Cobimetinib (Specialist drug)

INDICATION AND COMBINATION: for melanoma, cobimetinib is given with vemurafenib — confirm the presence of a BRAF V600E or V600K mutation in tumour specimens before starting. Review the full prescribing information for vemurafenib for its own dose modifications and serious risks. The label also describes adverse reactions in histiocytic neoplasms, but the dosage section gives only the 60 mg once-daily 21-of-28-days regimen. MISSED DOSE OR VOMITING: if a dose is missed, or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. DOSE REDUCTIONS: first dose reduction 40 mg orally once daily; second dose reduction 20 mg orally once daily; permanently discontinue if unable to tolerate 20 mg orally once daily. CYP3A DOSE MODIFICATION: do not take strong or moderate CYP3A inhibitors while taking cobimetinib. If concurrent short-term (14 days or less) use of a moderate CYP3A inhibitor is unavoidable in a patient taking 60 mg, reduce the cobimetinib dose to 20 mg; resume 60 mg after the inhibitor is discontinued. Use an alternative to a strong or moderate CYP3A inhibitor in patients already on a reduced dose (40 mg or 20 mg daily). TOXICITY MODIFICATIONS (examples from the label): Grade 3 haemorrhage — withhold up to 4 weeks, resume at the next lower dose if improved to Grade 0-1, otherwise permanently discontinue; Grade 4 haemorrhage — permanently discontinue. Asymptomatic LVEF fall of more than 10% from baseline and below the institutional lower limit of normal — withhold 2 weeks and repeat LVEF. Retinal vein occlusion — permanently discontinue; serous retinopathy — withhold up to 4 weeks then resume at the next lower dose. First occurrence of Grade 4 liver laboratory abnormality — withhold up to 4 weeks; recurrent Grade 4 — permanently discontinue. Grade 4 CPK elevation, or any CPK elevation with myalgia — withhold up to 4 weeks. Grade 2 (intolerable), Grade 3 or Grade 4 dermatologic reactions or photosensitivity — withhold or reduce. New primary malignancies — no dose modification required. MONITORING: evaluate LVEF before treatment, after one month, then every 3 months; monitor for new cutaneous and non-cutaneous malignancies before, during and for up to 6 months after the last dose; ophthalmological evaluation at regular intervals; liver laboratory tests and creatine phosphokinase periodically. PAEDIATRIC: safety and effectiveness have not been established in paediatric patients; a dose-escalation study in 55 patients aged 2 to 17 years achieved exposures lower than in adults at the approved dose, and juvenile rat data showed mortality at doses roughly equivalent to human ages 1-2 years. SOURCE: no UK SPC was fetched in this bundle; this draft is distilled from the US COTELLIC prescribing information and must be verified against the UK SPC. Fetched sections were truncated at the source-fetch limit.