Drug Interactions between amoxicillin / clarithromycin / lansoprazole and fexinidazole

GENERALLY AVOID: Fexinidazole can cause concentration-dependent prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Based on the exposure-response relationship, treatment with fexinidazole is predicted to cause an average increase of 19 msec in the Fridericia-corrected QT interval (QTcF) at the recommended dosing regimen. In addition, drugs that are inducers of hepatic CYP450 enzymes, such as apalutamide and enzalutamide, may significantly increase the plasma concentration of fexinidazole's active metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). The observed increase in QTcF appears to be associated with the sulfone (M2) metabolite of fexinidazole; therefore, an increase in the plasma concentration of the sulfone (M2) metabolite may increase the risk of QT prolongation. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of fexinidazole with other medications that can prolong the QT interval, block cardiac potassium channels, and/or induce bradycardia should generally be avoided. If coadministration is unavoidable, treatment with fexinidazole should not be initiated until the opposing drug is eliminated from the body (allow a washout period of 5 half-lives) or do not initiate treatment with the opposing drug until fexinidazole is eliminated from the body (allow a washout period of 7 days). All QT-prolonging drugs including fexinidazole should be interrupted in patients who develop clinically significant ventricular arrhythmia or a QTcF interval greater than 500 msec confirmed by repeat ECG. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.

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 fexinidazole may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of CYP450 1A2 and/or 2C19. The proposed mechanism is decreased clearance due to fexinidazole-mediated inhibition of CYP450 1A2 and/or 2C19. A clinical study evaluated the effect of fexinidazole following administration of 1,800 mg fexinidazole for 4 days, followed by 1,200 mg on Day 5, with single dose administration of 100 mg caffeine (probe substrate of CYP1A2) and 20 mg omeprazole (probe substrate of CYP2C19) on Day 4 in healthy subjects. The mean caffeine systemic exposure (AUC) was 2-fold higher, with no significant increase in the maximum plasma concentration (Cmax) compared to when caffeine was administered alone. The mean Cmax and AUC of omeprazole were approximately 2-fold higher compared to when omeprazole was administered alone.

MANAGEMENT: Until more information is available, caution is recommended when fexinidazole is used concomitantly with drugs that are substrates of CYP450 1A2 and/or 2C19. Clinical and laboratory monitoring may be appropriate whenever fexinidazole is added to or withdrawn from therapy with these drugs. Dosage adjustments may be considered if an interaction is suspected. Patients should be monitored for development of adverse effects.

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.