Cobimetinib (Monograph)

Brand name: Cotellic
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.

Uses for Cobimetinib

Melanoma

In combination with vemurafenib for treatment of adult patients with unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation (designated an orphan drug by FDA for this use).

FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 mutation test) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.

Per guidelines from the American Society of Clinical Oncology (ASCO), cobimetinib in combination with vemurafenib is recommended among first-line therapy options for treatment of BRAF mutant (V600) unresectable or metastatic melanoma; however, the guideline states that nivolumab plus ipilimumab is preferred first-line therapy over BRAF/mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combination therapy.

Limited data suggest greater efficacy (longer progression-free and overall survival, higher objective response rates) in patients with BRAF inhibitor-naïve disease versus those with disease progression during prior BRAF inhibitor therapy.

Histiocytic Neoplasms

Used as a single agent for treatment of adult patients with histiocytic neoplasms (designated an orphan drug by FDA for this use).

Cobimetinib Dosage and Administration

General

Pretreatment Screening

Confirm presence of b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation in patients with melanoma prior to initiation of combination therapy with cobimetinib and vemurafenib.
Perform a dermatologic evaluation prior to initiation of cobimetinib.
Evaluate left ventricular ejection fraction (LVEF) prior to initiation of cobimetinib.
Monitor liver function tests prior to initiation of cobimetinib.
Obtain baseline serum CPK and S_cr concentrations prior to initiation of cobimetinib.

Patient Monitoring

Perform dermatologic evaluation every 2 months during monotherapy with cobimetinib or when used in combination with vemurafenib. Continue monitoring for 6 months following discontinuance of cobimetinib when used in combination with vemurafenib.
Monitor for new noncutaneous malignancies during combination therapy with cobimetinib and vemurafenib.
Assess LVEF 1 month after initiation of cobimetinib therapy and then every 3 months during therapy. In patients restarting cobimetinib after dose reduction or interruption, assess LVEF at 2 weeks, 4 weeks, 10 weeks, 16 weeks, then as clinically appropriate.
Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during cobimetinib therapy.
Perform liver function tests monthly or more frequently as clinically indicated, during therapy.
Evaluate serum CPK and creatinine concentrations periodically and as clinically indicated, during therapy.

Other General Considerations

Avoid exposure to sunlight during therapy.
When used in combination with vemurafenib, the usual cautions, precautions, and contraindications associated with vemurafenib must be considered in addition to those associated with cobimetinib.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Available as cobimetinib fumarate; dosage expressed in terms of cobimetinib.

Adults

Melanoma

Oral

60 mg once daily on days 1–21 of each 28-day cycle; use in combination with vemurafenib. Continue therapy until disease progression or unacceptable toxicity occurs.

Histiocytic Neoplasms

Oral

60 mg once daily for 21 days followed by a 7-day rest period (courses of therapy are given in 28-day cycles); use as a single agent. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modifications

Adjust dosage in decrements of 20 mg daily.

Dosages <20 mg once daily not recommended; permanently discontinue drug if 20-mg daily dosage is not tolerated.

Hemorrhage

If grade 3 hemorrhage occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of withholding cobimetinib, permanently discontinue drug.

If grade 4 hemorrhage occurs, permanently discontinue drug.

Cardiomyopathy

If asymptomatic absolute decrease in left ventricular ejection fraction (LVEF) from baseline of >10% and to a level below lower limit of normal (LLN) occurs, interrupt cobimetinib therapy for 2 weeks and reassess LVEF. When LVEF recovers to at least the LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at a reduced dosage.

If symptomatic decrease in LVEF from baseline occurs, interrupt cobimetinib therapy for up to 4 weeks and reassess LVEF. When symptoms resolve, LVEF recovers to at least the LLN, and absolute decrease in LVEF from baseline is ≤10%, resume cobimetinib at a reduced dosage.

If LVEF remains below the LLN, absolute decrease in LVEF from baseline remains >10%, or symptoms persist, permanently discontinue drug.

If QT-interval prolongation occurs during combination therapy with cobimetinib and vemurafenib, dosage modification for vemurafenib may be required. Dosage adjustment for cobimetinib not necessary.

Dermatologic Reactions

If intolerable grade 2 dermatologic reactions or grade 3 or 4 dermatologic reactions occur, interrupt cobimetinib therapy or reduce dosage.

