Hypotension and bradyarrhythmias have been observed in patients receiving concurrent
telethromycin, an antibiotic in the ketolide class of antibiotics.
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 drugs.
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.
In vitro metabolic studies indicate that verapamil is metabolized by
cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant
interactions have been reported with inhibitors of CYP3A4 (e.g. erythromycin,
ritonavir) causing elevation of plasma levels of verapamil while inducers of
CYP3A4 (e.g. rifampin) have caused a lowering of plasma levels of verapamil,
therefore, patients should be monitored for drug interactions.
In a few reported cases, coadministration of verapamil with aspirin has led
to increased bleeding time greater than observed with aspirin alone.
The intake of grapefruit juice may increase drug levels of verapamil.
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. 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 underdigitalization. Whenever overdigitalization is suspected,
the daily dose of digitalis should be reduced or temporarily discontinued. Upon
discontinuation of ISOPTIN (verapamil HCl), the patient should be reassessed
to avoid underdigitalization.
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.
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 administration.
A study of 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
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 electrophysiological 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.
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.
Verapamil has been found to significantly inhibit ethanol elimination resulting
in elevated blood ethanol concentrations that may prolong the intoxicating effects
of alcohol. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
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
Increased sensitivity to the effects of lithium (neurotoxicity) has been reported
during concomitant verapamil-lithium therapy; lithuim levels have been observed
sometimes to increase, sometimes to decrease, and sometimes to be unchanged.
Patients receiving both drugs must be monitored carefully.
Verapamil may increase carbamazepine concentrations during combined therapy.
This may produce carbamazepine side effects such as diplopia, headache, ataxia,
Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Phenobarbital therapy may increase verapamil clearance.
Verapamil therapy may increase serum levels of cyclosporine.
Verapamil therapy may inhibit the clearance and increase the plasma levels
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.