Dosing and uses of Cotellic (cobimetinib)
Adult dosage forms and strengths
tablet
- 20 mg
Melanoma
Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafeniB
60 mg PO qDay for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity
Vemurafenib: 960 mg PO BID on days 1-28 of an every 28-day cycle
Dosage modifications
New primary malignancies (cutaneous and noncutaneous): No dosage modification required
Coadministration with CYP3A inhibitors
- Do not take strong or moderate CYP3A inhibitors while taking cobimetinib
- If concurrent short-term (≤14 days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60 mg, reduce dose to 20 mg; after the moderate CYP3A inhibitor is discontinued, resume previous cobimetinib dose
- Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily)
Dose reductions
- First dose reduction: 40 mg PO qDay
- Second dose reduction: 20 mg PO qDay
- Subsequent modification: Permanently discontinue cobimetinib if unable to tolerate 20-mg dose
Hemorrhage
- Grade 3: Withhold cobimetinib for up to 4 wk; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
- Grade 4: Permanently discontinue
Cardiomyopathy
- Asymptomatic
- Definition: Absolute decrease in LVEF from baseline of >10% and less than institutional lower limit of normal (LLN) Withhold cobimetinib for 2 wk; repeat LVEF
- Resume at next lower dose if all of the following are present: LVEF is ≥LLN and absolute decrease from baseline LVEF is ≤10%
- Permanently discontinue if any of the following are present: LVEF is <LLN or absolute decrease from baseline LVEF is >10%
- Symptomatic LVEF decrease from baseline
- Withhold cobimetinib for 4 wk; repeat LVEF
- Resume at next lower dose if all of the following are present:
- Symptoms resolve and LVEF is ≥LLN and absolute decrease from baseline LVEF is ≤10%
- Permanently discontinue if any of the following are present:
- Symptoms persist, or LVEF is <LLN or absolute decrease from baseline LVEF is >10%
Dermatologic reactions
- Grade 2 (intolerable) or grades 3 or 4: Withhold or reduce dose
Retinopathy or retinal vein occlusion
- Serous retinopathy: Withhold for up to 4 wk; if signs and symptoms improve, resume at the next lower dose level; permanently discontinue if not improved or symptoms recur at the lower dose within 4 wk
- Retinal vein occlusion: Permanently discontinue
Hepatoxicity
- First occurrence grade 4: Withhold for up to 4 wk; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
- Recurrent grade 4: Permanently discontinue
Rhabdomyolysis and elevated CPK
- Grade 4 creatine phosphokinae (CPK) elevation or any CPK elevation plus myalgia: Withhold for up to 4 wk; if improved to ≤grade 3, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
Photosensitivity
- Grade 2 (intolerable), grades 3 or 4: Withhold for up to 4 wk; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
Other adverse events
- Grade 2 (intolerable) adverse reactions or any grade 3
- Withhold for up to 4 wk; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 wk
- First occurrence of any grade 4 adverse reaction
- Withhold until adverse reaction improves to grade 0 or 1 and then resume at the next lower dose level, OR
- Permanently discontinue
- Recurrent grade 4 adverse reaction
- Permanently discontinue
Dosage considerations
Limitations of use: Not indicated for wild-type BRAF melanoma
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation
Pediatric dosage forms and strengths
Safety and efficacy not established
Cotellic (cobimetinib) adverse (side) effects
Adverse reactions are listed for all grades, unless otherwise stated
Data listed below are based on combination of cobimetinib plus vemurafeniB
>10%
Increased creatinine (99.6%)
Increased CPK (79%)
Increased AST (73%)
Lymphopenia (73%)
Increased alkaline phosphatase (71%)
Anemia (69%)
Increased ALT (68%)
Hypophosphatemia (68%)
Increased GGT (65%)
Diarrhea (60%)
Photosensitivity (46%)
Hypoalbuminemia (42%)
Nausea (41%)
Hyponatremia (38%)
Pyrexia (28%)
Hyperkalemia (26%)
Hypokalemia (25%)
Hypocalcemia (24%)
Vomiting (24%)
Thrombocytopenia (18%)
Acneiform dermatitis (16%)
Hypertension (15%)
Vision impaired (15%)
