Concomitant Use Contraindicated: Dantrolene (Infusion): Lethal ventricular fibrillation is regularly observed in animals when IV verapamil and dantrolene are administered concomitantly. The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see Contraindications).
Concomitant Use Requiring Caution: Lithium: Lithium neurotoxicity may occur in concomitant use with diltiazem. Therefore lithium concentrations in serum should be monitored.
Nitrate Derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects). In all the patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.
Theophylline: Increase in circulating theophylline levels.
Alpha-Antagonists: Increased antihypertensive effects.
Concomitant treatment with α-antagonists may produce or aggravate hypotension. The combination of diltiazem with an α-antagonist should be considered only with the strict monitoring of the blood pressure.
Amiodarone, Digoxin: Increased risk of bradycardia. Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.
Beta-Blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.
Other Antiarrhythmic Agents: Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended (additive risk of increased cardiac adverse effects). This combination should only be used under close clinical and ECG monitoring.
Carbamazepine: Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Rifampicin: Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin. The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
Anti-H2 Agents (Ranitidine): Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. An adjustment in diltiazem daily dose may be necessary.
Ciclosporin: Increase in circulating cyclosporin levels. It is recommended that the cyclosporin dose be reduced, renal function be monitored, circulating cyclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation. Diltiazem may increase the cardiac depressant effect of halothane and isoflurane.
General Information To Be Taken Into Account: Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction. The effect of other antihypertensive agents may be potentiated if used concomitantly with diltiazem. Diltiazem is metabolized by CYP3A4. A moderate (<2-fold) increase of diltiazem plasma concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates (eg, macrolide antibiotics, phenytoin, buspirone, nifedipine, sirolimus, tacrolimus, alfentanil, cisapride and HIV protease inhibitors) may result in an increase in plasma concentration of either co-administered drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
Benzodiazepines (Midazolam, Triazolam, Alprazolam): Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their t½. Special care should be taken when prescribing short-acting benzodiazepines metabolized by the CYP3A4 pathway in patients using diltiazem. Diltiazem may also increase the effect of alprazolam.
Corticosteroids (Methylprednisolone): Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein. The patient should be monitored when initiating methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be necessary.
Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins (eg, simvastatin, lovastatin, atorvastatin). The risk of myopathy and rhabdomyolysis due to statins metabolised by CYP3A4 may be increased with concomitant use of diltiazem. When possible, a non-CYP3A4 metabolised statin should be used together with diltiazem, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.
Incompatibilities: None known.