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| | ==Drug Interactions== |
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| ==DRUG INTERACTIONS==
| | Due to potential for additive effects, caution is warranted in patients receiving diltiazem hydrochloride injection concomitantly with other agent(s) known to affect cardiac contractility and/or SA or AV node conduction (see [[Diltiazem hydrochloride injection warnings|WARNINGS]]). |
| | As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem hydrochloride undergoes extensive metabolism by the [[cytochrome P-450 ]]mixed function oxidase system. Although specific pharmacokinetic drug-drug interaction studies have not been conducted with single intravenous injection or constant rate intravenous infusion, coadministration of diltiazem hydrochloride injection with other agents which primarily undergo the same route of biotransformation may result in competitive inhibition of metabolism. |
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| Due to the potential for additive effects, caution and careful titration are warranted in patients receiving CARDIZEM concomitantly with any agents known to affect cardiac contractility and/or conduction (see [[Diltiazem hydrochloride tablet extended release warnings |WARNINGS]]).
| | ===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. |
| Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with CARDIZEM (see [[Diltiazem hydrochloride tablet extended release warnings |WARNINGS]]).
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| 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.
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| ===Anesthetics. === | | ===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[[Diltiazem hydrochloride injection contraindications| 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. |
| | ===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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| 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.
| | ===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. |
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| ===Benzodiazepines.===
| | The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated. |
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| Studies showed that diltiazem increased the AUC of [[midazolam ]]and [[triazolam ]]by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of [[midazolam ]]and [[triazolam ]]also increased (1.5- to 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]].
| | ===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.<ref name="dailymed.nlm.nih.gov"> |
| | | <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = DILTIAZEM HYDROCHLORIDE INJECTION [AKORN, INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=81c5cf23-a6f8-454a-9575-d01edf49ed34 | publisher = | date = | accessdate = 5 March 2014 }}</ref> |
| ===Beta-blockers.===
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| Controlled and uncontrolled domestic studies suggest that concomitant use of CARDIZEM 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.
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| Administration of CARDIZEM (diltiazem hydrochloride) 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 (see [[Diltiazem hydrochloride tablet extended release warnings |WARNINGS]]).
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| ====Buspirone.====
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| In nine healthy subjects, diltiazem significantly increased the mean [[buspirone ]]AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax 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 coadministration, and should be based on clinical assessment.
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| ===Carbamazepine.=== | |
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| 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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| ===Cimetidine.===
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| 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.
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| ===Clonidine.=== | |
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| [[Sinus bradycardia ]]resulting in hospitalization and pacemaker insertion has been reported in association with the use of [[clonidine ]]concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and [[clonidine]].
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| ===Cyclosporine.===
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| 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 ]]trough dose ranging from 15% to 48% was necessary to maintain 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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| ===Digitalis.===
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| Administration of CARDIZEM 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 CARDIZEM therapy to avoid possible over- or under-digitalization (see [[Diltiazem hydrochloride tablet extended release warnings |WARNINGS]]).
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| ===Quinidine.===
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| Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T1/2 by 36%, and decreases its CLoral by 33%. Monitoring for [[quinidine ]]adverse effects may be warranted and the dose adjusted accordingly.
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| ===Rifampin.===
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| 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.
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| ===Statins.===
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| Diltiazem is an inhibitor of [[CYP3A4 ]]and has been shown to increase significantly the AUC of some [[statins]]. The risk of [[myopathy ]]and [[rhabdomyolysis ]]with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.
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| In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If co-administration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
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| In a ten-subject randomized, open label, 4-way cross-over study, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of [[lovastatin ]]resulted in 3- to 4-fold increase in mean [[lovastatin ]]AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by [[lovastatin]] or [[pravastatin]].<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = DILTIAZEM HYDROCHLORIDE INJECTION [AKORN, INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=81c5cf23-a6f8-454a-9575-d01edf49ed34 | publisher = | date = | accessdate = 5 March 2014 }}</ref>
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]
Drug Interactions
Due to potential for additive effects, caution is warranted in patients receiving diltiazem hydrochloride injection concomitantly with other agent(s) known to affect cardiac contractility and/or SA or AV node conduction (see WARNINGS).
As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem hydrochloride undergoes extensive metabolism by the cytochrome P-450 mixed function oxidase system. Although specific pharmacokinetic drug-drug interaction studies have not been conducted with single intravenous injection or constant rate intravenous infusion, coadministration of diltiazem hydrochloride injection with other agents which primarily undergo the same route of biotransformation may result in competitive inhibition of metabolism.
===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.
===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.
===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.
===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.
===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.
References