Skip to Content
How to talk to a doctor about advanced ovarian cancer >>

Cobimetinib

Pronunciation

(koe bi ME ti nib)

Index Terms

  • Cobimetinib Fumarate
  • Cotellic
  • GDC-0973
  • XL518

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Cotellic: 20 mg

Brand Names: U.S.

  • Cotellic

Pharmacologic Category

  • Antineoplastic Agent, MEK Inhibitor

Pharmacology

Cobimetinib is a potent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway (Larkin 2014); it reversibly inhibits MEK1 and MEK2, which are upstream regulators of the extracellular signal-related kinase (ERK) pathway. The ERK pathway promotes cellular proliferation. MEK1 and MEK2 are part of the BRAF pathway, which is activated by BRAF V600E and K mutations. Vemurafenib targets a different kinase in the RAS/RAF/MEK/ERK pathway; when cobimetinib and vemurafenib are used in combination, increased apoptosis and reduced tumor growth occurs.

Distribution

806 L

Metabolism

Hepatic; via CYP3A4 oxidation and UGT2B7 glucuronidation

Excretion

Feces (76%; ~7 as unchanged drug); Urine (~18%; ~2% as unchanged drug)

Time to Peak

Median: 2.4 hours (range: 1 to 24 hours)

Half-Life Elimination

Mean: 44 hours (range: 23 to 70 hours)

Protein Binding

95%; to plasma proteins

Special Populations: Hepatic Function Impairment

Exposure was decreased by 31% in patients with severe hepatic impairment compared to patients with normal hepatic function.

Use: Labeled Indications

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation (in combination with vemurafenib)

Contraindications

US labeling: There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Known hypersensitivity to cobimetinib or any component of the formulation.

Dosing: Adult

Melanoma, unresectable or metastatic (with BRAF V600E or V600K mutations): Oral: 60 mg once daily days 1 to 21 of each 28-day treatment cycle (in combination with vemurafenib); continue until disease progression or unacceptable toxicity (Larkin 2014).

Missed doses:

US labeling: If a dose is missed or if vomiting occurs after a dose is taken, resume with the next scheduled dose (do not take an additional dose).

Canadian labeling: A missed dose may be take up to 12 hours prior to the next dose. Do not administer 2 doses at the same time. If vomiting occurs after a dose is taken, resume with the next scheduled dose (do not take an additional dose).

Dosage adjustment for concurrent CYP3A4 inhibitors: Avoid concurrent use of strong or moderate CYP3A4 inhibitors with cobimetinib. If concurrent short-term use (≤14 days) of a moderate CYP3A4 inhibitor cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg; after the moderate CYP3A4 inhibitor is discontinued, resume the previous dose of 60 mg. If the current dose is 40 or 20 mg daily, alternatives to the strong or moderate CYP3A4 inhibitor should be used.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: There is no dosage adjustment provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment:

US labeling: Mild, moderate, or severe impairment (Child Pugh class A, B, or C): No initial dosage adjustment is necessary.

Canadian labeling: Mild, moderate, or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatotoxicity during treatment:

First occurrence of grade 4 lab abnormality (ALT, AST, or alkaline phosphatase >20 times ULN or total bilirubin >10 times ULN) or hepatotoxicity: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume at the next lower dose level. Permanently discontinue if not improved to grade 0 or 1 within 4 weeks.

Recurrent grade 4 lab abnormality or hepatotoxicity: Permanently discontinue.

Dosing: Adjustment for Toxicity

Recommended cobimetinib dose reductions for toxicity (vemurafenib may also require dosage adjustment):

First dose reduction: 40 mg once daily

Second dose reduction: 20 mg once daily

Subsequent modification (if unable to tolerate 20 mg once daily): Permanently discontinue

Note: The Canadian labeling recommends that once a dose is reduced for toxicity, it should not be increased at a later time.

Cardiotoxicity:

Asymptomatic cardiomyopathy (absolute decrease in LVEF >10% [from baseline] and less than the institutional lower limit of normal [LLN]): Withhold cobimetinib for 2 weeks and repeat LVEF. If LVEF ≥ LLN and absolute decrease from baseline is ≤10%, resume at the next lower dose level. Permanently discontinue if LVEF < LLN or absolute decrease from baseline is >10%.

Symptomatic cardiomyopathy (symptomatic LVEF decrease from baseline): Withhold cobimetinib for up to 4 weeks and repeat LVEF. If symptoms resolve and LVEF ≥ LLN and absolute decrease from baseline is ≤10%, resume at the next lower dose level. Permanently discontinue if symptoms persist or LVEF < LLN or absolute decrease from baseline is >10%.

CPK elevation or rhabdomyolysis:

Grade 4 CPK elevation (>10 times ULN) or any CPK elevation with myalgia: Withhold cobimetinib for up to 4 weeks; if improves to grade 3 or lower, resume at the next lower dose level. Permanently discontinue if not improved within 4 weeks.

Dermatologic toxicity:

Grade 2 or lower (tolerable): Manage with supportive care.

Grade 2 (intolerable) or grade 3 or 4: Withhold or reduce dose.

