Indication and Dosing
Indication1
COTELLIC® (cobimetinib) is indicated for use in combination with ZELBORAF® (vemurafenib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation
Patient selection1
Confirm that patients have a BRAFV600 mutation-positive tumour with a validated test prior to initiation of treatment with COTELLIC® + ZELBORAF®
Recommended dosage1,2
COTELLIC® is taken for the first 21 days of each 28-day cycle
- The recommended dose of COTELLIC® is 60 mg (three 20-mg tablets) taken orally once daily
ZELBORAF® is taken every day of each 28-day cycle
- The recommended dose of ZELBORAF® is 960 mg (four 240-mg tablets) taken orally every 12 hours

Continue treatment until the patient no longer derives benefit or until the development of unacceptable toxicity.1,2
Administration guidance
If a dose is missed1,2
- If a dose of COTELLIC® is missed, it can be taken up to 12 hours prior to the next dose
- A missed dose of ZELBORAF® can be taken up to 4 hours prior to the next dose. Both doses should not be taken at the same time
If vomiting occurs1,2
- If vomiting occurs when the COTELLIC® dose is taken, patients should not take another dose on that day and should continue treatment on the next day
- Do not take an additional dose if vomiting occurs after ZELBORAF® administration, but continue with the next scheduled dose as usual
Administration and handling1,2
Dose modification
Recommended dosage1,2
Flexible dose titration, if necessary
- Healthcare professionals may dose reduce, if needed, by advising patients to take fewer pills
COTELLIC® |
ZELBORAF® |
||
Grade of adverse eventa | Grade of adverse eventa |
||
Grade 1 or grade 2 (torelable) | No dose reduction. Maintain COTELLIC® at a dose of 60 mg once daily (3 tablets) |
Grade 1 or 2 (tolerable) | Maintain ZELBORAF® at a dose of 960 mg twice daily |
Grade 2 (intolerable) or Grade 3/4 | Grade 2 (intolerable) or Grade 3 | ||
1st Appearance | Interrupt treatment until Grade ≤1, restart treatment at 40 mg once daily | 1st Appearance | Interrupt treatment until Grade ≤1, restart treatment at 720 mg twice daily or at 480 mg twice daily if the dose had already been lowered |
2nd Appearance | Interrupt treatment until Grade ≤1, restart treatment at 20 mg once daily | 2nd Appearance | Interrupt treatment until Grade ≤1, restart treatment at 480 mg twice daily or permanently discontinue if dose had already been lowered to 480 mg twice daily |
3rd Appearance |
Consider permanent discontinuation |
3rd Appearance |
Permanently discontinue |
Grade 4 |
|||
1st Appearance |
Permanently discontinue or interrupted ZELBORAF® until Grade ≤1. Resume dosing at 480 mg twice daily or permanently discontinue if the dose had already been lowered to 480 mg twice daily |
||
2nd Appearance or persistence of any grade 4 AE after 1st dose reduction |
Permanently discontinue |
No filter results
aThe intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE).
Recommended COTELLIC® dose modifications1
- Healthcare professionals may dose reduce, if needed, by advising patients to take fewer pills
Adverse reactiona | Dose modification |
Haemorrhage |
|
Grade 3 |
COTELLIC® treatment should be interrupted during evaluation to avoid any potential contribution to the event. There is no data on the effectiveness of COTELLIC® dose modification for haemorrhage events. Clinical judgement should be applied when considering restarting treatment COTELLIC® treatment. ZELBORAF® dosing can be continued when COTELLIC® treatment is interrupted, if clinically indicated |
Grade 4 |
COTELLIC® treatment should be interrupted. For haemorrhage events attributed to COTELLIC®, treatment should be permanently discontinued |
Left ventricular dysfunction (LVEF) | |
Permanent discontinuation of COTELLIC®treatment should be considered if cardiac symptoms are attributed to COTELLIC® and do not improve after temporary interruption |
|
Asymptomatic LVEF 50% (or 40–49% and <10% absolute decrease from baseline) |
Continue COTELLIC® treatment at the current dose |
Asymptomatic LVEF <40% (or 40–49% and ≥10% absolute decrease from baseline) |
COTELLIC® treatment should be interrupted for 2 weeks, then repeat LVEF:
|
Symptomatic LVEF |
COTELLIC® treatment should be interrupted for 4 weeks, then repeat LVEF:
|
Rhabdomyolysis and creatine phosphokinase (CPK) elevations |
|
Rhabdomyolysis and symptomatic CPK elevations |
COTELLIC® treatment should be interrupted
|
Asymptomatic CPK elevations |
Grade 4: COTELLIC® treatment should be interrupted for 4 weeks
Grade ≤3: After rhabdomyolysis has been ruled out, COTELLIC® dosing does not need to be modified |
