Cobimetinib

Melanoma, Histiocytic Neoplasms

Oral Melanoma Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib 60 mg PO once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity Vemurafenib: 960 mg PO BID on days 1-28 of an every 28-day cycle Histiocytic Neoplasms Indicated as a single agent for adults with histiocytic neoplasms 60 mg PO once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Renal impairment Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary Severe (CrCl <30 mL/min): Safety and efficacy not established

Hepatic impairment Mild-to-severe (Child-Pugh A to C): No dosage adjustment necessary

May be taken with or without food.

Hypersensitivity.

New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of Cobimetinib. Hemorrhage: Major hemorrhagic events can occur with Cobimetinib. Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving Cobimetinib with vemurafenib compared with vemurafenib as a single agent. The safety of Cobimetinib has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with Cobimetinib. Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue Cobimetinib. Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. Permanently discontinue Cobimetinib for retinal vein occlusion (RVO). Hepatotoxicity: Monitor liver laboratory tests during treatment and as clinically indicated. Rhabdomyolysis: Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. Severe Photosensitivity: Advise patients to avoid sun exposure. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception MONITORING PARAMETERS Monitor for signs and symptoms of bleeding. Creatine kinase elevation: Baseline creatine kinase and creatinine levels should be measured before starting treatment, and then at monthly intervals during treatment or as clinically indicated. Left ventricular function: Ejection fraction should be evaluated before initiation of treatment, then after the first month of treatment and at least every 3 months thereafter (or as clinically indicated) until treatment discontinuation. Liver function: Monitor liver laboratory tests during tre

Not Classi Pregnancy Based on findings from animal reproduction studies and its mechanism of action, cobimetinib can cause fetal harm when administered to a pregnant woman In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9- to 1.4-times those observed in humans at the recommended human dose of 60 mg Advise pregnant women of the potential risk to a fetus Contraception: Advise females of reproductive potential to use effective contraception during treatment with and for 2 weeks after the final dose Infertility: Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potential Lactation Unknown if distributed in human breast milk Because of the potential for serious adverse reactions in a breastfed infant, advise women not to breastfeed during treatment and for 2 weeks after the final dose

Increased AUC w/ strong/moderate CYP3A inhibitors & P-glycoprotein (P-gp) inhibitors. Reduced exposure w/ strong CYP3A inducers. Contraindicated (43) armodafinil atazanavir bosentan carbamazepine clarithromycin clobazam cobicistat conivaptan dabrafenib darunavir dexamethasone efavirenz elvitegravir/cobicistat/emtricitabine/tenofovir DF enzalutamide eslicarbazepine acetate etravirine fosamprenavir fosphenytoin grapefruit idelalisib imatinib isoniazid lopinavir lumacaftor/ivacaftor mitotane nafcillin nefazodone nelfinavir nevirapine nicardipine pentobarbital phenobarbital phenytoin posaconazole primidone quinidine rifabutin rifampin rifapentine ritonavir St John's Wort tipranavir voriconazole

>10% Increased creatinine (99.6%) Increased CPK (79%) Increased AST (73%) Lymphopenia (73%) Increased alkaline phosphatase (71%) Anemia (69%) Increased ALT (68%) Hypophosphatemia (68%) Increased GGT (65%) Diarrhea (60%) Photosensitivity (46%) Hypoalbuminemia (42%) Nausea (41%) Hyponatremia (38%) Pyrexia (28%) Hyperkalemia (26%) Hypokalemia (25%) Hypocalcemia (24%) Vomiting (24%) Thrombocytopenia (18%) Acneiform dermatitis (16%) Hypertension (15%) Vision impaired (15%) Alopecia (15%) Stomatitis (14%) Hemorrhage (13%) Chorioretinopathy (13%) Retinal detachment (12%) Hyperkeratosis (11%) 1-10% Chills (10%) Erythema (10%)

Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation BRAF V600E and K mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2 Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model