Drug Interaction Report

Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein may increase the systemic exposure to indacaterol following oral inhalation, as it is a substrate of both the isoenzyme and efflux transporter. When a single 300 mcg dose of indacaterol inhalation powder was administered in combination with the potent dual CYP450 3A4/P-glycoprotein inhibitor, ketoconazole (200 mcg twice daily for 7 days), indacaterol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.3- and 1.9-fold, respectively. These changes probably reflect the impact of maximal combined inhibition. Similarly, verapamil 80 mg three times a day for 4 days increased indacaterol Cmax by 1.5-fold and AUC by 2-fold, while erythromycin 400 mg four times a day for 7 days increased indacaterol Cmax by 1.2-fold and AUC by 1.4-fold. Ritonavir 300 mg twice daily for 7.5 days had no effect on the Cmax of indacaterol, but increased its AUC by 1.7-fold. Indacaterol oral inhalation powder has been evaluated in clinical trials for up to one year at doses up to 600 mcg. No dosage adjustment is necessary at the 75 mcg dose when used with CYP450 3A4 and P-glycoprotein inhibitors.

ADJUST DOSING INTERVAL: According to the manufacturer, coadministration with a meal high in calories, fat, and protein reduces the absorption of indinavir. In ten patients given indinavir in this manner, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of indinavir decreased by an average of 84% and 77%, respectively. In contrast, grapefruit juice may have only minor effects on the oral bioavailability of indinavir. The manufacturer's package labeling states that administration of a single 400 mg dose of indinavir with 8 oz. of grapefruit juice decreased indinavir AUC by an average of 26%. Likewise, a study consisting of 14 HIV-infected subjects found no uniform nor significant changes in steady-state indinavir AUC during administration with double-strength grapefruit juice compared to water. There was, however, a delay in absorption (Tmax) due to grapefruit juice that is unlikely to be of clinical significance.

MANAGEMENT: To ensure maximal oral absorption, indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal (e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; corn flakes, skim milk and sugar).

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.