Diltiazem (Diltiazem Hydrochloride) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Drug Interactions

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.

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.

Benzodiazepines. Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3-4 fold and C_max by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5-2.5 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.

Beta-blockers. Intravenous diltiazem has been administered to patients on chronic oral beta-blocker therapy. The combination of the two drugs was generally well tolerated without serious adverse effects. If intravenous diltiazem is administered to patients receiving chronic oral beta-blocker therapy, the possibility for bradycardia, AV block, and/or depression of contractility should be considered (see CONTRAINDICATIONS). Oral administration of diltiazem 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.

Buspirone. In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5 fold and C_max 4.1 fold compared to placebo. The T_1/2 and T_max 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 co-administration, and should be based on clinical assessment.

Carbamazepine. Concomitant administration of oral diltiazem with carbamazepine has been reported to result in elevated plasma levels of carbamazepine (by 40 to 72%), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cimetidine. 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 be warranted.

Cyclosporine. 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 dose ranging from 15% to 48% was necessary to maintain cyclosporine trough 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.

Digitalis. Intravenous diltiazem has been administered to patients receiving either intravenous or oral digitalis therapy. The combination of the two drugs was well tolerated without serious adverse effects. However, since both drugs affect AV nodal conduction, patients should be monitored for excessive slowing of the heart rate and/or AV block.

Lovastatin. In a ten-subject study, coadministration of diltiazem (120 mg bid, diltiazem SR) with lovastatin resulted in a 3-4 times increase in mean lovastatin AUC and C_max versus lovastatin alone; no change in pravastatin AUC and C_max was observed during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Quinidine. Diltiazem significantly increases the AUC_(0→∞) of quinidine by 51%, T_1/2 by 36% and decreases its CL_oral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

Rifampin. 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.

OVERDOSAGE

Overdosage experience is limited. In the event of overdosage or an exaggerated response, appropriate supportive measures should be employed. The following measures may be considered:

Bradycardia: Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade administer isoproterenol cautiously.

High-degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

Hypotension: Vasopressors (e.g., dopamine or levarterenol bitartrate).

The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes, and repeated every 10-20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose.

The intravenous LD₅₀’s in mice and rats were 60 and 38 mg/kg, respectively. The toxic dose in man is not known.

CONTRAINDICATIONS

Diltiazem hydrochloride injection is contraindicated in:

1. Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker.

2. Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker.

3. Patients with severe hypotension or cardiogenic shock.

4. Patients who have demonstrated hypersensitivity to the drug.

5. Intravenous diltiazem and intravenous beta-blockers should not be administered together or in close proximity (within a few hours).

6. Patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome or short PR syndrome.

   As with other agents which slow AV nodal conduction and do not prolong the refractoriness of the accessory pathway (e.g., verapamil, digoxin), in rare instances patients in atrial fibrillation or atrial flutter associated with an accessory bypass tract may experience a potentially life-threatening increase in heart rate accompanied by hypotension when treated with diltiazem hydrochloride injection. As such, the initial use of diltiazem hydrochloride injection should be, if possible, in a setting where monitoring and resuscitation capabilities, including DC cardioversion/defibrillation, are present (see OVERDOSAGE). Once familiarity of the patient's response is established, use in an office setting may be acceptable.

7. Patients with ventricular tachycardia. Administration of other calcium channel blockers to patients with wide complex tachycardia (QRS≥0.12 seconds) has resulted in hemodynamic deterioration and ventricular fibrillation. It is important that an accurate pretreatment diagnosis distinguish wide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to administration of diltiazem hydrochloride injection.