Drug Interactions between amoxicillin / clarithromycin / lansoprazole and fedratinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of fedratinib, which is primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 2C19 and flavin-containing monooxygenase 3 (FMO3). When a single 300 mg oral dose of fedratinib (0.75 times the recommended dose) was coadministered with 200 mg twice daily ketoconazole, a potent CYP450 3A4 inhibitor, fedratinib total systemic exposure (AUC(inf)) increased by approximately 3-fold. Using physiologically based pharmacokinetic (PBPK) simulations, coadministration of fedratinib 400 mg once daily and ketoconazole 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold. Increased fedratinib exposure may potentiate the risk of adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies.

MANAGEMENT: Concomitant use of fedratinib with potent CYP450 3A4 inhibitors should be avoided when possible, and alternative agents with no or minimal CYP450 3A4 inhibitory potential should be considered in patients treated with fedratinib. If coadministration of a potent CYP450 3A4 inhibitor is necessary, the manufacturer recommends reducing the dosage of fedratinib to 200 mg once daily and closely monitoring patients (e.g., at least weekly) for toxicities. Further dosage adjustment or treatment interruption may be required based on patient tolerance and response. If coadministration of a potent CYP450 3A4 inhibitor is discontinued, the dosage of fedratinib should first be increased to 300 mg once daily for two weeks and then to 400 mg once daily thereafter as tolerated.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

MONITOR: Coadministration with inhibitors of CYP450 2C19 may increase the plasma concentrations of fedratinib, which is primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 2C19 and flavin-containing monooxygenase 3 (FMO3). However, clinical studies evaluating the interaction have not been conducted.

MANAGEMENT: Caution is advised when fedratinib is used with CYP450 2C19 inhibitors, particularly those that may also inhibit CYP450 3A4 (e.g., amiodarone, cimetidine, fexinidazole, isoniazid, osilodrostat, rucaparib) or if combined with other drugs that can inhibit CYP450 3A4. Patients should be monitored for adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies. Dosage adjustment or treatment interruption may be required based on patient tolerance and response in accordance with the prescribing information.

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.