Drug Interaction Report

GENERALLY AVOID: Coadministration of tofacitinib with other immuno- or myelosuppressive agents may potentiate the risk of infections as well as lymphoma and other malignancies. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib, most of whom were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Lymphoma and other malignancies have also been observed with tofacitinib use, with or without concomitant immunosuppressants. Epstein Barr virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive agents (basiliximab, high-dose corticosteroids, and mycophenolic acid) relative to cyclosporine plus the same induction regimen (2.3% vs. 0%).

MANAGEMENT: Concomitant use of tofacitinib with immuno- or myelosuppressive agents should generally be avoided. If coadministration is necessary, close monitoring is advised for the development of infections, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Lymphocyte and neutrophil counts as well as hemoglobin should be evaluated at baseline and regularly during therapy, and tofacitinib dosage adjusted as necessary in accordance with the product labeling. Patients should be advised to contact their physician if they develop signs and symptoms of infection such as fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, and pain or burning during urination. If a serious infection, an opportunistic infection, or sepsis develops, tofacitinib should be interrupted until the infection is controlled.

MONITOR: Grapefruit juice may increase the plasma concentrations of tofacitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, some authorities recommend avoiding consumption of grapefruit juice during tofacitinib therapy (Canada). Patients receiving tofacitinib therapy who ingest grapefruits or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

GENERALLY AVOID: Food does not significantly affect the oral bioavailability of diroximel fumarate. Administration of diroximel fumarate with a high-fat, high-calorie (900 to 1000 calories; 50% from fat) meal did not affect the systemic exposure (AUC) of its active metabolite, monomethyl fumarate (MMF), but decreased its peak plasma concentration (Cmax) by 44% and prolonged the time to reach peak concentration (Tmax) from 2.5 to 7.0 hours relative to administration in the fasted state. In comparison, administration of diroximel fumarate with low-fat, low-calorie (350 to 400 calories; 10 to 15 g fat) and medium-fat, medium-calorie (650 to 700 calories; 25 to 30 g fat) meals decreased the MMF Cmax by approximately 12% and 25%, respectively, while also leaving the AUC unaffected.

GENERALLY AVOID: Coadministration of diroximel fumarate with ethanol may reduce the plasma concentrations of monomethyl fumarate (MMF). The mechanism has not been reported. Following coadministration with 240 mL of 5% v/v and 40% v/v ethanol, the mean Cmax of MMF was reduced by 9% and 21%, respectively, relative to coadministration with water. The AUC of MMF was not significantly altered, indicating that ethanol did not induce dose dumping.

MANAGEMENT: Diroximel fumarate may be taken with or without food; however, high-fat, high-calorie meals or snacks should be avoided. The manufacturer recommends meals or snacks containing no more than 700 calories and no more than 30 grams of fat. Taking diroximel fumarate with food may improve tolerability for patients experiencing flushing or gastrointestinal adverse reactions. The manufacturer also recommends avoiding concomitant use of diroximel fumarate with ethanol.