Serous Retinopathy or Retinal Vein Occlusion

If serous retinopathy occurs, interrupt cobimetinib therapy for up to 4 weeks until visual manifestations improve, and then resume at a reduced dosage. If toxicity does not improve or if symptoms recur within 4 weeks of resuming therapy at a reduced dosage, permanently discontinue drug.

If retinal vein occlusion occurs, permanently discontinue drug.

Liver Laboratory Abnormalities and Hepatotoxicity

For first occurrence of grade 4 liver function test abnormalities, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If liver function test abnormalities do not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

If grade 4 liver function test abnormalities recur, permanently discontinue drug.

Rhabdomyolysis and CPK Elevations

In patients with grade 4 elevations in CPK concentration or any grade of CPK elevation with concomitant myalgia, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 3 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

Photosensitivity

If intolerable grade 2 photosensitivity or grade 3 or 4 photosensitivity occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

Development of New Primary Malignancies

No dosage adjustment necessary.

Other Toxicity

If intolerable grade 2 or any grade 3 adverse reaction occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

For first occurrence of any grade 4 adverse reaction, permanently discontinue drug or interrupt cobimetinib therapy until toxicity improves to grade 1 or less and then resume at a reduced dosage. If grade 4 adverse reaction recurs, permanently discontinue drug.

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Avoid concomitant use with potent or moderate inhibitors of CYP3A; if concomitant short-term (14 days or less) use of a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily. When concomitant use of the moderate CYP3A inhibitor is discontinued, resume the prior cobimetinib dosage of 60 mg once daily. In patients receiving a reduced dosage of cobimetinib (40 or 20 mg once daily), select an alternative drug with no or only mild CYP3A inhibitory activity.

Special Populations

Hepatic Impairment

Mild, moderate, or severe preexisting hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required.

Renal Impairment

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: No dosage adjustment required.

Severe renal impairment: Appropriate dosage not established.

Geriatric Patients

No specific dosage recommendations.

Cautions for Cobimetinib

Contraindications

None.

Warnings/Precautions

Severe Photosensitivity

Photosensitivity reactions, sometimes severe, reported.

Avoid exposure to sunlight during cobimetinib therapy. If photosensitivity reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Combination Therapy

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

New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and new primary melanoma reported in patients receiving cobimetinib with vemurafenib.

Perform dermatologic evaluation at baseline and every 2 months during therapy; continue monitoring for 6 months following discontinuance of cobimetinib when used in combination with vemurafenib. Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.

Monitor for new noncutaneous malignancies when cobimetinib is used in combination with vemurafenib.

Hemorrhage

Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), reported.

If hemorrhagic events occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Cardiomyopathy

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF), sometimes requiring temporary interruption, dosage modification, or permanent discontinuance of therapy, reported.

Safety not established in patients with baseline LVEF below the LLN or <50%.

Assess LVEF prior to and 1 month after initiation of therapy, then every 3 months during therapy. If left ventricular dysfunction occurs, interrupt therapy, reduce dosage, or permanently discontinue drug. Reassess LVEF approximately 2, 4, 10, and 16 weeks following reinitiation of the drug and then as clinically indicated.

Severe Dermatologic Reactions

Severe dermatologic reactions (e.g., severe rash), sometimes requiring hospitalization, reported.

If dermatologic reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Serous Retinopathy and Retinal Vein Occlusion

Ocular toxicities (e.g., serous retinopathy, retinal vein occlusion) reported.

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during therapy. If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Hepatotoxicity

Liver function test abnormalities reported.

Perform liver function tests prior to initiation of therapy and then monthly, or more frequently as clinically indicated. If liver function test abnormalities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Rhabdomyolysis

Rhabdomyolysis (grade 3 or 4 elevations of serum CPK, including asymptomatic elevations over baseline) reported.

Evaluate serum CPK and S_cr concentrations at baseline, periodically during therapy, and as clinically indicated. If elevated CPK concentrations occur, evaluate for manifestations of rhabdomyolysis and for other potential causes. If increased CPK concentrations occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryotoxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during cobimetinib therapy and for ≥2 weeks after drug discontinuance. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether cobimetinib is distributed into human milk. Discontinue nursing during therapy and for 2 weeks after drug discontinuance.

Females and Males of Reproductive Potential

May impair female and male fertility.

