Prescribing Information for Cobimetinib

Cobimetinib (Cotellic) is an oral, highly selective MEK1/2 inhibitor. Cobimetinib reversibly inhibits the catalytic activity of MEK1 and MEK2, blocking the phosphorylation and activation of downstream ERK2, thereby inhibiting tumor cell proliferation and inducing apoptosis.

Indications

Melanoma

Indicated in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Confirm the presence of a BRAF V600E or V600K mutation using an FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 Mutation Test) prior to initiating therapy.

Histiocytic Neoplasms

Indicated as a single agent for the treatment of adult patients with histiocytic neoplasms.

General Dosing Considerations

Pre-treatment Screening

Confirm the presence of a BRAF V600E or V600K mutation prior to initiating cobimetinib in combination with vemurafenib in patients with melanoma.

Perform dermatologic evaluations prior to initiating cobimetinib.

Evaluate left ventricular ejection fraction (LVEF) prior to initiating cobimetinib.

Monitor liver function tests prior to initiating cobimetinib.

Obtain baseline serum CPK and Scr concentrations prior to initiating cobimetinib.

Patient Monitoring

Perform dermatologic evaluations every 2 months during treatment with cobimetinib as monotherapy or in combination with vemurafenib. When used in combination with vemurafenib, continue monitoring for 6 months after discontinuation of cobimetinib.

Monitor for new non-dermatologic malignancies during combination therapy with cobimetinib and vemurafenib.

Evaluate LVEF at 1 month after initiating cobimetinib, and then every 3 months during treatment. For patients restarting cobimetinib after dose reduction or interruption, evaluate LVEF at 2 weeks, 4 weeks, 10 weeks, 16 weeks, and as clinically indicated thereafter.

Perform ophthalmologic evaluations periodically during treatment and as clinically indicated (e.g., upon new or worsening visual disturbances).

Perform liver function tests monthly during treatment, or more frequently as clinically indicated.

Evaluate serum CPK and creatinine concentrations periodically during treatment and as clinically indicated.

Other General Considerations

Avoid sun exposure during treatment.

When used in combination with vemurafenib, consider the general precautions, warnings, and contraindications associated with vemurafenib in addition to cobimetinib-related precautions.

Dosage and Administration

Method of Administration

Administer orally once daily, with or without food.

Recommended Dosage

Supplied as cobimetinib fumarate; dosages are expressed in terms of cobimetinib base.

Melanoma

60 mg orally once daily for Days 1–21 of each 28-day cycle; in combination with vemurafenib. Continue treatment until disease progression or unacceptable toxicity.

Histiocytic Neoplasms

60 mg orally once daily for 21 consecutive days followed by 7 days off (in 28-day cycles); as monotherapy. Continue treatment until disease progression or unacceptable toxicity.

Common Adverse Reactions

1. In patients receiving cobimetinib in combination with vemurafenib for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, adverse reactions (≥20%) included diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.

2. In patients receiving cobimetinib in combination with vemurafenib, Grade 3 or 4 laboratory abnormalities (≥5%) included increased CPK, increased aminotransferases (i.e., AST, ALT), lymphopenia, increased alkaline phosphatase, hypophosphatemia, increased GGT, and hyponatremia.

3. In patients receiving cobimetinib monotherapy for histiocytic neoplasms, adverse reactions (≥20%) included acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritus, dyspepsia, vomiting, dyspnea, and urinary tract infection.

4. In patients receiving cobimetinib monotherapy for histiocytic neoplasms, Grade 3 or 4 laboratory abnormalities (≥5%) included hyponatremia, increased CPK, hypokalemia, increased Scr, increased AST, hypocalcemia, lymphopenia, leukopenia, and anemia.

Warnings and Precautions

Severe Photosensitivity

Photosensitivity reactions, including severe cases, have been reported. Avoid sun exposure during cobimetinib treatment. If photosensitivity occurs, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Combination Therapy

When used in combination with vemurafenib, consider the warnings, precautions, and contraindications of vemurafenib.

