cobimetinib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Metastatic/unresectable melanoma with the BRAF V600E or V600K mutation (in combination with vemurafenib).
Histiocytic neoplasms.

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 and histiocytic neoplasms.

Absorption: 46% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 95%.

Metabolism/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.

(blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2.4 hr	unknown

Contraindicated in:

Concurrent use of strong or moderate CYP3A4 inhibitors or inducers;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Left ventricular ejection fraction <50%;
Severe renal impairment (CCr <30 mL/min);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Drug-drug:

Strong or moderate CYP3A4 inhibitors, including itraconazole, may ↑ levels; avoid concurrent use
Strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenytoin, and rifampin, may ↓ levels; avoid concurrent use.

Drug-Natural Products:

St. John's wort may ↓ levels; avoid concurrent use.

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).

Assess skin prior to starting therapy and every 2 mo during and for 6 mo following therapy for new lesions. If new lesions appear, evaluate and remove as needed. If Grade 2 (intolerable), Grade 3, or Grade 4 rash or other skin reactions occur, withhold or reduce dose.
Monitor for bleeding and hemorrhage periodically during therapy. If Grade 3 hemorrhage occurs, hold therapy for up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved within 4 wk, permanently discontinue. If Grade 4 hemorrhage occurs, permanently discontinue therapy.
Monitor left ventricular ejection fraction (LVEF) prior to initiation, 1 mo after initiation, and every 3 mo until discontinuation. If asymptomatic, absolute ↓ LVEF from baseline of >10% and <institutional lower limit of normal (LLN), hold therapy for 2 wk; repeat LVEF. Resume at next lower dose if all of following are present: LVEF is ≥LLN and absolute ↓ from baseline LVEF ≤10%. Discontinue permanently if any of following are present: LVEF is <LLN or absolute ↓ from baseline LVEF >10%. If symptomatic LVEF ↓ from baseline, hold therapy for up to 4 wk, repeat LVEF. Resume at next lower dose if all of following are present: symptoms resolve and LVEF is ≥LLN and absolute ↓ from baseline LVEF is ≤10%. Discontinue permanently if any of following are present: symptoms persist, or LVEF <LLN, or absolute ↓ from baseline LVEF >10%. If restarting cobimetinib after a dose reduction or interruption, evaluate LVEF at approximately 2 wk, 4 wk, 10 wk, and 16 wk, and as clinically indicated.
Perform ophthalmological evaluations periodically during therapy and if patient reports new or worsening visual disturbances. If serious retinopathy occurs, hold therapy for up to 4 wk. If signs and symptoms improve, resume at next lower dose. If not improved or symptoms recur at lower dose within 4 wk, permanently discontinue. If retinal vein occlusion occurs, permanently discontinue therapy.
Assess for photosensitivity during therapy. If Grade 2 (intolerable), Grade 3, or Grade 4 photosensitivity occurs, withhold therapy up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved within 4 wk, permanently discontinue.

Lab Test Considerations:

Confirm presence of BRAF V600E or V600K mutation in tumor specimens starting therapy with cobimetinib with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.May cause ↑ AST, ALT, alkaline phosphatase, and GGT. Monitor liver function tests before starting and monthly during therapy, and as clinically indicated. For 1st occurrence of Grade 4 hepatotoxicity, hold therapy up to 4 wk. If improved to Grade 0 or 1, resume at next lower dose. If not improved to Grade 0 or 1 within 4 wk, permanently discontinue. If Grade 4 hepatotoxicity recurs, discontinue therapy permanently.
- Obtain CK and serum creatinine levels at baseline and periodically during therapy. If Grade 4 CK ↑ or any CK ↑ and myalgia occur, hold therapy up to 4 wk. If improved to Grade 3 or lower, resume at next lower dose level. If not improved within 4 wk, permanently discontinue.
- May cause hypophosphatemia, hyponatremia, hypoalbuminemia, hypokalemia, hyperkalemia, and hypocalcemia.
- May cause anemia, lymphopenia, and thrombocytopenia.

Dose reduction guidelines: 1st dose reduction, 40 mg once daily. 2nd dose reduction, 20 mg once daily. Subsequent modification, discontinue therapy permanently if unable to tolerate 20 mg once daily.
PO: Administer three 20-mg tablets once daily without regard to food.

Instruct patient to take cobimetinib as directed. If dose is missed or vomiting occurs after dose, do not repeat, take next dose as scheduled.
Advise patient to notify health care professional immediately if skin changes (new wart, skin sore that bleeds or does not heal, change in size or color of mole), signs and symptoms of bleeding (blood in urine, red or black stools, unusual or excessive vaginal bleeding, bleeding of gums, abdominal pain, headache, dizziness, feeling weak), cardiomyopathy (persistent coughing or wheezing, tiredness, shortness of breath, increased heart rate, swelling of ankles and feet), eye problems (blurred vision, halos, distorted vision, other vision changes, partly missing vision), liver injury (yellowing of skin or white of eyes, feeling tired or weak, dark or brown [tea color] urine, loss of appetite, nausea or vomiting), rhabdomyolysis (muscle aches, dark, reddish urine, muscle spasms, weakness), or rash occur.
Advise patient to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. May require dose reduction or discontinuation.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Rep: May cause fetal harm. Advise patient use effective contraception and avoid breastfeeding during and for at least 2 wk following therapy. May reduce fertility in females and males of reproductive potential.

Decrease in progression of melanoma and histiocytic neoplasms.

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