Drug Interactions between fluvoxamine and Omeclamox-Pak

MONITOR: Coadministration with fluvoxamine may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 3A4 activity by fluvoxamine.

MANAGEMENT: Caution is advised if fluvoxamine must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluvoxamine is added to or withdrawn from therapy.

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MONITOR: Coadministration with fluvoxamine may increase the plasma concentrations of omeprazole and other proton pump inhibitors in a dose-dependent manner. The mechanism is fluvoxamine inhibition of the CYP450 2C19 metabolism of proton pump inhibitors. In 12 healthy volunteers, pretreatment with fluvoxamine for 7 days (10 mg once or twice a day) resulted in a 174% increase in the mean 8-hour area under the plasma concentration-time curve (AUC) of a single 20 mg oral dose of omeprazole compared to administration of omeprazole alone. When the dosage of fluvoxamine was increased (25 mg once or twice a day for 7 days), the mean 8-hour AUC of single-dose omeprazole increased 330%. The interaction apparently does not occur in poor metabolizers (PMs) of CYP450 2C19, which comprise approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and PMs of CYP450 2C19--fluvoxamine (25 mg orally twice a day for 6 days) increased the Cmax, AUC, and elimination half-life (T1/2) of a single 40 mg oral dose of omeprazole by 3.7-, 6.2-, and 2.6-fold, respectively, in homozygous EMs and by 2.0-, 2.5, and 1.4-fold, respectively, in heterozygous EMs compared to placebo. The AUC ratio of 5-hydroxyomeprazole to omeprazole, which is considered an index of CYP450 2C19 activity, was decreased during fluvoxamine treatment to 17% in homozygous EMs and 49% in heterozygous EMs. In contrast, no changes in omeprazole pharmacokinetics or AUC ratio of 5-hydroxyomeprazole to omeprazole were observed in PMs. No adverse effects were attributed to the increased omeprazole exposure in the study.

MANAGEMENT: Although proton pump inhibitors are generally well tolerated, caution is advised if they are prescribed with fluvoxamine. Dosage adjustment should be considered in patients who experience excessive adverse effects such as drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, and dry mouth.

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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.

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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.

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