Drug Interactions between letrozole / ribociclib and Tice BCG

CONTRAINDICATED: Administration of intravesical BCG during immunosuppressant or intense antineoplastic therapy may be associated with a risk of disseminated infection due to enhanced replication of the BCG strain of Mycobacterium bovis in the presence of diminished immune competence. Deaths have been reported as a result of systemic BCG infection and sepsis. Patients may be immunosuppressed if they have recently received or are receiving alkylating agents, antimetabolites, radiation, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (e.g., greater than or equal to 2 mg/kg/day or 20 mg/day of prednisone or equivalent for 14 consecutive days or more), or long-term topical or inhaled corticosteroids. In addition, these patients may not develop an adequate immune response to BCG, which would reduce its anti-tumor efficacy.

MANAGEMENT: Use of intravesical BCG in immunosuppressed patients with congenital or acquired immune deficiencies, including those due to concurrent disease (e.g., AIDS, leukemia, lymphoma), cancer therapy (e.g., cytotoxic drugs, radiation) or immunosuppressive therapy (e.g., corticosteroids), is considered contraindicated. Clinicians should be aware that BCG may persist in the urinary tract for several months after BCG instillations, and delayed manifestations of disseminated BCG infection may develop months or years after BCG therapy. Patients who receive cancer or immunosuppressive therapy after BCG instillation may be at increased risk.

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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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