Drug Interactions between amoxicillin / clarithromycin / lansoprazole and bedaquiline

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of bedaquiline, which is primarily metabolized by CYP450 3A4 to its less active N-monodesmethyl metabolite, M2. In healthy volunteers, administration of bedaquiline (400 mg once daily for 14 days) in combination with ketoconazole (400 mg once daily for 4 days) increased bedaquiline peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 9%, 22% and 33%, respectively, compared to administration alone. The potential for increased risk of adverse reactions should be considered, including prolongation of the QT interval and liver enzyme and bilirubin elevations.

MONITOR CLOSELY: Bedaquiline can cause dose-related prolongation of the QT interval. Theoretically, 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. In one clinical study, the mean increase in Fridericia-corrected QT interval (QTcF) was 9.9 msec in subjects receiving bedaquiline and 3.5 msec in subjects receiving placebo after the first week of treatment. The largest mean increase in QTc during the 24 weeks of bedaquiline treatment was 15.7 msec, compared to 6.2 msec for placebo at week 18. QT increases from baseline in the bedaquiline group persisted even after treatment was stopped. There were no documented cases of torsade de pointes in the safety database. 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: Concomitant use of potent CYP450 3A4 inhibitors such as ceritinib, clarithromycin, ketoconazole, posaconazole, saquinavir, telithromycin, and voriconazole given systemically for more than 14 consecutive days should generally be avoided during treatment with bedaquiline unless the benefit is anticipated to outweigh the risk. Because these agents may also cause QT interval prolongation, caution is recommended when they are used together with bedaquiline. ECG, serum electrolytes (potassium, magnesium, calcium), and liver function tests (ALT, AST, alkaline phosphatase, bilirubin) should be monitored before starting bedaquiline therapy and periodically during treatment in accordance with the product labeling. Hypokalemia, hypomagnesemia, and hypocalcemia must be corrected prior to bedaquiline administration. All QT-prolonging drugs including bedaquiline 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 prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Patients should also seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

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.