Drug Interactions between amoxicillin / clarithromycin / lansoprazole and ruxolitinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ruxolitinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single 10 mg dose of ruxolitinib following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for four days) resulted in a 33% increase in ruxolitinib peak plasma concentration (Cmax) and a 91% increase in systemic exposure (AUC) compared to administration of ruxolitinib alone. The half-life was also prolonged from 3.7 to 6.0 hours in the presence of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole.

MANAGEMENT: Indication specific dose modifications should be made when ruxolitinib is coadministered with strong CYP450 3A4 inhibitors. Ruxolitinib 10 mg twice a day is the recommended starting dose for patients with myelofibrosis (MF) coadministered strong CYP450 3A4 inhibitors when the platelet count is at least 100 X 10(9)/L and 5 mg once a day when the platelet counts is at least 50 X 10(9)/L and less than 100 x 10(9)/L. The recommended starting dose for patients with Polycythemia vera (PV) coadministered potent CYP450 3A4 inhibitors is ruxolitinib 5 mg twice a day. For patients with MF or PV who are stabilized on ruxolitinib 10 mg twice a day or greater and starting a potent CYP450 3A4 inhibitor, the ruxolitinib dose should be reduced by 50% (rounded up to the closest available tablet strength). For patients with MF or PV stabilized on a dose of 5 mg twice a day and starting fluconazole (at a dose of 200 mg per day or less), the ruxolitinib dose should be reduced to 5 mg once a day. For patients with MF or PV stabilized on ruxolitinib 5 mg once a day, concomitant use of strong CYP450 3A4 inhibitors should be avoided or ruxolitinib therapy interrupted for the duration of strong CYP450 3A4 inhibitor use. For patients with for acute graft versus host disease (GVHD) coadministered strong CYP450 3A4 inhibitors, the ruxolitinib dose should be reduced to 5 mg once a day with concomitant ketoconazole use; however, no dose adjustments are necessary with other potent CYP450 3A4 inhibitors. For patients with GVHD receiving itraconazole, blood counts should be monitored more frequently for toxicity and ruxolitinib dose adjustments made, if necessary. Additional dosage modifications should be made with careful monitoring of safety and efficacy.

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.

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.