Cobimetinib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of cobimetinib.
Drugs List
Therapeutic Indications
Uses
Treatment of unresectable or metastatic melanoma with BRAF V600 mutation
Treatment of adults patients with unresectable or metastatic melanoma with BRAF V600 mutation in combination with vemurafenib.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
60mg once daily for 21 consecutive days followed by a 7 day break.
Treatment should continue until it no longer benefits the patient or the development of unacceptable toxicity.
Additional Dosage Information
Missed Doses
If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once daily regimen. In the case of vomiting, the patient should not take an additional dose on that day. Treatment should be continued as prescribed the following day.
General dose modifications
Graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE). Doses omitted for toxicity should not be replaced. Where doses are reduced, do not increase the dose again at a later stage.
Grade 2 (intolerable) or Grade 3 or 4 toxicity:
First occurrence: Interrupt treatment until grade 1 or below, restart at 40mg once daily.
Second occurrence: Interrupt treatment until grade 1 or below, restart at 20mg once daily.
Third occurrence: Consider permanent discontinuation.
Dose modifications due to haemorrhage
Grade 3 haemorrhage:
Interrupt treatment whilst evaluating the cause. Decision to restart treatment should follow clinical judgement. Vemurafenib dosing can continue during interruptions to cobimetinib treatment (if clinically indicated).
Grade 4 haemorrhage or cerebral haemorrhage:
Interrupt treatment whilst evaluating the cause. Permanently discontinue if haemorrhage event attributed to cobimetinib.
Dose modifications due to left ventricular dysfunction (LVD)
When restarting treatment with a reduced dose due to LVD, measure left ventricular ejection fraction (LVEF) after 2 weeks, 4 weeks, 10 weeks, and 16 weeks and thereafter as clinically indicated. Where cobimetinib treatment is modified, vemurafenib can be continued (if clinically indicated).
Asymptomatic and LVEF below 40% (or asymptomatic, LVEF 40 to 49% and absolute decrease from baseline LVEF 10% or more):
Interrupt treatment for 2 weeks.
If after 2 weeks, absolute decrease from baseline LVEF has improved to less than 10%: First occurrence, restart treatment at 40mg once daily. Second occurrence, restart treatment at 20mg once daily. Third occurrence, permanently discontinue treatment.
If after 2 weeks LVEF remains below 40% (or absolute decrease from baseline LVEF remains at 10% or more): Permanently discontinue treatment.
Symptomatic LVD (regardless of LVEF):
Interrupt treatment for 4 weeks.
If after 4 weeks symptoms resolve and absolute decrease from baseline LVEF is less than 10%: First occurrence, restart treatment at 40mg once daily. Second occurrence, restart treatment at 20mg once daily. Third occurrence, permanently discontinue treatment.
If after 4 weeks symptoms resolve but LVEF is below 40% (or absolute decrease from baseline is 10% or more): Permanently discontinue treatment.
If after 4 weeks symptoms persist (regardless of LVEF): Permanently discontinue treatment.
Dose modifications due to rhabdomyolysis or CPK elevations
Where cobimetinib treatment is modified, vemurafenib dosing can be continued (if clinically indicated).
Asymptomatic CPK elevations, grade 3 or less:
Rule out rhabdomyolysis. No dose modifications required.
Asymptomatic CPK elevations, grade 4:
Interrupt treatment.
If within 4 weeks, CPK elevations reduce to grade 3 or less: Consider restarting treatment, if clinically indicated, at 20mg once daily. Monitor closely.
If after 4 weeks, CPK elevations remain at grade 4: Permanently discontinue treatment.
Symptomatic CPK elevations or confirmed rhabdomyolysis:
Interrupt treatment.
If within 4 weeks, CPK elevations improve by one grade or more: Consider restarting treatment, if clinically indicated, at 20mg once daily. Monitor closely.
If after 4 weeks, no improvement in rhabdomyolysis or toxicity grading: Permanently discontinue treatment.
Dose modification advice when cobimetinib is used in combination with vemurafenib
Modifications for vemurafenib may also be required, consult vemurafenib product information for details.
Grade 4 liver laboratory abnormalities:
Interrupt treatment for up to 4 weeks.
If abnormality reduces to grade 1 or less within 4 weeks: Restart treatment at 20mg once daily.
If abnormality remains at grade 2 or more within 4 weeks: Permanently discontinue treatment.
If abnormality initially improves but returns to grade 4: Permanently discontinue treatment.
Photosensitivity
Grade 2 (tolerable) or less: Manage with supportive care
Grade 2 (intolerable) or grade 3 or more: Interrupt treatment until grade 1 or below, no dose modifications required.
