Drug Interactions between amoxicillin / clarithromycin / omeprazole and idelalisib

GENERALLY AVOID: Coadministration of idelalisib with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. The use of idelalisib has been associated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal. Serious and fatal hepatotoxicity occurred in 14% of patients treated with idelalisib in premarketing trials. Liver enzyme elevations were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. Following treatment resumption at a lower dose, 26% of patients had recurrence of ALT and AST elevations.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of idelalisib, which is a substrate of both the isoenzyme and efflux transporter. In healthy volunteers, administration of a single 400 mg dose of idelalisib with the potent CYP450 3A4 and P-gp inhibitor ketoconazole (400 mg daily for 4 days) resulted in a 1.8-fold increase in mean idelalisib systemic exposure (AUC). No change was observed in mean peak plasma concentration (Cmax).

MANAGEMENT: The use of idelalisib with other potentially hepatotoxic agents such as azole antifungal agents, macrolide antibiotics, nefazodone, ritonavir, and telithromycin should be avoided whenever possible. In addition, these agents are potent CYP450 3A4/P-gp inhibitors and may increase the toxicity of idelalisib. Caution is advised if coadministration is required. Patients should be closely monitored for hepatotoxicity and other toxicities of idelalisib such as diarrhea, colitis, intestinal perforation, pneumonitis, neutropenia and thrombocytopenia, and the dosing adjusted or interrupted as necessary. Patients should have serum ALT, AST, and bilirubin measured prior to initiation of treatment and regularly during treatment in accordance with the product labeling. Permanent discontinuation of idelalisib is recommended in those who experience recurrent hepatotoxicity following dosage reduction. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.