Drug Interactions between azathioprine and letrozole / ribociclib

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.

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MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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