Drug Interactions between bedaquiline and celecoxib / tramadol

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.

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

GENERALLY AVOID: Coadministration of bedaquiline with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. In clinical trials, hepatic adverse drug reactions developed in more bedaquiline-treated patients than in those who received other drugs used to treat tuberculosis. In patients receiving bedaquiline or placebo in combination with other drugs used to treat multidrug-resistant tuberculosis, reversible aminotransferase elevations of at least 3 times the upper limit of normal (ULN) developed more frequently in the bedaquiline treatment group [10.8%] than in the placebo group [5.7%].

MANAGEMENT: The use of bedaquiline with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; androgens and anabolic steroids; other antituberculous agents; azole antifungal agents; ACE inhibitors; disulfiram; endothelin receptor antagonists; ketolide and macrolide antibiotics; interferons; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice), especially in patients with diminished hepatic reserve. Patients treated with bedaquiline should have serum ALT, AST, alkaline phosphatase, and bilirubin monitored at baseline and monthly during treatment, or as often as needed. An increase of serum aminotransferases to greater than 3 times ULN should be followed by repeat testing within 48 hours. Patients should be advised to 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. Discontinue bedaquiline if aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times ULN, aminotransferase elevations are greater than 8 times ULN, or aminotransferase elevations persist beyond 2 weeks.