cobimetinib, Cotellic

 Indications

Treatment of metastatic/unresectable melanoma with

the BRAF V600E or V600K mutation (in combination

with vemurafenib).

Action

Inhibits the activity of mitogen-activated extracellular

kinase (MEK) 1 and 2 which are enzymes that normally

promote cellular proliferation. Therapeutic Effects:

Decreased progression of melanoma.

Pharmacokinetics

Absorption: 46% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 95%.

Metabolism and Excretion: Mostly metabolized

by the liver (via CYP3A4 enzyme system and glucuronidation).

6.6% excreted in feces unchanged; 20% excreted

in urine (mostly as metabolites).

Half-life: 44 hr.

TIME/ACTION PROFILE (blood levels)

ROUTE ONSET PEAK DURATION

PO unknown 2.4 hr unknown

Contraindications/Precautions

Contraindicated in: Concurrent use of strong or

moderate CYP3A4 inhibitors or inducers; OB: May

cause fetal harm; Lactation: Breast feeding should be

avoided during treatment and for 2 wk after therapy.

Use Cautiously in: Left ventricular ejection fraction

50%; Severe renal impairment (CCr 30 mL/min);

Rep: Women of childbearing potential (use effective

contraception); Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CV: CARDIOMYOPATHY, hypertension. Derm: alopecia,

erythema, photosensitivity, rash. EENT: retinopathy. F

and E: hyperkalemia, hypocalcemia, hypokalemia, hyponatremia,

hypophosphatemia. GI: HEPATOTOXICITY,

diarrhea, hypoalbuminemia, nausea, stomatitis, vomiting.

GU:qserum creatinine,pfertility. Hemat: HEMORRHAGE,

anemia, lymphopenia, thrombocytopenia.

MS:qcreatine kinase, RHABDOMYOLYSIS. Misc: MALIGNANCY,

fever.

Interactions

Drug-Drug: Strong or moderate CYP3A4 inhibitors,

including itraconazole, mayqlevels; avoid concurrent

use. Strong or moderate CYP3A4 inducers, including

carbamazepine, efavirenz, phenytoin, and rifampin

mayplevels; avoid concurrent use.

Drug-Natural Products: St. John’s wort mayp

levels; avoid concurrent use.

Route/Dosage

PO (Adults): 60 mg once daily for days 1–21 of each

28–day cycle; continue until disease progression or

unacceptable toxicity; Concurrent short-term use of

moderate CYP3A4 inhibitor—20 mg once daily; resume

60 mg once daily once 3A4 inhibitor discontinued

(avoid use of strong or moderate CYP3A4 inhibitor

if patient already taking reduced dose of 20–40 mg

once daily).

Availability

Tablets: 20 mg.