Avoid concurrent use of cobimetinib and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s Wort

Hepatic impairment

Mild-to-severe (Child-Pugh A to C): No dosage adjustment necessary

Renal impairment

Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
Severe (CrCl <30 mL/min): Safety and efficacy not established

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 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 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