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Cotellic

Generic Name: Cobimetinib Fumarate
Class: Antineoplastic Agents
Chemical Name: (2E)-2-Butenedioate (2:1) [3,4 - difluoro - 2 - [(2 - fluoro - 4 - iodophenyl)amino]phenyl][3 - hydroxy - 3 - (2S) - 2 - piperidinyl - 1 - azetidinyl] - methanone
Molecular Formula: 2(C21H21F3IN3O2)•C4H4O4
CAS Number: 1369665-02-0

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.1 2 10 21

Uses for Cotellic

Melanoma

In combination with vemurafenib for treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation1 2 (designated an orphan drug by FDA for this use).3

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.1 2

Not indicated for use in patients with wild-type BRAF melanoma.1

Limited data suggest greater efficacy (longer progression-free and overall survival, higher objective response rates) in patients with BRAF inhibitor-naive disease versus those with disease progression during prior BRAF inhibitor therapy.22 23

Cotellic Dosage and Administration

General

  • Confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.1

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Dosage

Available as cobimetinib fumarate; dosage expressed in terms of cobimetinib.1

Adults

Melanoma
Oral

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

Avoid concomitant use with potent or moderate inhibitors of CYP3A; if concomitant short-term use of a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily.1 (See Interactions.)

Dosage Modification for Toxicity
Oral

Adjust dosage in decrements of 20 mg daily.1

Dosages <20 mg once daily not recommended; permanently discontinue drug if 20-mg daily dosage is not tolerated.1

Hemorrhage
Oral

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.1 If toxicity does not improve within 4 weeks of withholding cobimetinib, permanently discontinue drug.1

If grade 4 hemorrhage occurs, permanently discontinue drug.1

Cardiovascular Toxicity
Oral

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.1 When LVEF recovers to at least the LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at a reduced dosage.1 (See Cardiac Effects under Cautions.)

If symptomatic decrease in LVEF from baseline occurs, interrupt cobimetinib therapy for up to 4 weeks and reassess LVEF.1 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.1

If LVEF remains below the LLN, absolute decrease in LVEF from baseline remains >10%, or symptoms persist, permanently discontinue drug.1

If QT-interval prolongation occurs during combination therapy with cobimetinib and vemurafenib, dosage modification for vemurafenib may be required.1 22 Dosage adjustment for cobimetinib not necessary.22

Dermatologic Effects
Oral

If intolerable grade 2 dermatologic reactions or grade 3 or 4 dermatologic reactions occur, interrupt cobimetinib therapy or reduce dosage.1

Ocular Effects
Oral

If serous retinopathy occurs, interrupt cobimetinib therapy for up to 4 weeks until visual manifestations improve, and then resume at a reduced dosage.1 If toxicity does not improve or if symptoms recur within 4 weeks of resuming therapy at a reduced dosage, permanently discontinue drug.1

If retinal vein occlusion occurs, permanently discontinue drug.1

Hepatotoxicity
Oral

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.1 If liver function test abnormalities do not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1

If grade 4 liver function test abnormalities recur, permanently discontinue drug.1

Musculoskeletal Effects
Oral

In patients with grade 4 elevations in CK concentration or any grade of CK 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.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1

Photosensitivity Reactions
Oral

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.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1

Development of New Primary Malignancies
Oral

No dosage adjustment necessary.1

Other Toxicity
Oral

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.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1

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.1 If grade 4 adverse reaction recurs, permanently discontinue drug.1

Prescribing Limits

Adults

Melanoma
Oral

Dosages <20 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment (total bilirubin concentration at or below ULN with AST concentration exceeding ULN or total bilirubin concentration above ULN, but not >1.5 times the ULN, with any AST concentration): No dosage adjustment required.1 (See Hepatic Impairment under Cautions.)

Moderate or severe preexisting hepatic impairment: Not studied.1

Renal Impairment

Mild (Clcr 60–89 mL/minute) or moderate (Clcr 30–59 mL/minute) renal impairment: No dosage adjustment required.1

Severe renal impairment: Appropriate dosage not established.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Cotellic

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Photosensitivity Reactions

Photosensitivity reactions, sometimes severe, reported.1 2

Avoid exposure to sunlight during cobimetinib therapy.1 (See Advice to Patients.) If photosensitivity reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Combination Therapy

When used in combination with vemurafenib, consider cautions, precautions, and contraindications of vemurafenib.1

Development of New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and new primary melanoma reported.1 2 Median time to detection of cutaneous squamous cell carcinoma, keratoacanthoma, or basal cell carcinoma was 4 months after initiating combination therapy with cobimetinib and vemurafenib in the coBRIM study in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation.1 New primary melanoma reported in 2 patients at 9 and 12 months after initiation of combination therapy with cobimetinib and vemurafenib.1

