Version May 2024
Histiocytic neoplasms: Oral: 60 mg once daily on days 1 to 21 of each 28-day treatment cycle (as a single agent) until disease progression or unacceptable toxicity.
Melanoma, unresectable or metastatic (with BRAF V600E or V600K mutations): Oral: 60 mg once daily on days 1 to 21 of each 28-day treatment cycle (in combination with vemurafenib) until disease progression or unacceptable toxicity (Larkin 2014).
Off-label combination: Oral: 60 mg once daily on days 1 to 21 of each 28-day treatment cycle (in combination with atezolizumab and vemurafenib) until disease progression or unacceptable toxicity; prior to initiating atezolizumab, patients should receive a 28-day treatment cycle of cobimetinib and vemurafenib (Gutzmer 2020). Refer to protocol for further information.
Missed doses: 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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 established).
Hepatic impairment prior to treatment: Mild, moderate, or severe impairment (Child Pugh class A, B, or C): No initial dosage adjustment is necessary.
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 cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved to grade 0 or 1 within 4 weeks.
Recurrent grade 4 lab abnormality or hepatotoxicity: Permanently discontinue cobimetinib.
|
Initial (usual) dose |
60 mg once daily |
|
First dose reduction |
40 mg once daily |
|
Second dose reduction |
20 mg once daily |
|
If unable to tolerate 20 mg once daily |
Permanently discontinue cobimetinib. |
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Note: If using in combination, vemurafenib may also require dosage adjustment. | |
|
Target organ |
Adverse reaction |
Dosage modification |
|---|---|---|
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a LVEF = left ventricular ejection fraction. | ||
|
Cardiotoxicity |
Asymptomatic, absolute decrease in LVEF >10% (from baseline) and less than the institutional LLN |
Withhold cobimetinib for 2 weeks and repeat LVEF. If LVEF ≥ LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if LVEF < LLN or absolute decrease from baseline is >10%. |
|
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 cobimetinib at the next lower dose level. Permanently discontinue cobimetinib 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 cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks. |
|
Dermatologic toxicity |
Grade 2 (intolerable) or grade 3 or 4 |
Withhold or reduce cobimetinib dose. |
|
New primary cutaneous or noncutaneous malignancy |
No cobimetinib dosage modification is necessary. | |
|
Suspicious lesions |
Manage with excision and dermatopathologic evaluation. | |
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Hemorrhage |
Grade 3 |
Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks. |
|
Grade 4 |
Permanently discontinue cobimetinib. | |
|
Ocular |
Serous retinopathy |
Withhold cobimetinib for up to 4 weeks; if signs/symptoms improve, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved or if symptoms recur within 4 weeks at the lower dose. |
|
Retinal vein occlusion |
Permanently discontinue cobimetinib. | |
|
Photosensitivity |
Grade 2 (intolerable), grade 3 or 4 |
Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib 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 cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks. |
|
Grade 4, first occurrence |
Withhold cobimetinib until adverse reaction improves to grade 0 or 1 and then resume cobimetinib at the next lower dose level or permanently discontinue. | |
|
Grade 4, recurrent |
Permanently discontinue cobimetinib. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Percentages reported as part of combination chemotherapy regimens in adults.
>10%:
Cardiovascular: Decreased left ventricular ejection fraction (grades 2/3: 26%), hypertension (15%)
Dermatologic: Acneiform eruption (16%), skin photosensitivity (46%), skin rash (grades 3/4: 2% to 16%)
Endocrine & metabolic: Hyperkalemia (26%), hypoalbuminemia (42%), hypocalcemia (24%), hypokalemia (25%), hyponatremia (38%), hypophosphatemia (68%)
Gastrointestinal: Diarrhea (60%; grades 3/4: 6%), nausea (41%; grades 3/4: 1%), stomatitis (14%; grades 3/4: 1%), vomiting (24%; grades 3/4: 1%)
Hematologic & oncologic: Anemia (69%; grades 3/4: 3%), hemorrhage (13%; grades 3/4: 1%), lymphocytopenia (73%; grades 3/4: 10%), thrombocytopenia (18%)
Hepatic: Increased gamma-glutamyl transferase (65%), increased serum alanine aminotransferase (68%), increased serum alkaline phosphatase (71%), increased serum aspartate aminotransferase (73%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (79%)
Ophthalmic: Retinopathy (serious: 26%; including chorioretinopathy [13%] and retinal detachment [12%]), visual impairment (15%)
Renal: Increased serum creatinine (100%)
Miscellaneous: Fever (28%)
1% to 10%:
Dermatologic: Basal cell carcinoma (5%), squamous cell carcinoma of skin (≤6%)
Gastrointestinal: Gastrointestinal hemorrhage (4%)
Genitourinary: Genitourinary tract hemorrhage (2%), hematuria (2%)
Hematologic & oncologic: Keratoacanthoma (≤6%)
Hepatic: Abnormal bilirubin levels (grades 3/4: 2%)
Nervous system: Chills (10%)
Respiratory: Pneumonitis (<10%)
<1%:
Hematologic & oncologic: Malignant melanoma (second primary), malignant neoplasm (noncutaneous)
Nervous system: Cerebral hemorrhage
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known hypersensitivity to cobimetinib or any component of the formulation.
