Drug Interactions between Kisqali Femara Co-Pack and natalizumab

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.

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.