Rash
Grade 2 (tolerable) or less: Manage with supportive care
Grade 2 (intolerable) or grade 3 or more acneiform rash: Follow advice for 'general dose modifications' (see above). Vemurafenib dosing can continue (if clinically indicated) during any modifications to cobimetinib.
Contraindications
Children under 18 years
Severe haemorrhage
Breastfeeding
Galactosaemia
Pregnancy
Precautions and Warnings
Predisposition to haemorrhage
Cerebral metastases
Glucose-galactose malabsorption syndrome
Hepatic impairment
Lactose intolerance
Left ventricular ejection fraction below lower limit of normal
Left ventricular ejection fraction value of 50% or less
Severe renal impairment
Advise ability to drive/operate machinery may be affected by side effects
Confirm BRAF V600 mutation status of tumour prior to treatment
Treatment to be initiated and supervised by a specialist
Contains lactose
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Assess LVEF before treatment, 1 month after starting, then every 3 months
Monitor hepatic function before initiating and at monthly intervals
If visual disturbances occur, perform ophthalmic evaluation
Monitor creatine phosphokinase before and at monthly intervals
Monitor creatinine before and at monthly intervals
Monitor visual acuity during and after treatment
Advise patient to report any blurred vision or any other eye symptoms
Consider rhabdomyolysis if creatine phosphokinase is elevated
Discontinue if rhabdomyolysis or CPK rise persists despite interruption
Interrupt therapy/reduce dose if rhabdomyolysis or CPK rise occurs
Reduce dose if grade 3 diarrhoea recurs
Reduce dose or discontinue temporarily if photosensitivity/rash occur
Consider discontinuing if grade 4 liver function abnormality occurs
Discontinue or review if symptoms of congestive heart failure occur
Discontinue treatment and/or reduce dose if LVEF decreases
Interrupt or reduce dose if grade 3 liver function abnormality occurs
Interrupt or reduce dose if serous retinopathy occurs
Interrupt treatment until visual symptoms improve to grade 1 or below
Suspend treatment if grade 3 or greater diarrhoea occurs
Discontinue therapy if grade 4 bleeding occurs
Interrupt therapy if grade 3 bleeding occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Two reliable methods of contraception should be used simultaneously
Female:Barrier contraception required during & for 3 months after treatment
Combination with vemurafenib in patients who have progressed on a BRAF inhibitor.
Consider alternative treatment options in patients who have progressed on a prior BRAF inhibitor. (Limited) data has shown decreased efficacy in this patient group.
Serous retinopathy
Serous retinopathy has been reported with a median time to inset of 1 month. At each review assess for symptoms of new or worsening visual disturbances. If symptoms are identified refer for an ophthalmological examination. If serous retinopathy is diagnosed interrupt treatment until grade 1 or less. Further dose modifications, treatment interruptions or discontinuations should follow advice for general dose modifications (see Dosage; Additional Dose Information).
Liver laboratory abnormalities
Liver laboratory abnormalities have been reported when cobimetinib is used in combination with vemurafenib. Dependent on grade treatment may need to be interrupted/reduced/discontinued (see Dosage; Hepatic Impairment).
Pregnancy and Lactation
Pregnancy
Cobimetinib is contraindicated during pregnancy.
Use of cobimetinib during pregnancy is contraindicated by the manufacturer. Animal studies have shown teratogenic effects. Human data is limited and as such a potential risk cannot be ruled out.
Lactation
Cobimetinib is contraindicated during breastfeeding.
The manufacturer advises that the patient either discontinues cobimetinib or discontinues breastfeeding. The presence of cobimetinib in human breast milk and the effects on exposed infants are unknown.
Side Effects
Acne-like rash
Anaemia
Basal cell carcinoma
Blurred vision
Chills
Creatine phosphokinase increased
Decreased ejection fraction
Dehydration
Dermatological and photosensitivity reactions
Diarrhoea
Gamma glutamyl transferase (GGT) increased
Haemorrhage
Hyperglycaemia
Hyperkeratosis
Hypertension
Hyponatraemia
Hypophosphataemia
Impaired vision
Increase in alkaline phosphatase
Increase in serum ALT/AST
Keratoacanthoma
Maculopapular rash
Nausea
Photosensitivity
Pneumonitis
Pyrexia
Rash
Retinal detachment
Rhabdomyolysis
Serous retinopathy
Serum bilirubin increased
Serum creatinine increased
Squamous cell carcinoma
Sunburn
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: August 2019
Reference Sources
Summary of Product Characteristics: Cotellic 20mg film coated tablets. Roche Products Limited. Revised March 2018.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 12 July 2019
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.