Drug Interactions between bexarotene and doravirine / lamivudine / tenofovir disoproxil

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.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 100 mg dose of doravirine with the potent CYP450 3A4 inducer rifampin (600 mg once daily) decreased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 57%, 88% and 97%, respectively, compared to administration of doravirine alone. When doravirine was administered with rifabutin 300 mg once daily in 12 study subjects, doravirine Cmax did not change, but AUC and C24hr decreased by an average of 50% and 68%, respectively. When doravirine 100 mg once daily was initiated following cessation of treatment with efavirenz 600 mg once daily in 17 study subjects, doravirine Cmax, AUC and C24hr decreased by an average of 35%, 62% and 85%, respectively, on the first day and 14%, 32% and 50%, respectively, 14 days later. The extent to which other, less potent CYP450 3A4 inducers may affect doravirine is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of doravirine should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.