Drug Interactions between Geodon and netupitant / palonosetron

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In placebo-controlled trials in adults, oral ziprasidone increased the QTc interval by approximately 10 msec at the highest recommended daily dosage of 160 mg compared to placebo. In a study comparing the QT prolonging effect of several antipsychotic drugs at the maximum plasma concentration following administration alone in patient volunteers, the mean increase in QTc (QT interval corrected for heart rate) from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol, olanzapine, quetiapine, and risperidone), but was approximately 14 msec less than the prolongation observed for thioridazine. In another study evaluating the QT prolonging effect of intramuscular ziprasidone versus intramuscular haloperidol (control) at the maximum plasma concentration following administration in patient volunteers, the mean increase in QTc from baseline for ziprasidone (20 mg and 30 mg doses given 4 hours apart) was 4.6 msec after the first injection and 12.8 msec after the second injection, which at 30 mg is 1.5 times the highest recommended dose. The mean increase in QTc from baseline for haloperidol (7.5 mg and 10 mg doses given 4 hours apart) was 6.0 msec following the first injection and 14.7 msec following the second injection. No patients had a QTc interval exceeding 500 msec. 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: Coadministration of ziprasidone with other drugs that can prolong the QT interval is considered contraindicated.

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Coadministration with inhibitors of CYP450 3A4 may only modestly increase the plasma concentrations of ziprasidone, as less than 1/3 of ziprasidone metabolic clearance occurs via oxidation mediated by CYP450 3A4. In 14 healthy subjects, coadministration with the potent CYP450 3A4 inhibitor ketoconazole (400 mg orally once a day for 5 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ziprasidone (40 mg single oral dose) by approximately 1/3 compared to placebo. These changes, although statistically significant, were not considered clinically important. There were also no serious adverse events, laboratory or ECG abnormalities, or clinically significant alterations in vital signs throughout the study. Likewise, in 10 healthy subjects, the nonspecific CYP450 inhibitor cimetidine (800 mg orally once a day for 3 days) increased the AUC of ziprasidone (40 mg single oral dose) by just 6% compared to when ziprasidone was administered alone. These findings suggest that ziprasidone dose modifications are unlikely to be necessary in patients receiving potent CYP450 3A4 inhibitors.

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