Alopecia (15%)
Stomatitis (14%)
Hemorrhage (13%)
Chorioretinopathy (13%)
Retinal detachment (12%)
Hyperkeratosis (11%)
Grades 3-4
- Increased GGT (21%)
- Increased CPK (14%)
- Hypophosphatemia (12%)
- Increased ALT (11%)
1-10%
Chills (10%)
Erythema (10%)
Grades 3-4
- Lymphopenia (10%)
- Increased AST (8%)
- Increased alkaline phosphatase (7%)
- Hyponatremia (6%)
- Diarrhea (6%)
- Hypokalemia (4.5%), Hyperkalemia (2.9%)
- Photosensitivity (4%)
- Hypertension (4%)
- Increased creatinine (3.3%)
- Anemia (2.5)
- Acneiform dermatitis (2%)
- Pyrexia (2%)
- Retinal detachment (2%)
- Nausea (1%) Vomiting (1%)
- Stomatitis (1%) Hemorrhage (1%)
<1% Grades 3-4
Vision impaired
Chorioretinopathy
Hypoalbuminemia
Hypocalcemia
Warnings
Contraindications
None
Cautions
Refer to the Dosage modification section for instructions on withholding, decreasing, or permanently discontinuing cobimetinib in the event of adverse reactions
New primary malignancies can occur; monitor for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose (see Dosage modifications)
Major hemorrhagic events reported; monitor for signs and symptoms of bleeding (see Dosage modifications)
The risk of cardiomyopathy is increased in patients receiving cobimetinib with vemurafenib compared with vemurafenib as a single agent; safety has not been established in patients with decreased LVEF; evaluate LVEF before treatment, after 1 month of treatment, then q3 months thereafter during treatment (see Dosage modifications)
May cause severe dermatologic reactions; monitor for severe rashes (see Dosage modifications)
Serous retinopathy and retinal vein occlusion reported; perform an ophthalmological evaluation at regular intervals and for any visual disturbances (see Dosage modifications)
Hepatotoxicity reported; monitor liver laboratory tests during treatment and as clinically indicated (see Dosage modifications)
Monitor CPK periodically and as clinically indicated for signs and symptoms of rhabdomyolysis (see Dosage modifications)
Severe photosensitivity may occur; advise patients to avoid sun exposure (see Dosage modifications)
Avoid coadministration with moderate or strong CYP3A4 inhibitors or inducers; if unable to avoid short-term use of moderate CYP3A4 inhibitors, reduce cobimetinib dose (see Dosage modifications)
Can cause fetal harm; advise females of reproductive potential of the potential risk to a fetus and to use effective contraception
Pregnancy
Pregnancy
Based on findings from animal reproduction studies and its mechanism of action, cobimetinib can cause fetal harm when administered to a pregnant woman
In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9- to 1.4-times those observed in humans at the recommended human dose of 60 mg
Advise pregnant women of the potential risk to a fetus
Contraception: Advise females of reproductive potential to use effective contraception during treatment with and for 2 weeks after the final dose
Infertility: Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potentiaL
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in a breastfed infant, advise women not to breastfeed during treatment and for 2 weeks after the final dose
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Cotellic (cobimetinib)
Mechanism of action
Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2
MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation
BRAF V600E and K mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2
Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations
Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation modeL
Absorption
Bioavailability: 46%
Peak plasma time: 2.4 hr
Peak plasma concentration: 273 ng/mL
AUC: 4340 ng·h/mL
Distribution
Protein bound: 95%
Vd: 806 L
Metabolism
CYP3A oxidation and UGT2B7 glucuronidation are the major metabolic pathways for cobimetiniB
Elimination
Half-life: 44 hr
Clearance: 13.8 L/hr
Excretion: 76% feces (6.6% unchanged); 17.8% urine (1.6% unchanged)
Administration
Instructions
May take with or without food
Missed or vomited dose: Resume dosing with the next scheduled dose
Storage
Store at room temperature below 30°C (86°F)
