Drug Interactions between bexarotene and Triumeq PD

MONITOR CLOSELY: Coadministration with other drugs that are known to increase triglyceride levels or cause pancreatic toxicity may potentiate the risk of pancreatitis associated with the use of bexarotene. In clinical studies consisting of a total of 152 patients with cutaneous T-cell lymphoma (CTCL) and 352 patients with non-CTCL cancers treated with bexarotene, acute pancreatitis was reported in 4 CTCL and 6 non-CTCL cancer patients, with one fatality. The reported cases were associated with marked elevations in fasting serum triglycerides, the lowest being 770 mg/dL in one patient. Major, dose-related lipid abnormalities occur in most patients treated with bexarotene. Approximately 70% of patients with CTCL who received an initial dose of 300 mg/m2/day had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% of these patients had values over 800 mg/dL, with a median of about 1200 mg/dL. The incidence of NCI Grade 3 or 4 triglyceride elevations was 28% in CTCL patients receiving an initial dose of 300 mg/m2/day, but increased to 45% in CTCL patients receiving greater than 300 mg/m2/day. Significant increases in total cholesterol and decreases in HDL cholesterol were also reported at a high rate. Hyperlipidemic effects were reversible with cessation of therapy, and could generally be mitigated by bexarotene dose reduction or concomitant antilipemic therapy.

MANAGEMENT: Caution is advised when bexarotene is given in combination with other medications that are known to increase triglyceride levels or associated with pancreatic toxicity. Other risk factors such as a history of pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, or biliary tract disease should also be considered when weighing benefits versus risks of bexarotene therapy. All patients treated with bexarotene should have fasting blood lipids measured before initiating therapy, weekly during therapy until the lipid response to bexarotene is established (usually within two to four weeks), and at 8-week intervals thereafter. Fasting triglycerides should be normal, or normalized with appropriate intervention, prior to initiating bexarotene. Attempts should be made to maintain triglyceride levels below 400 mg/dL to minimize the risk of pancreatitis and other clinical sequelae. If fasting triglycerides are elevated, antilipemic therapy should be instituted, and if necessary, bexarotene dose reductions or treatment discontinuation. Patients should be advised to seek medical attention if they experience potential symptoms of pancreatitis such as persistent nausea, vomiting, abdominal tenderness, and upper abdominal pain, especially that which is made worse after eating or radiates to the back.

Coadministration with inducers of UGT1A and CYP450 3A4 isoenzymes may decrease the plasma concentrations of dolutegravir, which is primarily metabolized by UGT1A1 with some contribution from CYP450 3A4. Dolutegravir is also a substrate of UGT1A3, UGT1A9, and P-glycoprotein in vitro. In 9 study subjects, administration of dolutegravir 50 mg once daily with rifabutin 300 mg once daily decreased dolutegravir trough plasma concentration (Cmin; 24 hours postdose) by 30% compared to administration without rifabutin. The clinical significance is unknown. Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution may be advisable if dolutegravir is used in combination with mild or moderate UGT1A/CYP450 3A4 inducers.