Drug Interactions between amprenavir and droperidol / fentanyl

MONITOR CLOSELY: The use of droperidol has been associated with QT interval prolongation, torsade de pointes and other serious arrhythmias, and sudden death. The concurrent administration of agents that can produce bradycardia, a known risk factor for QT interval prolongation, such as benzodiazepines and opiates, particularly intravenous opiates, may increase the risk of QT interval prolongation. In addition, hypotensive effects and central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking droperidol with benzodiazepines or opiates, especially in elderly or debilitated patients.

MANAGEMENT: Extreme caution and close monitoring are recommended if droperidol must be administered concomitantly with other bradycardic drugs. The dosage of droperidol should be individualized and titrated to the desired effect. Routine vital sign and ECG monitoring is recommended. When droperidol is used in combination with benzodiazepines or opiates, patients should be monitored for potentially excessive or prolonged CNS or respiratory depression as well as severe hypotension. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of fentanyl, which is primarily metabolized by the isoenzyme. Increased fentanyl concentrations could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Conversely, discontinuation of a CYP450 3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy, and possibly even lead to a withdrawal syndrome in patients who had developed physical dependence to fentanyl. In eleven healthy volunteers, coadministration of the potent inhibitor ritonavir (200 mg orally three times a day on day 1; 300 mg three times a day on day 2; one morning dose of 300 mg on day 3) and intravenous fentanyl (5 mcg/kg two hours after the afternoon dose of ritonavir on day 2) resulted in a 174% increase in fentanyl systemic exposure (AUC) and a 67% decrease in fentanyl clearance compared to administration of fentanyl alone (with placebo). No other formulations of fentanyl such as patches or buccal tablets were studied.

MANAGEMENT: Patients receiving fentanyl with potent or moderate CYP450 3A4 inhibitors should be carefully monitored, and dosage adjustments made accordingly as needed. This is particularly important when an inhibitor is added after a stable dose of fentanyl has been achieved. Some authorities recommend avoiding concomitant use of fentanyl during and for 2 weeks after treatment with itraconazole. Patients and/or their caregivers should be advised to seek medical attention if potential signs and symptoms of toxicity occur, such as dizziness, confusion, fainting, extreme sedation, unresponsiveness, bradycardia, slow or difficult breathing, and shortness of breath. When discontinuing CYP450 3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur. Patients treated with transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

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MONITOR: Coadministration with drugs that are potent inhibitors of CYP450 3A4 and/or 1A2 may increase the plasma concentrations of droperidol, which is predicted to be metabolized by these isoenzymes. While clinical data are lacking, the possibility of prolonged pharmacological action and adverse effects such as central nervous system depression, extrapyramidal reactions, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered. Cases of QT interval prolongation and/or torsade de pointes have been reported in patients receiving droperidol at or below recommended doses. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of droperidol should be considered during coadministration of potent inhibitors of CYP450 3A4 and/or 1A2. Some manufacturers advise that to minimize the risk of ventricular arrhythmia, an ECG should be performed in all patients prior to initiating therapy with droperidol and periodically thereafter. Therapeutic response to droperidol should be monitored more closely following initiation, discontinuation, or dosing change of the concomitant inhibitor, and the droperidol dosage adjusted as necessary.

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