Drug Interactions between amoxicillin / clarithromycin / lansoprazole and fosaprepitant

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.

Switch to consumer interaction data

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of aprepitant, which is primarily metabolized by the isoenzyme. According to the manufacturer, administration of a single 125 mg dose of aprepitant on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 10 days) resulted in a 5-fold increase in mean aprepitant systemic exposure (AUC) and a 3-fold increase in mean terminal half-life. In patients with mild to moderate hypertension, coadministration of aprepitant (approximately 230 mg once a day) and the moderate inhibitor diltiazem (120 mg three times a day for 5 days) resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in that of diltiazem. No clinically significant changes in ECG, heart rate, or blood pressure were observed beyond those induced by diltiazem alone.

MANAGEMENT: Caution is advised if aprepitant is prescribed in combination with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, conivaptan, idelalisib, nefazodone, telithromycin, cobicistat, delavirdine, and protease inhibitors. Pharmacologic response to aprepitant should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored during coadministration with aprepitant.

Switch to consumer interaction data

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, administration of the CYP450 3A4 substrate dexamethasone (20 mg orally on day 1 and 8 mg on days 2 through 5) in combination with aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) resulted in a 2.2-fold increase in dexamethasone systemic exposure (AUC) on days 1 and 5. Similarly, aprepitant increased the AUC of methylprednisolone (125 mg intravenously on day 1 and 40 mg orally on days 2 and 3) by 1.34-fold on day 1 and 2.5-fold on day 3. The effect of aprepitant on the pharmacokinetics of CYP450 3A4 substrates is expected to be greater when the substrates are administered orally as opposed to intravenously and may be altered following prolonged administration.

MANAGEMENT: Caution is advised when aprepitant or fosaprepitant is used concomitantly with drugs 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 aprepitant or fosaprepitant is added to or withdrawn from therapy. Chronic, continuous use of aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during long-term use.

Switch to consumer interaction data

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.

Switch to consumer interaction data