Drug Interactions between bedaquiline and lopinavir / ritonavir

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. In another study where patients with no treatment options received other QT-prolonging drugs used to treat tuberculosis, concurrent use of bedaquiline resulted in additive QT prolongation proportional to the number of QT-prolonging drugs in the treatment regimen. Patients receiving bedaquiline alone with no other QT-prolonging drugs developed a mean QTcF increase over baseline of 23.7 msec. There was no QT segment duration in excess of 480 msec in this group, whereas patients receiving at least two other QT-prolonging drugs developed a mean QTcF prolongation of 30.7 msec over baseline, resulting in QTcF segment durations in excess of 500 msec in one patient. Mean increases in QTc were also larger in the 17 subjects who were using clofazimine with bedaquiline than in those who were not using clofazimine with bedaquiline (31.9 msec versus 12.3 msec at week 24). 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: Caution is recommended if bedaquiline is used in combination with other drugs that can prolong the QT interval. ECG and serum electrolytes, including potassium, magnesium and calcium, 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.

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.

MANAGEMENT: The concomitant use of potent CYP450 3A4 inhibitors such as clarithromycin, cobicistat, conivaptan, delavirdine, nefazodone, telithromycin, and most protease inhibitors and azole antifungal agents 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. Appropriate clinical monitoring for bedaquiline-related adverse reactions is recommended if coadministration is required. 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. 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.