Drug Interaction Report

MONITOR: The concomitant use of the CD20-directed cytolytic antibody ocrelizumab with other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, may result in an increased risk of immunosuppression. However, data is conflicting. Factors that appear to be associated with a risk of serious infections include higher doses of ocrelizumab than those recommended for multiple sclerosis (MS), other comorbidities, and concomitant use in patients on chronic immunosuppressants/corticosteroids. Ocrelizumab alone has been reported to increase the risk for respiratory tract infections and herpes-related infections in MS trials. In the postmarketing setting, hepatitis B reactivation, cases of progressive multifocal leukoencephalopathy (PML), and immune-mediated colitis have been reported. In relapsing MS (RMS) studies, 58% of ocrelizumab-treated patients experienced infections compared to 52% of interferon-treated patients. However, the proportion of patients reporting serious infection was higher in the interferon-treated group (2.9% versus 1.3%). On the other hand, when ocrelizumab is used concomitantly with immunosuppressants in other autoimmune conditions (e.g., rheumatoid arthritis) some studies have reported an increase in serious infections such as atypical pneumonia, pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, and histoplasmosis have been reported from some studies, including rare reports of fatalities.

MANAGEMENT: The increased risk of additive immunosuppression should be considered if co-administering ocrelizumab with other immunosuppressive therapy. Some authorities recommend avoiding concomitant use of other immunosuppressive therapies with ocrelizumab, except for the use of corticosteroids for symptomatic treatment of a MS relapse. Patients should be advised to notify their doctor if they develop signs or symptoms of infection, including upper or lower respiratory tract infection, skin infection, herpes related infection, or PML. If switching from a drug with prolonged immune effects (e.g., daclizumab, fingolimod, natalizumab, teriflunomide, mitoxantrone), the duration and mechanism of action should be considered prior to starting ocrelizumab therapy. The product labeling should be consulted for more specific recommendations.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.