USE:
The doses of Isoptin as prescribed by the physician are to be taken regularly. The tablets (or halved tablets) are to be swallowed whole with some liquid, preferably with or shortly after meals.
Angina pectoris and supraventricular dysrhythmia: Half to one tablet every 12 hours.
Hypertension: One tablet per day (preferably in the morning). If the desired response is not obtained in 7 days, the dose may be increased to one tablet in the morning, and half a tablet at night. The maximum recommended dose is one tablet every 12 hours.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Constipation, headache, fatigue, palpitations, first and second degree AV block, SA block, epigastric pain, flush, dizziness, urticaria and temporary skin rash may occur. Reports of individuals experiencing exacerbation of arthritis, increased urination, burning sensation of the gums, mild tremor and severe facial pain are known.
Precautions:
Breast feeding: Verapamil is excreted in human milk. Breast feeding should be discontinued while Isoptin is administered.
Use in patients with impaired hepatic function: Since verapamil is highly metabolised by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 15 hours; hence approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacological effects should be carried out.
Use in patients with attenuated neuromuscular transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Use in patients with impaired renal function: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by haemodialysis. Until further data are available, it should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage.
Drug interactions:
Beta-blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, AV conduction, and/or cardiac contractility. The combination should be used only with caution and close monitoring.
Digitalis: Chronic verapamil treatment can increase serum digoxin levels by 50 to 70% during the first week of therapy, and this can result in digitalis toxicity. Whenever overdigitalisation is suspected, the daily dose of digitalis should be reduced or temporarily discontinued.
Antihypertensive agents: Verapamil may intensify the blood pressure lowering effect of concomitantly administered antihypertensive, and this often makes it possible to reduce the dose of the antihypertensives, particularly in patients on long-term treatment with Isoptin.
Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarisation. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of AV conduction.
Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. There has been a report of increased quinidine levels during verapamil therapy.
Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacological profile of both drugs and the clinical experience suggest beneficial interactions.
Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.
Lithium: Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.
Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy.
Rifampicin: Therapy with rifampicin may markedly reduce oral verapamil bioavailability.
Phenobarbitone: Phenobarbitone therapy may increase verapamil clearance.
Cyclosporin: Verapamil may increase serum levels of cyclosporin.
Inhalation anaesthetics: Animal experiments have shown that inhalation anaesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anaesthetics and calcium antagonists should be titrated carefully to avoid excessive cardiovascular depression.
Neuromuscular blocking agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarising). It may be necessary to decrease the dose of verapamil and / or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Bradycardia, hypotension, atrioventricular dissociation, hyperglycaemia. Treatment is symptomatic and supportive.

IDENTIFICATION:
Light green, oblong film coated tablet with single score-line.

PRESENTATION:
Packs of 30 and 100 film coated tablets in amber glass bottles.

STORAGE INSTRUCTIONS:
Store at room temperature (below 30° C), protected from light.
Keep out of reach of children.

REGISTRATION NUMBER:
V/7.1/280

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Knoll Pharmaceuticals South Africa (Pty) Ltd
Corner George Road/16th Street, Midrand.
P.O. Box 3030, Halfway House 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
28 September 1990

        Knoll logo
        BASF Group
        989007
        Britepak
        10/98
Updated on this site: June 2000

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