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Verapamil (Verapamil Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS



Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects.

Beta-blockers: Controlled studies in small numbers of patients suggest that the concomitant use of verapamil hydrochloride and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contract contractility.

In one study involving 15 patients treated with high doses of propranolol (median dose, 480 mg/day; range, 160 to 1,280 mg/day) for severe angina, with preserved left ventricular function (ejection fraction greater than 35%), the hemodynamic effects of additional therapy with verapamil hydrochloride were assessed using invasive methods. The addition of verapamil to high-dose beta-blockers induced modest negative inotropic and chronotropic effects that were not severe enough to limit short-term (48 hours) combination therapy in this study. These modest cardiodepressant effects persisted for greater than 6, but less than 30 hours after abrupt withdrawal of beta-blockers and were closely related to plasma levels of propranolol. The primary verapamil/beta-blocker interaction in this study appeared to be hemodynamic rather than electrophysiologic.

In other studies verapamil did not generally induce significant negative inotropic, chronotropic, or dromotropic effects in patients with preserved left ventricular function receiving low or moderate doses of propranolol (less than or equal to 320 mg/day); in some patients, however, combined therapy did produce such effects. Therefore, if combined therapy is used, close surveillance of clinical status should be carried out. Combined therapy should usually be avoided in patients with atrioventricular conduction abnormalities and those with depressed left ventricular function.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digitoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29% respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporary discontinued. On discontinuation of verapamil hydrochloride use, the patient should be reassessed to avoid underdigitalization.

Antihypertensive agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic agents:

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 repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular 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.

The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Other:

Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic 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 of unchanged.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully.

Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital: Phenobarbital therapy may increase verapamil clearance.

Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin.

Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

Inhalation anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each 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 depolarizing). 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3, 5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.


OVERDOSAGE



Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially the extended-release formulation), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the extended-release formulation. Verapamil is known to decrease gastrointestinal transit time.

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium injection may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or fixed high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures, including cardiopulmonary resuscitation.


CONTRAINDICATIONS



Verapamil Hydrochloride Tablets are contraindicated in:

1. Severe left ventricular dysfunction (see WARNINGS)

2. Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock

3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)

4. Second-or-third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)

5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS)

6. Patients with known hypersensitivity to verapamil hydrochloride.


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