Drug Interactions between amoxicillin / clarithromycin / omeprazole and pemigatinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of pemigatinib, which is primarily metabolized by the isoenzyme in vitro. When itraconazole, a potent CYP450 3A4 inhibitor, was administered following a single oral pemigatinib dose of 4.5 mg, pemigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 88%, respectively. Concomitant use of moderate CYP450 3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50% to 80%. Increased exposure to pemigatinib may increase the incidence and severity of serious adverse reactions such as hyperphosphatemia (which can cause precipitation of calcium-phosphate crystals over time that can lead to hypocalcemia, soft tissue mineralization such as cutaneous calcification and calcinosis, secondary hyperparathyroidism, anemia, muscle cramps, seizures, QT prolongation, and arrhythmias), serous retinal detachment (which may cause symptoms such as blurred vision, visual floaters, or photopsia), palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), arthralgia, stomatitis, diarrhea, nausea, vomiting, and constipation.

MANAGEMENT: Concomitant use of pemigatinib with potent CYP450 3A4 inhibitors should be avoided. If coadministration is required, a reduction in the dosage of pemigatinib is recommended. Patients receiving 13.5 mg of pemigatinib should have the dosage reduced to 9 mg, and those receiving 9 mg should have the dosage reduced to 4.5 mg. After discontinuation of the potent CYP450 3A4 inhibitor for 3 plasma half-lives, the pemigatinib dosage that was taken prior to initiating the inhibitor may be resumed.

MONITOR: Coadministration of pemigatinib with proton pump inhibitors may result in a reduction in the plasma concentrations of pemigatinib. The mechanism for this interaction has not been delineated. When studied in healthy subjects, coadministration with esomeprazole did not result in a clinically important change in pemigatinib exposure; however, in more than one-third of patients treated with proton pump inhibitors, a significant reduction in pemigatinib systemic exposure was observed.

MANAGEMENT: Until more information is available, caution is recommended when pemigatinib is used concomitantly with proton pump inhibitors. Patients should be monitored for potentially reduced efficacy.

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.