Drug Interactions between alosetron and osilodrostat

GENERALLY AVOID: Coadministration with inhibitors of CYP450 1A2 may increase the plasma concentrations of alosetron, which has been shown in vivo to be predominantly metabolized by the isoenzyme. When a single 1 mg dose of alosetron was administered to 40 healthy female subjects following pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (in escalating doses from 50 to 200 mg/day for 16 days) increased alosetron systemic exposure (AUC) and half-life by approximately 6-fold and 3-fold, respectively. Fluvoxamine is known to also inhibit CYP450 2C9 and 3A4, both of which have been shown in vitro to be involved in the metabolism of alosetron. However, it is uncertain to what extent inhibition of these isoenzymes actually contribute to the interaction. Concomitant administration of alosetron with less potent CYP450 1A2 inhibitors has not been evaluated.

MANAGEMENT: Because alosetron is associated with potentially serious and life-threatening, dose-related gastrointestinal adverse effects, concomitant use with CYP450 1A2 inhibitors should generally be avoided if possible (use with fluvoxamine is specifically contraindicated). If coadministration is required, it may be appropriate to initially prescribe a lower dosage of alosetron (e.g., 1 mg once a day). However, the product labeling does not offer recommendations for a dosage adjustment. Patients should be advised to immediately discontinue alosetron and notify their physician if they experience constipation or signs and symptoms of ischemic colitis such as rectal bleeding, bloody diarrhea, and new or worsening abdominal pain. Alosetron should not be resumed if ischemic colitis is diagnosed. Ischemic colitis and other serious complications such as obstruction, perforation, impaction, and toxic megacolon have resulted in hospitalization, blood transfusion, surgery, and death.