HMG-CoA reductase inhibitors
The use of HMG-CoA reductase inhibitors that are CYP3A4
substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.
Co-administration of multiple doses of 10 mg of verapamil
with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that
following simvastatin alone. Limit the dose of simvastatin in patients on
verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower
starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin)
may be required as verapamil may increase the plasma concentration of these
Concomitant therapy with beta-adrenergic blockers and
verapamil may result in additive negative effects on heart rate,
atrioventricular conduction and/or cardiac contractility. The combination of
sustained-release verapamil and beta-adrenergic blocking agents has not been
studied. However, there have been reports of excessive bradycardia and AV
block, including complete heart block, when the combination has been used for
the treatment of hypertension. For hypertensive patients, the risks of combined
therapy may outweigh the potential benefits. The combination should be used only
with caution and close monitoring.
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.
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 digoxin 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 carefully monitored to avoid over- or
under-digitalization. Whenever over-digitalization is suspected, the daily dose
of digitalis should be reduced or temporarily discontinued. On discontinuation
of CALAN use, the patient should be reassessed to avoid under-digitalization.
Verapamil administered concomitantly with oral antihypertensive
agents (eg, 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.
Disopyramide: Until data on possible interactions
between verapamil and disopyramide phosphate are obtained, disopyramide should
not be administered within 48 hours before or 24 hours after verapamil
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.
Alcohol: Verapamil has been found to inhibit
ethanol elimination significantly, resulting in elevated blood ethanol
concentrations that may prolong the intoxicating effects of alcohol (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and metabolism).
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
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: 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
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
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.
Telithromycin: Hypotension and bradyarrhythmias
have been observed in patients receiving concurrent telithromycin, an
antibiotic in the ketolide class.
Clonidine: Sinus bradycardia resulting in
hospitalization and pacemaker insertion has been reported in association with
the use of clonidine concurrently with verapamil. Monitor heart rate in
patients receiving concomitant verapamil and clonidine.