Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine (ODV). The possibility of prolonged and/or increased pharmacologic effects of venlafaxine should be considered. Although venlafaxine is primarily metabolized by CYP450 2D6, there is some evidence that CYP450 3A4 may play a minor role, thus any alteration in its activity levels could conceivably affect the metabolism of venlafaxine. The interaction may be of greater concern in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent). In healthy volunteers, administration of single-dose venlafaxine with the potent CYP450 3A4 inhibitor ketoconazole (100 mg twice daily) increased venlafaxine systemic exposure (AUC) by 21% in extensive metabolizers and 70% (range -2% to 206%) in poor metabolizers of CYP450 2D6; increased AUC of ODV by 23% in extensive metabolizers and 33% (range -38% to 105%) in poor metabolizers; and increased combined AUC of venlafaxine and ODV by 23% in extensive metabolizers and 53% in poor metabolizers (range 4% to 134%). Venlafaxine and ODV peak plasma concentration (Cmax) also increased by 26% and 14%, respectively, in extensive metabolizers and 48% and 29%, respectively, in poor metabolizers.

MANAGEMENT: Caution is recommended when venlafaxine is used with CYP450 3A4 inhibitors.

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.

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.