Avoid pregnancy during cobimetinib therapy and for ≥2 weeks after drug discontinuation. Advise women of childbearing potential to use an effective method of contraception during cobimetinib therapy and for ≥2 weeks after discontinuation.

Pediatric Use

Safety and efficacy not established.

Cobimetinib exposure at the maximally tolerated dosage in pediatric patients was lower than observed in adult patients receiving recommended dosage.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Hepatic impairment does not substantially affect systemic exposure of cobimetinib; dosage adjustment not necessary in such patients.

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment; however, cobimetinib undergoes minimal renal elimination.

In a population pharmacokinetic analysis, systemic exposure not altered by mild or moderate renal impairment; dosage adjustment not necessary in such patients.

Not studied in patients with severe renal impairment.

Common Adverse Effects

Adverse effects (≥20%) receiving cobimetinib in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation include diarrhea, photosensitivity reaction, nausea, pyrexia, vomiting.

Laboratory abnormalities of grade 3 or 4 severity (≥5%) receiving cobimetinib in combination with vemurafenib include elevated concentrations of CPK, elevated concentrations of aminotransferases (i.e., AST, ALT), lymphopenia, elevated concentrations of alkaline phosphatase, hypophosphatemia, elevated concentrations of GGT, hyponatremia.

Adverse effects (≥20%) receiving cobimetinib monotherapy for histiocytic neoplasms include acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritis, dyspepsia, vomiting, dyspnea, urinary tract infections.

Laboratory abnormalities of grade 3 or 4 severity (≥5%) receiving cobimetinib monotherapy for histiocytic neoplasms include hyponatremia, elevated concentrations of CPK, hypokalemia, increased S_cr, elevated concentrations of AST, hypocalcemia, lymphopenia, leukopenia, anemia.

Drug Interactions

Principally metabolized by CYP3A and UGT2B7.

Substrate of CYP3A. May inhibit CYP isoenzymes 3A and 2D6. At clinically relevant concentrations, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2C19 or induce CYP isoenzymes 1A2, 2B6, and 3A4.

Substrate of P-glycoprotein (P-gp). Does not inhibit P-gp at clinically relevant concentrations.

In vitro, neither a substrate nor inhibitor of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3 at clinically relevant concentrations.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure of cobimetinib. Avoid concomitant use.

Moderate CYP3A inhibitors: Possible increased systemic exposure of cobimetinib. Simulations suggest that administration of cobimetinib 20 mg once daily with a moderate CYP3A inhibitor for <14 days results in steady-state concentrations similar to those achieved with cobimetinib 60 mg once daily alone. Avoid concomitant use. If concomitant short-term therapy (≤14 days) with a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily; when the moderate CYP3A inhibitor is discontinued, resume prior cobimetinib dosage of 60 mg once daily. In patients receiving a reduced cobimetinib dosage (40 or 20 mg once daily), select alternative drug with no or mild CYP3A inhibitory activity.

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib. Simulations suggest that concomitant use of a potent or moderate CYP3A inducer may decrease cobimetinib exposure by 83 or 73%, respectively. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction not observed to date.

Substrates of CYP3A: Pharmacokinetic interaction not observed to date.

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Possible increased concentrations of cobimetinib.

Specific Drugs and Foods

Drug	Interaction	Comments
Anticonvulsants (e.g., carbamazepine, phenytoin)	Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib	Moderate or potent CYP3A inducers: Avoid concomitant use
Antifungals, azoles (e.g., itraconazole)	Moderate or potent CYP3A inhibitors: Possible increased cobimetinib exposure Itraconazole: Increased cobimetinib AUC (by 6.7-fold) and peak concentrations (by 3.2-fold)	Moderate or potent CYP3A inhibitors: Avoid concomitant use If short-term (≤14 days) use of an antifungal with moderate CYP3A inhibitory activity cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when the antifungal is discontinued; select alternative antifungal with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Antimycobacterials, rifamycins (e.g., rifampin)	Possible decreased systemic exposure and reduced efficacy of cobimetinib	Avoid concomitant use
Ciprofloxacin	Possible increased cobimetinib exposure	Avoid concomitant use If short-term (≤14 days) ciprofloxacin use cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when ciprofloxacin is discontinued; select alternative anti-infective with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Dextromethorphan	No change in systemic exposure of single-dose dextromethorphan
Macrolides (erythromycin)	Possible increased cobimetinib exposure	Avoid concomitant use If short-term (≤14 days) erythromycin use cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when erythromycin is discontinued; select alternative anti-infective with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Midazolam	No change in systemic exposure of single-dose midazolam
Rabeprazole	No substantial effect on cobimetinib exposure
St. John’s wort (Hypericum perforatum)	Possible decreased systemic exposure and reduced efficacy of cobimetinib	Avoid concomitant use
Vemurafenib	No clinically important pharmacokinetic interaction

Cobimetinib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 46%.