New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and new primary melanoma have been reported in patients treated with cobimetinib in combination with vemurafenib. Perform dermatologic evaluations at baseline and every 2 months during treatment; continue monitoring for 6 months after cobimetinib discontinuation when used with vemurafenib. Initiate appropriate management and excise suspicious skin lesions for pathological evaluation.

Monitor for new non-cutaneous malignancies during cobimetinib treatment in combination with vemurafenib.

Hemorrhage

Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in critical locations or organs), has been reported. If bleeding events occur, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Cardiomyopathy

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF) has been reported, sometimes requiring temporary interruption, dose modification, or permanent treatment discontinuation. Safety has not been established in patients with a baseline LVEF below the lower limit of normal or <50%.

Evaluate LVEF prior to initiating treatment, at 1 month after treatment initiation, and every 3 months thereafter during treatment. If left ventricular dysfunction occurs, interrupt treatment, reduce the dose, or permanently discontinue the drug. Re-evaluate LVEF at approximately 2, 4, 10, and 16 weeks after restarting the drug, and as clinically indicated thereafter.

Severe Dermatologic Reactions

Severe dermatologic reactions (e.g., severe rash) have been reported, sometimes requiring hospitalization. If skin reactions occur, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Serous Retinopathy and Retinal Vein Occlusion

Ocular toxicities (e.g., serous retinopathy, retinal vein occlusion) have been reported. Perform periodic ophthalmologic evaluations during treatment and as clinically indicated (e.g., upon new or worsening visual disturbances). If ocular toxicity occurs, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Hepatotoxicity

Abnormal liver function tests have been reported. Perform liver function tests prior to initiating treatment and monthly thereafter, or more frequently as clinically indicated. If liver function abnormalities occur, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Rhabdomyolysis

Rhabdomyolysis (Grade 3 or 4 elevations in serum CPK, including asymptomatic increases over baseline) has been reported. Evaluate serum CPK and Scr concentrations at baseline, periodically during treatment, and as clinically indicated. If elevated CPK levels occur, evaluate for signs of rhabdomyolysis and other potential causes. If CPK elevation occurs, interrupt treatment, reduce the dose, or permanently discontinue the drug.

Embryo-Fetal Toxicity and Mortality

May cause fetal harm. Embryotoxicity and teratogenicity have been demonstrated in animals. Avoid pregnancy during cobimetinib treatment and for ≥2 weeks following discontinuation. Apprise pregnant women or female patients of childbearing potential of the potential hazard to a fetus.

Use in Specific Populations

Pregnancy

May cause fetal harm.

Lactation

It is unknown whether cobimetinib is present in human milk. Discontinue breastfeeding during treatment and for 2 weeks after the final dose.

Females and Males of Reproductive Potential

May impair fertility in females and males. Avoid pregnancy during cobimetinib treatment and for ≥2 weeks following discontinuation. Advise females of reproductive potential to use effective contraception during cobimetinib treatment and for ≥2 weeks after the final dose.

Pediatric Use

Safety and effectiveness have not been established. Cobimetinib exposure at the maximum tolerated dose in pediatric patients was lower than that in adult patients receiving the recommended dose.

Geriatric Use

Clinical experience in patients aged ≥65 years is insufficient to determine whether they respond differently from younger adults.

Hepatic Impairment

Hepatic impairment did not significantly affect systemic exposure to cobimetinib; no dose adjustment is required for these patients.

Renal Impairment

No formal pharmacokinetic studies have been conducted in patients with renal impairment; however, renal elimination of cobimetinib is minimal.

In population pharmacokinetic analyses, mild or moderate renal impairment did not alter systemic exposure; no dose adjustment is required for these patients.

Cobimetinib has not been studied in patients with severe renal impairment.

Storage Conditions

Store at room temperature (<30°C) is recommended.