Noncutaneous malignancies reported in 0.8% of patients receiving cobimetinib in combination with vemurafenib compared with 1.2% of those receiving vemurafenib alone.1

Perform dermatologic evaluation at baseline and every 2 months during therapy; continue monitoring for 6 months following discontinuance of cobimetinib and vemurafenib.1 Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.1

Monitor for new noncutaneous malignancies.1

Hemorrhage

Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), reported.1 Increased incidence of GI hemorrhage, reproductive system hemorrhage, or hematuria observed during combination therapy with cobimetinib and vemurafenib compared with vemurafenib alone.1 Cerebral hemorrhage reported in 2 patients receiving combination therapy compared with none of those receiving vemurafenib alone.1

If hemorrhagic events occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Cardiac Effects

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF), sometimes requiring temporary interruption, dosage modification, or permanent discontinuance of therapy, reported.1 2 Median time to first onset of left ventricular dysfunction was 4 months in the coBRIM study.1 Left ventricular dysfunction resolved (i.e., LVEF exceeded LLN or was within 10% of baseline) in most patients; median time to resolution was 3 months.1

Safety not established in patients with baseline LVEF below the LLN or <50%.1

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

Dermatologic Effects

Severe dermatologic reactions, sometimes requiring hospitalization, reported.1 Median time to onset of grade 3 or 4 rash in patients receiving combination therapy with cobimetinib and vemurafenib was 11 days in the coBRIM study.1 Grade 3 or 4 rash resolved completely in most patients; median time to resolution was 21 days.1

If dermatologic reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Ocular Effects

Ocular toxicities (e.g., serous retinopathy, retinal vein occlusion) reported.1 2 Serous retinopathy usually occurred 2 days to 9 months following initiation of therapy.1 Duration ranged from 1 day to 15 months.1

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during therapy.1 If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Hepatic Toxicity

Liver function test abnormalities reported.1 2

Perform liver function tests prior to initiation of therapy and then monthly, or more frequently as clinically indicated.1 If liver function test abnormalities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Musculoskeletal Effects

Rhabdomyolysis reported.22 Median time to first occurrence of grade 3 or 4 CK elevations was 16 days in patients receiving combination therapy with cobimetinib and vemurafenib in the coBRIM study; median time to complete resolution was 15 days.1

Evaluate serum CK and Scr concentrations at baseline, periodically during therapy, and as clinically indicated.1 If elevated CK concentrations occur, evaluate for manifestations of rhabdomyolysis and for other potential causes.1 If increased CK concentrations occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxicity and teratogenicity demonstrated in animals.1

Pregnancy should be avoided during cobimetinib therapy and for ≥2 weeks after drug discontinuance.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Impairment of Fertility

May impair female and male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether cobimetinib is distributed into milk.1 Discontinue nursing during therapy and for 2 weeks after drug discontinuance.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Pharmacokinetic profile not established in patients with moderate to severe hepatic impairment.1 Exposure may be increased, since cobimetinib is principally metabolized by the liver.1

In a population pharmacokinetic analysis, systemic exposure not altered by mild hepatic impairment; dosage adjustment not necessary in such patients.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment.1

In a population pharmacokinetic analysis, systemic exposure not altered by mild or moderate renal impairment; dosage adjustment not necessary in such patients.1 21 (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment.1

Common Adverse Effects

Diarrhea,1 2 photosensitivity reaction,1 2 nausea,1 2 pyrexia,1 2 vomiting,1 2 acneiform rash,1 hypertension,1 vision impairment,1 stomatitis,1 chorioretinopathy,1 2 hemorrhage,1 retinal detachment,1 chills,1 arthralgia,2 elevated Scr concentrations,1 elevated CK concentrations,1 2 elevated AST or ALT concentrations,1 2 lymphopenia,1 elevated alkaline phosphatase concentrations,1 anemia,1 hypophosphatemia,1 elevated γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations,1 hypoalbuminemia,1 hyponatremia,1 hyperkalemia,1 hypokalemia,1 hypocalcemia,1 thrombocytopenia.1

Interactions for Cotellic

Principally metabolized by CYP3A and UGT2B7.1

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

Substrate of P-glycoprotein (P-gp).1 Does not inhibit P-gp at clinically relevant concentrations.1

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

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure of cobimetinib.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Moderate CYP3A inhibitors: Possible increased systemic exposure of cobimetinib.1 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.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.) 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.1 In patients receiving a reduced cobimetinib dosage (40 or 20 mg once daily), select alternative drug with no or mild CYP3A inhibitory activity.1