Grade 2 (intolerable) or grade 3 or 4 non-acneiform or maculopapular rash (Canadian labeling): Continue without dosage modification (if clinically indicated).

New primary cutaneous or noncutaneous malignancies: No cobimetinib dosage modification is necessary.

Hemorrhage:

Grade 3: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume at the next lower dose level. Permanently discontinue if not improved within 4 weeks.

Grade 4: Permanently discontinue.

Ocular:

Serous retinopathy: Withhold cobimetinib for up to 4 weeks; if signs/symptoms improve, resume at the next lower dose level. Permanently discontinue if not improved or symptoms recur within 4 weeks at the lower dose.

Retinal vein occlusion: Permanently discontinue.

Photosensitivity:

Grade 2 or lower (tolerable): Manage with supportive care.

Grade 2 (intolerable), grade 3 or 4: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume at the next lower dose level. Permanently discontinue if not improved within 4 weeks.

Other toxicities:

Grade 2 (intolerable), or any grade 3: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume at the next lower dose level. Permanently discontinue if not improved within 4 weeks.

Grade 4, first occurrence: Withhold cobimetinib until adverse reaction improves to grade 0 or 1 and then resume at the next lower dose level or permanently discontinue.

Grade 4, recurrent: Permanently discontinue.

Administration

Oral: May be administered with or without food. The Canadian labeling recommends swallowing tablets whole with water.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).

Storage

Store below 30°C (86°F).

Drug Interactions

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Cobimetinib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Cobimetinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cobimetinib. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Adverse Reactions

Percentages reported as part of combination chemotherapy regimens.

>10%:

Cardiovascular: Decreased left ventricular ejection fraction (grades 2/3: 26%), hypertension (15%)

Dermatologic: Skin photosensitivity (46% to 47%, grades 3/4: 4%; includes solar dermatitis and sunburn), acneiform eruption (16%, grades 3/4: 2%)

Endocrine & metabolic: Hypophosphatemia (68%), increased gamma-glutamyl transferase (65%; grades 3/4: 21%), hypoalbuminemia (42%), hyponatremia (38%), hyperkalemia (26%), hypokalemia (25%), hypocalcemia (24%)

Gastrointestinal: Diarrhea (60%), nausea (41%), vomiting (24%), stomatitis (14%; includes aphthous stomatitis, mucositis, and oral mucosa ulcer)

Hematologic & oncologic: Lymphocytopenia (73%, grades 3/4: 10%), anemia (69%; grades 3/4: 3%), thrombocytopenia (18%), hemorrhage (13%, grades 3/4: 1%; includes bruise, ecchymoses, epistaxis, gingival hemorrhage, hematemesis, hematochezia, hemoptysis, hemorrhoidal bleeding, hypermenorrhea, melena, menometrorrhagia, nail bed bleeding, pulmonary hemorrhage, purpura, rectal hemorrhage, rupture of ovarian cyst, subarachnoid hemorrhage, subgaleal hematoma, traumatic hematoma, uterine hemorrhage, and vaginal hemorrhage)

Hepatic: Increased serum AST (73%, grades 3/4: 7% to 8%), increased serum alkaline phosphatase (71%, grades 3/4: 7%), increased serum ALT (68%, grades 3/4: 11%)

Neuromuscular & skeletal: Increased creatine phosphokinase (79%, grades 3/4: 12% to 14%)

Ophthalmic: Visual impairment (15%, grades 3/4: <1%; includes blurred vision, decreased visual acuity), chorioretinopathy (13%, grades 3/4: <1%), retinal detachment (12%, grades 3/4: 2%; includes detachment of macular retinal pigment epithelium and retinal pigment epithelium detachment)

Renal: Increased serum creatinine (100%; grades 3/4: 3%)

Miscellaneous: Fever (28%)

1% to 10%:

Central nervous system: Chills (10%)

Dermatologic: Skin rash (grades 3/4: 16%; grade 4: 2%; rash resulting in hospitalization: 3%)

Gastrointestinal: Gastrointestinal hemorrhage (4%)

Genitourinary: Genitourinary tract hemorrhage (2%), hematuria (2%)

Hematologic & oncologic: Keratoacanthoma (≤6%), squamous cell carcinoma of skin (≤6%), basal cell carcinoma (5%)

Hepatic: Abnormal bilirubin levels (grades 3/4: 2%)

<1% (Limited to important or life-threatening): Cerebral hemorrhage, malignant melanoma (second primary), malignant neoplasm (non-cutaneous)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: Symptomatic or asymptomatic declines in left ventricular ejection fraction (LVEF) may occur with cobimetinib. Safety has not been established in patients with baseline LVEF below the institutional lower limit of normal (LLN) or below 50%. Assess LVEF (by echocardiogram or MUGA scan) prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued. May require treatment interruption, dose reduction and/or discontinuation. Also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. The median time to first onset of LVEF decline was 4 months (range: 23 days to 13 months). Decreased LVEF resolved to >LLN or within 10% of baseline at nearly two-thirds of patients with a median time to resolution of 3 months (range: 4 days to 12 months).

