Drug Interaction Report

GENERALLY AVOID: Concomitant or recent use of immunosuppressant, immunomodulating, or antineoplastic agents in patients treated with natalizumab may increase the risk of infections including progressive multifocal leukoencephalopathy (PML), a severely disabling, potentially fatal opportunistic viral infection of the brain caused by John Cunningham Virus (JCV). In clinical trials, PML occurred in two of 1869 patients with multiple sclerosis treated with natalizumab for a median of 120 weeks and one of 1043 patients with Crohn's disease after eight doses of natalizumab. Both of the MS patients were receiving concomitant interferon beta therapy, and the third patient was immunocompromised due to recent treatment with azathioprine. In the postmarketing setting, additional cases of PML have been reported in patients who were receiving no concomitant immunomodulatory therapy. Longer treatment duration of natalizumab, especially beyond 2 years, and the presence of anti-JCV antibodies are additional risk factors for the development of PML. Other potentially serious or life-threatening infections that may occur include herpes encephalitis or meningitis and opportunistic infections such as pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and Burkholderia cepacia.

MANAGEMENT: The safety and efficacy of natalizumab in combination with immunosuppressant, immunomodulating, antineoplastic, or other myelosuppressive agents have not been established. In general, patients receiving chronic therapy with such agents should not be treated with natalizumab due to potentially increased risk of PML and other serious infections. For patients with Crohn's disease who start natalizumab while on chronic corticosteroid therapy, begin steroid withdrawal as soon as a therapeutic benefit is achieved. Natalizumab should be discontinued if patient is unable to stop using systemic corticosteroids within six months. All patients treated with natalizumab should be monitored closely during and for at least six months following discontinuation of treatment. The drug should be discontinued immediately at the first sign or symptom suggestive of PML, although it is not known if early detection of PML and discontinuation of natalizumab will mitigate the disease. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Due to the long half-life of natalizumab, immune effects are possible for up to 2 to 3 months following its discontinuation.

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.