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%. The median time to first onset of LVEF decline was 29 days to 4 months (range: 22 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 ~1 to 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). 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) when outdoors.
• Hemorrhage: Hemorrhage, including major symptomatic bleeding in a critical area/organ, may occur with cobimetinib. Grade 3 to 4 bleeding has occurred. Cerebral hemorrhage, GI bleeding, reproductive system hemorrhage, and hematuria have been reported.
• Hepatotoxicity: Hepatotoxicity (including grades 3 or 4 transaminase, total bilirubin, or alkaline phosphatase elevations) may occur with cobimetinib.
• Hypertension: Hypertension has been observed with cobimetinib in combination with vemurafenib, including grades 3 or 4 hypertension.
• 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). The time to onset of second primary melanoma (rare) was 9 to 12 months. Vemurafenib may be associated with the development of noncutaneous malignancy.
• 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). The time to first onset of serous retinopathy ranged between 2 days to 9 months with a duration of 1 day to 15 months.
• 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). If CPK is elevated, evaluate for signs/symptoms of rhabdomyolysis or other etiology.
Other warnings/precautions:
• Appropriate use: Prior to initiating therapy when used in combination with vemurafenib in patients with unresectable or metastatic melanoma, 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Cotellic: 20 mg
No
Tablets (Cotellic Oral)
20 mg (per each): $150.80
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Cotellic: 20 mg
Available through specialty pharmacies. Further information may be obtained from the manufacturer, Genentech, at 1-888-249-4918, or at http://www.cotellic.com.
Oral: May be administered with or without food. In a clinical trial, cobimetinib tablets were administered whole with water; tablets should not be chewed, cut, or crushed (Larkin 2013 [Protocol GO28141]).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Cobimetinib may cause teratogenicity, reproductive toxicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Histiocytic neoplasms: Treatment of histiocytic neoplasms in adults.
Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in adults with a BRAF V600E or V600K mutation (in combination with vemurafenib).
Cobimetinib may be confused with binimetinib, cabozantinib, capmatinib, ceritinib, crizotinib, dabrafenib, encorafenib, selumetinib, trametinib, vemurafenib.
Cotellic may be confused with cobicistat.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Cobimetinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Cobimetinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Cobimetinib. Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cobimetinib. Risk X: Avoid combination
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Levoketoconazole: Cobimetinib may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Grapefruit juice may increase cobimetinib serum concentrations. Management: Avoid grapefruit juice.
Patients who could become pregnant should use effective contraception during therapy and for 2 weeks after the final cobimetinib dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to cobimetinib would be expected to cause fetal harm.
It is not known if cobimetinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 2 weeks after the last cobimetinib dose.
Avoid grapefruit juice.
BRAF V600K or V600E mutation status (prior to treatment when used in combination with vemurafenib in unresectable or metastatic melanoma); LFTs (baseline and monthly during treatment, more frequently if clinically indicated); creatine phosphokinase (CPK) and serum creatinine (baseline and periodically during treatment, more frequently if clinically indicated); electrolytes (prior to and routinely during treatment). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multiple-gated acquisition (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. Monitor ECG prior to and routinely during treatment.
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. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring specifics: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Assess BP at baseline and each clinical visit (as well as outpatient monitoring weekly for initial 3 months, then monthly thereafter). In patients receiving cobimetinib plus vemurafenib assess ECG at baseline, at 2 and 4 weeks, then every 3 months thereafter; obtain a baseline echocardiography in high- and very-high risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (consider repeating every 4 months during the first year); consider echocardiography in low- and moderate-risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (ESC [Lyon 2022]).
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.
Protein binding: 95%; to plasma proteins.
Metabolism: Hepatic; via CYP3A4 oxidation and UGT2B7 glucuronidation.
Bioavailability, absolute: 46%.
Half-life elimination, mean: 44 hours (range: 23 to 70 hours).
Time to peak, median: 2.4 hours (range: 1 to 24 hours).
Excretion: Feces (76%; ~7 as unchanged drug); Urine (~18%; ~2% as unchanged drug).
Clearance: 13.8 L/hour.
Hepatic function impairment: Exposure was decreased by 31% in patients with severe hepatic impairment compared to patients with normal hepatic function.
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