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Dilt-CD (Diltiazem Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Drug Interactions

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other 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 diltiazem (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.

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.

OVERDOSAGE

The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.

The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.

There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure and in cases of cardiac failure inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

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 to 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.

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. 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. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:

Bradycardia

Administer atropine (0.60 to 1.0 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 norepinephrine).

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

CONTRAINDICATIONS

Diltiazem 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 hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

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