• Dermatologic toxicity: Severe rash and other skin reactions (including grades 3 and 4 toxicity) may occur; some events required hospitalization. The median time to onset of grade 3 and 4 rash events was 11 days (range: 3 days to ~3 months); most patients with grades 3 and 4 rash experienced complete resolution at a median time of 21 days (range: 4 days to 17 months). May require treatment interruption, dose reduction and/or discontinuation. Photosensitivity was reported in nearly one-half of patients (may be severe). The median time to first onset of photosensitivity was 2 months (range: 1 day to 14 months); the median duration was 3 months (range: 2 days to 14 months). Photosensitivity resolved in nearly two-thirds of patients. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF 30 or higher) when outdoors. Photosensitivity may require treatment interruption, dose reduction, and/or discontinuation.

• Hemorrhage: Hemorrhage, including major symptomatic bleeding in a critical area/organ, may occur with cobimetinib. Grade 3 to 4 bleeding has occurred. Cerebral hemorrhage, gastrointestinal bleeding, reproductive system hemorrhage, and hematuria have been reported. May require treatment interruption, dose reduction, and/or discontinuation.

• Hepatotoxicity: Hepatotoxicity (including grades 3 or 4 transaminase, total bilirubin, or alkaline phosphatase elevations) may occur with cobimetinib. Monitor liver function test at baseline and monthly during treatment, or as clinically necessary. Grade 3 and 4 elevations may require treatment interruption, dose reduction, and/or discontinuation.

• Hypersensitivity: Grade 3 hypersensitivity events have been reported (rare) (Cotellic Canadian product labeling 2016).

• Hypertension: Hypertension may occur with cobimetinib in combination with vemurafenib, both in patients with and without preexisting hypertension; grades 3 or 4 hypertension has been observed. Monitor blood pressure.

• Malignancy: New primary cutaneous malignancies may occur. Malignancies included cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA), basal cell carcinoma (BCC), and second primary melanoma. The median time to detection of first cuSCC or KA was 4 months (range: 2 to 11 months); the median time to first detection of BCC was 4 months (range: 1 to 13 months). Dermatologic exams should be performed prior to initiation, every 2 months during treatment, and for 6 months following discontinuation of cobimetinib/vemurafenib combination therapy. Suspicious lesions should be managed with excision and dermatopathologic evaluation. Dosage adjustment is not recommended for new cutaneous malignancies. Vemurafenib may be associated with the development of noncutaneous malignancy; monitor for signs/symptoms of noncutaneous malignancy during combination treatment.

• Ophthalmic effects: Ocular toxicities may occur, including serous retinopathy (fluid accumulation under retina layers). Chorioretinopathy and retinal detachment have been reported; retinal vein occlusion has also been reported (case reports); permanently discontinue if retinal vein occlusion occurs. The time to first onset of serous retinopathy ranged between 2 days to 9 months with a duration of 1 day to 15 months. Perform ophthalmic examinations regularly during treatment, and with reports of new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt treatment until visual symptoms improve; may require treatment interruption, dose reduction, and/or discontinuation.

• Rhabdomyolysis: Rhabdomyolysis and creatine phosphokinase (CPK) elevations may occur with cobimetinib. The median time to first occurrence of grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months), with a median time to resolution of 15 days (range: 9 days to 11 months). Obtain baseline serum CPK and creatinine levels at baseline, periodically during treatment and as clinically indicated. If CPK is elevated, evaluate for signs/symptoms of rhabdomyolysis or other etiology. Depending on severity, may require treatment interruption, dose reduction, and/or discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Prior to initiating therapy, confirm BRAF V600K or V600E mutation status with an approved test; approved for use in patients with BRAF V600K and BRAF V600E mutations. Not indicated for use in patients with wild-type BRAF melanoma.

Monitoring Parameters

BRAF V600K or V600E mutation status (prior to treatment); liver function tests (baseline and monthly during treatment, more frequently if clinically indicated); creatine phosphokinase and serum creatinine (baseline and periodically during treatment, more frequently if clinically indicated). Assess left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued; also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. The Canadian labeling also recommends ECG monitoring prior to and routinely during treatment.

Monitor blood pressure regularly; dermatologic exams (baseline, every 2 months during treatment, and for 6 months following discontinuation); ophthalmic examinations (baseline, regularly during treatment and with reports of new or worsening visual disturbances); monitor for signs/symptoms of dermatologic toxicity, hemorrhage, noncutaneous malignancy, photosensitivity, and rhabdomyolysis.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, cobimetinib would be expected to cause fetal harm. Women of reproductive potential should use effective contraception during therapy and for 2 weeks after the final dose. The Canadian labeling recommends the use of two forms of effective contraception during therapy and for at least 3 months following discontinuation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, acne, nausea, vomiting, or mouth sores. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), shortness of breath, abnormal heartbeat, severe dizziness, passing out, loss of strength and energy, abdominal pain, severe headache, skin growth, vision changes, eye pain, severe eye irritation, blindness, visual halos or bright colors around lights, chills, sunburn, skin irritation, skin changes, muscle pain, muscle weakness, or mole changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience,and judgment in diagnosing, treating, and advising patients.

Hide