Liver laboratory abnormalities |
|
Grade 1 and 2 |
COTELLIC® should be continued at the prescribed dose |
Grade 3 |
COTELLIC® should be continued at the prescribed dose; ZELBORAF® may be reduced as clinically appropriate |
Grade 4 |
COTELLIC® and ZELBORAF® treatment should be interrupted
|
Photosensitivity |
|
Grade ≤2 (tolerable) |
Manage with supportive care |
Grade 2 (intolerable) or Grade ≥3 |
COTELLIC® and ZELBORAF(F) treatment should be interrupted until resolution to Grade ≤1. Treatment can be restarted with no change in COTELLIC® dose; ZELBORAF® dosing should be reduced as clinically appropriate |
Rash |
|
Rash events may occur with either COTELLIC® or ZELBORAF® treatment. The dose of COTELLIC® and/or ZELBORAF® may be either temporarily interrupted and/or reduced as clinically indicated |
|
Grade ≤2 (tolerable) |
Manage with supportive care. COTELLIC® dosing remains unchanged. |
Grade 2 (intolerable) or Grade ≥3 acneiform rash |
COTELLIC® treatment should be reduced to the next lower dose level. ZELBORAF® dosing can be continued when COTELLIC® treatment is modified (if clinically indicated) |
Grade 2 (intolerable) or Grade ≥3 non-acneiform or maculopapular rash |
COTELLIC® treatment can be continued at the current dose. ZELBORAF® dosing may be either temporarily interrupted and/or reduced |
Serous retinopathy |
|
Grade ≥2 |
Discontinue treatment until symptoms improve until Grade ≤1 |
Grade ≤1 |
COTELLIC® treatment should be reduced as outlined in the dose reduction table |
Diarrhoea |
|
Grade ≥3 |
Manage with anti-diarrhoeal agents and supportive care. For Grade ≥3 diarrhoea that occurs despite supportive care, COTELLIC® and ZELBORAF® should be interrupted until diarrhoea has improved to Grade ≤1. If Grade ≥3 diarrhoea recurs, the dose of COTELLIC® and ZELBORAF® should be reduced as outlined in the dose reduction table. |
No filter results
LVEF=left ventricular ejection fraction; LLN=lower limit of normal
aThe intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE).
Recommended ZELBORAF® dose modifications 2
Adverse reactiona | Dose modification |
Dose modification schedule based on prolongation of the QT interval |
|
QTc value |
|
1st occurrence of QTc >500 ms during treatment and change from pre-treatment value remains <60 ms |
Temporarily interrupt ZELBORAF® until QTc is <500 ms. Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose had already been lowered) |
2nd occurrence of QTc >500 ms during treatment and change from pre-treatment value remains <60 ms |
Temporarily interrupt ZELBORAF® until QTc is <500 ms. Resume dosing at 480 mg twice daily (or permanently discontinue if the dose had already been lowered to 480 mg twice daily) |
3rd occurrence of QTc >500 ms during treatment and change from pre-treatment value remains <60 ms |
Temporarily interrupt ZELBORAF® until QTc is <500 ms. Resume dosing at 480 mg twice daily (or permanently discontinue if the dose had already been lowered to 480 mg twice daily) |
QTc increase meets values of both >500 ms and >60 ms change from pre-treatment values | Permanently discontinue
|
QTc >500 ms at baseline |
Treatment not recommended |
No filter results
Dose modifications for concurrent CYP3A inhibitors1
- Patients should not take strong CYP3A inhibitors while taking COTELLIC®. If short-term (7 days or less) use of a strong CYP3A inhibitor is unavoidable, consider interrupting COTELLIC® therapy during its use
- If concurrent use of moderate CYP3A inhibitors is unavoidable, patients should be closely monitored for safety
- ZELBORAF® should be used with caution in combination with strong inhibitors of CYP3A4
Dose modifications for concurrent CYP3A inducers1,2
- Co-administration of COTELLIC® with a moderate and strong CYP3A inducer should be avoided, with alternative agents with no or minimal CYP3A induction should be considered
- ZELBORAF® should be used with caution when co-administered with strong CYP3A4 inducers. If concomitant use of a strong CYP3A4 inducer is unavoidable, it must be considered that there may be suboptimal exposure to ZELBORAF®
Discontinuation or interruption
Rates of treatment discontinuation in the coBRIM study3
- 14% of patients receiving COTELLIC® + ZELBORAF® discontinued treatment due to an adverse event
- The most common reason for treatment discontinuation was an increase in aspartate aminotransferase (AST), occurring in 2% of patients
Rates of dose interruption or reduction in the coBRIM study3
- Dose interruption or reduction due to adverse reactions in the COTELLIC® + ZELBORAF® group occurred in 35% of patients receiving COTELLIC® and 30% of patients receiving ZELBORAF®