Diltiazem precautions

List of precautions
General Drug Interactions Beta-blockers Cimetidine Digitalis Anesthetics Cyclosporine Carbamazepine Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Nursing Mothers Pediatric Use

General
Diltiazem is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of Diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events may be transient and may disappear despite continued use of Diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

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Drug Interactions
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Diltiazem concomitantly with any agents known to affect cardiac contractility and/or conduction.

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Diltiazem.

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Coadministration 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, dosages 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.

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Beta-blockers
Controlled and uncontrolled domestic studies suggest that concomitant use of Diltiazem 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 Diltiazem 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.

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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 1,200 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 probably 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.

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Digitalis
Administration of Diltiazem 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 Diltiazem therapy to avoid possible over- or under-digitalization.

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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.

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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.

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Carbamazepine
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 drug interaction.

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Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.

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Pregnancy
Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

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Nursing Mothers
Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

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Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

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