Due to the potential for additive effects, caution and
careful titration are warranted in patients receiving CARDIZEM concomitantly
with any agents known to affect cardiac contractility and/or conduction (see WARNINGS).
Pharmacologic studies indicate that there may be additive
effects in prolonging AV conduction when using beta-blockers or digitalis
concomitantly with CARDIZEM (see WARNINGS).
As with all drugs, care should be exercised when treating
patients with multiple medications. Diltiazem is both a substrate and an
inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are
specific substrates, inhibitors, or inducers of this enzyme system may have a
significant impact on the efficacy and side effect profile of diltiazem.
Patients taking other drugs that are substrates of CYP450 3A4, especially
patients with renal and/or hepatic impairment, may require dosage adjustment
when starting or stopping concomitantly administered diltiazem in order to
maintain optimum therapeutic blood levels.
The depression of cardiac contractility, conductivity,
and automaticity, as well as the vascular dilation associated with anesthetics,
may be potentiated by calcium channel blockers. When used concomitantly,
anesthetics and calcium blockers should be titrated carefully.
Studies showed that diltiazem increased the AUC of
midazolam and triazolam by 3-to 4-fold and the Cmax by 2-fold, compared to
placebo. The elimination half-life of midazolam and triazolam also increased
(1.5-to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic
effects seen during diltiazem coadministration can result in increased clinical
effects (e.g., prolonged sedation) of both midazolam and triazolam.
Controlled and uncontrolled domestic studies suggest that
concomitant use of CARDIZEM and beta-blockers is usually well tolerated.
Available data are not sufficient, however, to predict the effects of
concomitant treatment, particularly in patients with left ventricular
dysfunction or cardiac conduction abnormalities.
Administration of CARDIZEM (diltiazem hydrochloride)
concomitantly with propranolol in five normal volunteers resulted in increased
propranolol levels in all subjects, and bioavailability of propranolol was
increased approximately 50%. In vitro, propranolol appears to be displaced from
its binding sites by diltiazem. If combination therapy is initiated or
withdrawn in conjunction with propranolol, an adjustment in the propranolol
dose may be warranted (see WARNINGS).
In nine healthy subjects, diltiazem significantly
increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to
placebo. The T½ and Tmax of buspirone were not significantly affected by
diltiazem. Enhanced effects and increased toxicity of buspirone may be possible
during concomitant administration with diltiazem. Subsequent dose adjustments
may be necessary during coadministration, and should be based on clinical
Concomitant administration of diltiazem with
carbamazepine has been reported to result in elevated serum levels of
carbamazepine (40% to 72% increase) resulting in toxicity in some cases.
Patients receiving these drugs concurrently should be monitored for a potential
A study in six healthy volunteers has shown a significant
increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%)
after a 1-week course of cimetidine at 1200 mg per day and a single dose of
diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The
effect may be mediated by cimetidine's known inhibition of hepatic cytochrome
P-450, the enzyme system responsible for the first-pass metabolism of
diltiazem. Patients currently receiving diltiazem therapy should be carefully
monitored for a change in pharmacological effect when initiating and
discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may
Sinus bradycardia resulting in hospitalization and
pacemaker insertion has been reported in association with the use of clonidine
concurrently with diltiazem. Monitor heart rate in patients receiving
concomitant diltiazem and clonidine.
A pharmacokinetic interaction between diltiazem and
cyclosporine has been observed during studies involving renal and cardiac
transplant patients. In renal and cardiac transplant recipients, a reduction of
cyclosporine trough dose ranging from 15% to 48% was necessary to maintain
concentrations similar to those seen prior to the addition of diltiazem. If
these agents are to be administered concurrently, cyclosporine concentrations
should be monitored, especially when diltiazem therapy is initiated, adjusted,
or discontinued. The effect of cyclosporine on diltiazem plasma concentrations
has not been evaluated.
Administration of CARDIZEM with digoxin in 24 healthy
male subjects increased plasma digoxin concentrations approximately 20%.
Another investigator found no increase in digoxin levels in 12 patients with coronary
artery disease. Since there have been conflicting results regarding the effect
of digoxin levels, it is recommended that digoxin levels be monitored when
initiating, adjusting, and discontinuing CARDIZEM therapy to avoid possible
over-or under-digitalization (see WARNINGS).
Diltiazem significantly increases the AUC (0→infin;) of quinidine by 51%, T½
by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse
effects may be warranted and the dose adjusted accordingly.
Coadministration of rifampin with diltiazem lowered the
diltiazem plasma concentrations to undetectable levels. Coadministration of
diltiazem with rifampin or any known CYP3A4 inducer should be avoided when
possible, and alternative therapy considered.
Diltiazem is an inhibitor of CYP3A4 and has been shown to
increase significantly the AUC of some statins. The risk of myopathy and
rhabdomyolysis with statins metabolized by CYP3A4 may be increased with
concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized
statin together with diltiazem; otherwise, dose adjustments for both diltiazem
and the statin should be considered along with close monitoring for signs and
symptoms of any statin related adverse events.
In a healthy volunteer cross-over study (N=10),
co-administration of a single 20 mg dose of simvastatin at the end of a 14 day
regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean
simvastatin AUC versus simvastatin alone. Subjects with increased average
steady-state exposures of diltiazem showed a greater fold increase in
simvastatin exposure. Computer-based simulations showed that at a daily dose of
480 mg of diltiazem, an 8-to 9-fold mean increase in simvastatin AUC can be
expected. If co-administration of simvastatin with diltiazem is required, limit
the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
In a ten-subject randomized, open label, 4-way cross-over
study, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks)
with a single 20 mg dose of lovastatin resulted in 3-to 4-fold increase in mean
lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was
no significant change in 20 mg single dose pravastatin AUC and Cmax during
diltiazem coadministration. Diltiazem plasma levels were not significantly
affected by lovastatin or pravastatin.