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib.1 22 Simulations suggest that concomitant use of a potent or moderate CYP3A inducer may decrease cobimetinib exposure by 83 or 73%, respectively.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction not observed to date.1

Substrates of CYP3A: Pharmacokinetic interaction not observed to date.1

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Possible increased concentrations of cobimetinib.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiodarone

Possible increased cobimetinib exposure1 22

Avoid concomitant use1

Anticonvulsants (e.g., carbamazepine, phenytoin)

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib1

Moderate or potent CYP3A inducers: Avoid concomitant use1

Antifungals, azoles (e.g., fluconazole, itraconazole, posaconazole, voriconazole)

Moderate or potent CYP3A inhibitors: Possible increased cobimetinib exposure1 22

Itraconazole: Increased cobimetinib AUC (by 6.7-fold) and peak concentrations (by 3.2-fold)1

Moderate or potent CYP3A inhibitors: Avoid concomitant use1

If short-term (≤14 days) use of an antifungal with moderate CYP3A inhibitory activity (e.g., fluconazole) 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)1

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased systemic exposure and reduced efficacy of cobimetinib1

Avoid concomitant use1

Antiretroviral agents, HIV protease inhibitors (e.g., fosamprenavir, lopinavir, ritonavir)

Moderate or potent CYP3A inhibitors: Possible increased cobimetinib exposure1 22

Moderate or potent CYP3A inhibitors: Avoid concomitant use1

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz)

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib1

Moderate or potent CYP3A inducers: Avoid concomitant use1

Calcium-channel blocking agents, nondihydropyridine (diltiazem, verapamil)

Diltiazem, verapamil: Possible increased cobimetinib exposure1 22

Diltiazem, verapamil: Avoid concomitant use1

Ciprofloxacin

Possible increased cobimetinib exposure1 22

Avoid concomitant use1

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)1

Cobicistat

Possible increased cobimetinib exposure1 22

Avoid concomitant use1

Dextromethorphan

No change in systemic exposure of single-dose dextromethorphan1

Grapefruit or grapefruit juice

Possible increased cobimetinib exposure1 22

Avoid concomitant use1 22

Imatinib

Possible increased cobimetinib exposure1 22

Avoid concomitant use1

Macrolides (clarithromycin, erythromycin, telithromycin)

Clarithromycin, erythromycin, telithromycin: Possible increased cobimetinib exposure1 22

Clarithromycin, erythromycin, telithromycin: Avoid concomitant use1

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)1

Midazolam

No change in systemic exposure of single-dose midazolam1

Nefazodone

Possible increased cobimetinib exposure1 22

Avoid concomitant use1

Rabeprazole

No substantial effect on cobimetinib exposure1

St. John’s wort (Hypericum perforatum)

Possible decreased systemic exposure and reduced efficacy of cobimetinib1

Avoid concomitant use1

Vemurafenib

No substantial effect on pharmacokinetics of either drug1 19 21

Cotellic Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 46%.1

Following oral administration, peak plasma concentrations are attained in 2.4 hours.1

Mean systemic accumulation ratio is 2.4-fold when administered daily.1

Steady-state concentrations are achieved in approximately 9 days.1

Food

High-fat meal does not affect exposure.1

Special Populations

In patients with mild hepatic impairment, systemic exposure similar to that in patients with normal hepatic function.1 Pharmacokinetics not studied in patients with moderate or severe hepatic impairment.1

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function.1 Pharmacokinetics not studied in patients with severe renal impairment.1

Age (19–88 years), gender, and ethnicity do not substantially affect pharmacokinetics.1 21

Distribution

Extent

Not known whether cobimetinib is distributed into milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

95%.1

Elimination

Metabolism

Metabolized mainly by CYP3A and UGT2B7.1

Elimination Route

Eliminated mainly in feces (76%) and to a lesser extent in urine (17.8%), mainly as metabolites.1 22

Half-life

44 hours.1

Stability

Storage

Oral

Tablets

Room temperature <30°C.1

Actions

  • Potent, selective, reversible inhibitor of MEK 1 and 2 activation.1 2 10 21

  • MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1

  • Approximately 40–60% of cutaneous melanomas carry a BRAF mutation.4 5 8 10 11 Most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E);4 6 8 9 10 11 mutation involving substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.8 9 10 11

  • BRAF V600 mutations result in activation of BRAF pathway that includes MEK 1 and 2.1

  • 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).6 7 8 9 10

  • Combination therapy with a BRAF inhibitor (i.e., dabrafenib, vemurafenib) and an MEK inhibitor (i.e., cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.1 2 14 20

  • 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.1

  • Prevents vemurafenib-mediated growth enhancement of wild-type BRAF tumor cell line in mice bearing tumor xenografts.1