Following oral administration, peak plasma concentrations are attained in 2.4 hours.

Mean systemic accumulation ratio is 2.4-fold when administered daily.

Steady-state concentrations are achieved in approximately 9 days.

Food

High-fat meal does not affect exposure.

Special Populations

In patients with mild or moderate hepatic impairment, systemic exposure similar to that in individuals with normal hepatic function; systemic exposure 31% lower in individuals with severe hepatic impairment.

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function. Pharmacokinetics not studied in patients with severe renal impairment.

Age (19–88 years), gender, and ethnicity do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether cobimetinib is distributed into human milk.

Plasma Protein Binding

95%.

Elimination

Metabolism

Metabolized mainly by CYP3A and UGT2B7.

Elimination Route

Eliminated mainly in feces (76%) and to a lesser extent in urine (17.8%), mainly as metabolites.

Half-life

44 hours.

Stability

Storage

Oral

Tablets

Room temperature <30°C.

Actions

Potent, selective, reversible inhibitor of MEK 1 and 2 activation.
MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.
Approximately 40–60% of cutaneous melanomas carry a BRAF mutation. Most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E); mutation involving substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.
BRAF V600 mutations result in activation of BRAF pathway that includes MEK 1 and 2.
Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).
Combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.
Combination therapy with cobimetinib and vemurafenib resulted in increased apoptosis and reduced tumor growth of melanoma cell lines testing positive for BRAF V600E compared with either drug alone.
Prevents vemurafenib-mediated growth enhancement of wild-type BRAF tumor cell line in mice bearing tumor xenografts.

Advice to Patients

If a dose is missed or vomited, administer the next dose at the regularly scheduled time; do not take an additional dose to replace the missed or vomited dose.
Risk of new primary cutaneous malignancies. Contact a clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, mole that changes in size or color) occur.
Risk of hemorrhage. Contact a clinician promptly and seek immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., blood in stool or urine, unusual vaginal bleeding) occur.
Risk of cardiomyopathy. Importance of cardiac monitoring before and during cobimetinib therapy. Contact a clinician promptly if manifestations of left ventricular dysfunction (e.g., shortness of breath, persistent coughing or wheezing, fatigue, peripheral edema, tachycardia) occur.
Risk of serious adverse dermatologic effects. Contact a clinician promptly if a serious reaction (e.g., rash affecting a large area, blistering or peeling of skin) occurs.
Risk of serous retinopathy or retinal vein occlusion. Contact a clinician promptly if visual disturbances (i.e., blurred, distorted, partial, or halo vision) occur.
Risk of hepatotoxicity. Importance of liver function test monitoring before and during cobimetinib therapy. Immediately report any possible manifestations of hepatotoxicity (e.g., jaundice, dark or tea-colored urine, nausea, vomiting, fatigue, loss of appetite).
Risk of rhabdomyolysis. Importance of monitoring CK concentrations before and during cobimetinib therapy. Immediately report any possible manifestations of rhabdomyolysis (e.g., dark or red urine; muscle pain, spasms, or weakness).
Risk of photosensitivity reactions. Use a broad-spectrum sunscreen and lip balm (SPF ≥30), wear protective clothing, and avoid exposure to sunlight during therapy. Contact a clinician if skin becomes red, painful, itchy, warm to touch, irritated, or thick, dry, or wrinkled; if bumps or small papules develop; or if a rash from sunlight exposure occurs.
Risk of fetal harm. Advise women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥2 weeks after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Advise women to avoid breast-feeding while receiving cobimetinib and for 2 weeks after discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at https://www.ahfsdruginformation.com.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cobimetinib is obtained through specialty pharmacies. Contact manufacturer or consult the Cotellic product website[Web] for specific availability information.