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
indication-dosage.png

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

  • No fasting required; COTELLIC® and ZELBORAF® may be taken with or without food, but consistent intake of both daily doses of ZELBORAF® on an empty stomach should be avoided
  • Both COTELLIC® and ZELBORAF® tablets should be swallowed whole with water
  • Store in original packaging; protect ZELBORAF® from moisture

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:
  • If <10% absolute decrease from baseline, follow recommended dose reduction strategy
  • If <40% (or ≥10% absolute decrease from baseline), treatment should be permanently discontinued
Symptomatic LVEF
 COTELLIC® treatment should be interrupted for 4 weeks, then repeat LVEF:
  • If asymptomatic and <10% absolute decrease from baseline, follow recommended dose reduction strategy
  • If asymptomatic and <40% (or ≥10% absolute decrease from baseline), treatment should be permanently discontinued
If symptomatic regardless of LVEF, treatment should be permanently discontinued
Rhabdomyolysis and creatine phosphokinase (CPK) elevations
Rhabdomyolysis and symptomatic CPK elevations

COTELLIC® treatment should be interrupted

  • If rhabdomyolysis or symptomatic CPK elevations do not improve within 4 weeks, COTELLIC® treatment should be permanently discontinued
  • If severity is improved by at least one grade within 4 weeks, COTELLIC® could be restarted at a dose reduced by 20 mg, if clinically indicated. Patients should be closely monitored. Vemurafenib dosing can be continued when COTELLIC® treatment is modified 
Asymptomatic CPK elevations    

Grade 4: COTELLIC® treatment should be interrupted for 4 weeks

  • If CPK elevations do not improve to Grade ≤3, COTELLIC® should be permanently discontinued
  • If CPK improves to Grade ≤3, COTELLIC® could be restarted, if clinically indicated, at a dose reduced by 20 mg, and and the patient should be closely monitored. Vemurafenib dosing can be continued when COTELLIC® treatment is modified

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
  • If severity is improved to Grade ≤1 within 4 weeks, COTELLIC® should be restarted at a dose reduced by 20 mg and ZEBORAF® at a clinically appropriate dose
  • If no improvement to Grade ≤1 within 4 weeks, or if Grade 4 abnormalities recur after initial improvement, COTELLIC® and ZELBORAF® treatment should be permanently discontinued
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®