Advice to Patients

  • If a dose is missed or vomited, importance of taking the next dose at the regularly scheduled time; do not take an additional dose to replace the missed or vomited dose.1

  • Risk of new primary cutaneous malignancies.1 Importance of contacting 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.1

  • Risk of hemorrhage.1 Importance of contacting a clinician promptly and seeking immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., blood in stool or urine, unusual vaginal bleeding) occur.1

  • Risk of cardiomyopathy.1 Importance of cardiac monitoring before and during cobimetinib therapy.1 Importance of contacting a clinician promptly if manifestations of left ventricular dysfunction (e.g., shortness of breath, persistent coughing or wheezing, fatigue, peripheral edema, tachycardia) occur.1

  • Risk of serious adverse dermatologic effects.1 Importance of contacting a clinician promptly if a serious reaction (e.g., rash affecting a large area, blistering or peeling of skin) occurs.1

  • Risk of serous retinopathy or retinal vein occlusion.1 Importance of contacting a clinician promptly if visual disturbances (i.e., blurred, distorted, partial, or halo vision) occur.1

  • Risk of hepatotoxicity.1 Importance of liver function test monitoring before and during cobimetinib therapy.1 Importance of immediately reporting any possible manifestations of hepatotoxicity (e.g., jaundice, dark or tea-colored urine, nausea, vomiting, fatigue, loss of appetite).1

  • Risk of rhabdomyolysis.1 Importance of monitoring CK concentrations before and during cobimetinib therapy.1 Importance of immediately reporting any possible manifestations of rhabdomyolysis (e.g., dark or red urine; muscle pain, spasms, or weakness).1

  • Risk of photosensitivity reactions.1 Importance of using a broad-spectrum sunscreen and lip balm (SPF ≥30), wearing protective clothing, and avoiding exposure to sunlight during therapy.1 Importance of contacting a clinician if skin becomes red, painful, itchy, or warm; irritated; or thick, dry, or wrinkled; if bumps or small papules develop; or if a rash from sunlight exposure occurs.1

  • Risk of fetal harm.1 Necessity of advising 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.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding during and for 2 weeks after discontinuance of therapy.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

20 mg (of cobimetinib)

Cotellic

Genentech

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Genentech. Cotellic (cobimetinib) tablets prescribing information. South San Francisco, CA; 2015 Nov.

2. Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371:1867-76. [PubMed 25265494]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Feb 11.

4. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364:2507-16. [PubMed 21639808]

5. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363:809-19. [PubMed 20818844]

6. Russo AE, Torrisi E, Bevelacqua Y et al. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol. 2009; 34:1481-9. [PubMed 19424565]

7. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med. 2011; 364:2547-8. [PubMed 21639809]

8. Liu Y, Sheikh MS. Melanoma: Molecular Pathogenesis and Therapeutic Management. Mol Cell Pharmacol. 2014; 6:228. [PubMed 25745537]

9. Ascierto PA, Kirkwood JM, Grob JJ et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012; 10:85. [PubMed 22554099]

10. Richman J, Martin-Liberal J, Diem S et al. BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert Opin Pharmacother. 2015; 16:1285-97. [PubMed 26001180]

11. Rauschenberg R, Garzarolli M, Dietrich U et al. Systemic therapy of metastatic melanoma. J Dtsch Dermatol Ges. 2015; 13:1223-37. [PubMed 26612791]

12. Genentech Inc. Zelboraf(vemurafenib) tablets prescribing information. South San Francisco, CA; 2015 Aug.

13. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366:707-14. [PubMed 22356324]

14. Sanlorenzo M, Choudhry A, Vujic I et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014; 71:1102-1109.e1. [PubMed 25440439]

15. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 2012; 18:263-72. [PubMed 22096025]

16. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464:427-30. [PubMed 20179705]

17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366:207-15. [PubMed 22256804]

18. Weeraratna AT. RAF around the edges--the paradox of BRAF inhibitors. N Engl J Med. 2012; 366:271-3. [PubMed 22256810]

19. Ribas A, Gonzalez R, Pavlick A et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014; 15:954-65. [PubMed 25037139]

20. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367:1694-703. [PubMed 23020132]

21. Han K, Jin JY, Marchand M et al. Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol. 2015; 76:917-24. [PubMed 26365290]

22. Roche Pharma AG. Cotellic (cobimetinib) tablets summary of product characteristics. Welwyn Garden City, United Kingdom. (undated)

23. Pavlick AC, Ribas A, Gonzalez R et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol. 2015; 33 (American Society of Clinical Oncology Annual Meeting Abstracts): Abstract No. 9020

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