Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect the cardiac contractility and/or conduction (see Warnings). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using β-blockers or digitalis concomitantly with diltiazem (see Warnings). As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Co-administration of diltiazem with other agents which follow the same route of biotransformation may result in the competitive inhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosage of similarly metabolized drugs, particularly those of low therapeutic ratio, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.
Beta-Blockers: Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and β-blockers is usually well tolerated. But available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Administration of diltiazem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately by 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 If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted.
Cimetidine: A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine at 1200 mg/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 diltiazem dose may be warranted.
Anesthetics: 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.
Cyclosporin: A pharmacokinetic interaction between diltiazem and cyclosporin has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporin dose ranging from 15-48% was necessary to maintain cyclosporin through concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporin concentrations should be monitored especially when diltiazem therapy is initiated, adjusted or discontinued. The effect of cyclosporin-diltiazem plasma concentrations has not been evaluated.
Carbamazepine: Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40-72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.