Drug Interaction Report

Coadministration with drugs that are inducers of the CYP450 3A4 isoenzyme may only modestly decrease the plasma concentrations of ziprasidone, as less than 1/3 of ziprasidone metabolic clearance occurs via oxidation mediated by CYP450 3A4. In nine healthy subjects, pretreatment with the potent CYP450 3A4 inducer carbamazepine (100 mg/day titrated to 400 mg/day over 5 days) for 25 days decreased the mean peak plasma concentration (Cmax) and 12-hour area under the concentration-time curve (AUC) of ziprasidone (20 mg orally twice a day for 3 days) by 27% and 36%, respectively, compared to when ziprasidone was administered alone. The half-life was decreased by 1 hour. These changes, although statistically significant, were not considered clinically important. There were also no serious adverse events or clinically significant alterations in ECG or vital signs throughout the study. These findings suggest that ziprasidone dose modifications are unlikely to be necessary in patients receiving potent CYP450 3A4 inducers.

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.