Drug Interaction Report

GENERALLY AVOID: The use of azathioprine with other immunosuppressive or myelosuppressive agents may result in additive hematologic toxicities and increased risk of infections, particularly in transplant patients. Azathioprine alone may cause dose-related and potentially life-threatening bone marrow suppression, although it is usually reversible when managed promptly. Leucopenia, anemia, thrombocytopenia, and rarely, agranulocytosis, pancytopenia, and aplastic anemia have been reported. Dose-related reductions in numbers of circulating total white cells, granulocytes, and lymphocytes may also occur. Treatment with azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids, has been associated with increased susceptibility to infections including severe or atypical infection and reactivation with varicella zoster virus, hepatitis B, cytomegalovirus, and other infectious agents. Very rare cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), a severely disabling and potentially fatal opportunistic viral infection of the brain, have also been reported. In addition, chronic use of azathioprine with other immunosuppressants may increase the risk of lymphoma, skin cancer, and other malignancies. Again, the risk is greatest in transplant patients, with the exception of hepatosplenic T-cell lymphoma (HSTCL), which has occurred primarily in patients with Crohn's disease or ulcerative colitis, especially adolescent and young adult males.

MANAGEMENT: Concomitant use of azathioprine with other immunosuppressive or myelosuppressive agents should be avoided whenever possible. Close clinical and laboratory monitoring for hematologic toxicity is advised if coadministration is required. Since azathioprine is considered a slow-acting drug, delayed myelosuppression may occur, and effects may persist even after the drug has been discontinued. Prompt reduction in dosage or temporary withdrawal of azathioprine may be necessary if a persistently low or rapid decline in leucocyte count occurs, or if there is other evidence of bone marrow depression.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.