Cobimetinib

Registered South African indications:

• Unresectable or metastatic melanoma with BRAF V600 mutation

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment
• Risk factors for bleeding
  - Brain metastases
  - Coadministration with agents that increase bleeding risk, such as antiplatelet or anticoagulant therapy
• Baseline left ventricular ejection fraction below institutional lower limit of normal or below 50%
• Non-Caucasian patients (See additional prescribing points)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• Coadministration with vemurafenib in patients who have progressed on a prior BRAF inhibitor
• Coadministration with vemurafenib in patients with a BRAF V600 mutation-positive melanoma which has metastasised to the brain
• Coadministration with moderate or strong CYP3A inhibitors (See additional prescribing points)
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: tab

Used for the treatment of 

• Unresectable or metastatic melanoma
  - Used in combination with vemurafenib for the treatment of patients with a BRAF V600 mutation

Before starting this treatment, patients must have BRAF V600 mutation-positive melanoma tumour status confirmed by a validated test

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Caution; positive evidence of risk in animal studies
• There are no data from the use of cobimetinib in pregnant women
• Studies in animals have shown embryolethality and foetal malformations of the great vessels and skull
• Cobimetinib should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus
• Women of childbearing potential should be advised to use two effective contraceptive methods, such as a condom or other barrier method (with spermicide, if available) during treatment with cobimetinib and for at least three months following treatment discontinuation

Breastfeeding

• Caution; not recommended
• It is not known whether cobimetinib is excreted in human breast milk
• A risk to the newborns/infants cannot be excluded
• A decision should be made whether to discontinue breastfeeding or discontinue cobimetinib therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• There are no data in humans for cobimetinib
• In animals, no fertility studies have been performed, but adverse effects were seen on reproductive organs. The clinical relevance of this is unknown

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  There are minimal data for cobimetinib in patients with severe renal impairment, therefore an effect cannot be excluded

Hepatic Impairment

• Caution; no dose adjustment recommended
  Patients with severe hepatic impairment may have increased plasma concentrations of unbound cobimetinib compared to patients with normal hepatic function. Hepatic laboratory abnormalities can occur with cobimetinib and caution should be used in patients with any degree of hepatic impairment

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders

• Hypertension
• Haemorrhage
• Decreased ejection fraction

Respiratory Disorders

• Pneumonitis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea

Hepatobiliary Disorders

• Increased alanine transaminase
• Increased aspartate aminotransferase
• Increased gamma-glutamyltransferase
• Increased alkaline phosphatase
• Increased blood bilirubin

Endocrine and Metabolic Disorders

• Dehydration
• Hypophosphataemia
• Hyponatremia
• Hyperglycaemia

Musculoskeletal Disorders

• Rhabdomyolysis
• Increased creatine phophokinase

Skin and Subcutaneous Tissue Disorders

• Photosensitivity
• Sunburn
• Solar dermatitis
• Actinic elastosis
• Rash
• Maculo-papular rash
• Acneiform dermatitis
• Hyperkeratosis

Immune, Blood and Lymphatic System Disorders

• Basal cell carcinoma
• Cutaneous squamous cell carcinoma
• Keratoacanthoma
• Anaemia
• Fever
• Chills

Sensory Disorders

• Serous retinopathy
  - Chorioretinopathy
  - Retinal detachment
• Blurred vision
• Visual impairment

• CYP3A inhibitors (See additional prescribing points)
• Itraconazole
• Ritonavir
• Cobicstat
• Telaprevir
• Lopinavir
• Voriconazole
• Clarithromycin
• Telithromycin
• Posaconazole
• Nefazodone
• Amiodarone
• Erythromycin
• Fluconazole
• Miconazole
• Diltiazem
• Verapamil
• Delavirdine
• Amprenavir
• Fosamprenavir
• Imatinib
• CYP3A inducers (See additional prescribing points)
• Carbamazepine
• Rifampicin
• Phenytoin
• P-glycoprotein inhibitors
• Ciclosporin
• Verapamil
• CYP1A2 substrates (in vitro interaction)
• Theophylline (in vitro interaction)
• Breast Cancer Resistance Protein (BCRP) substrates (in vitro interaction)
• OATP1B1 transporters (in vitro interaction)
• OATP1B3 transporters (in vitro interaction)
• OCT1 transporters (in vitro interaction)

Other

• Grapefruit juice
• St. John's wort

• BRAF V600K or V600E mutation status (before treatment initiation)
• Hepatic function
• Electrolytes
• Left ventricular ejection fraction measurements (echocardiogram or multiple-gated acquisition scan)
• Electrocardiogram
• Hepatitis B screening (hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen)

Specific cases may require:

• CPK and serum creatinine levels
• Visual and ophthalmic examination
• Dermatologic exams
• Signs and symptoms of
  - Rhabdomyolysis
  - Dermatologic toxicity
  - Noncutaneous malignancy
  - Photosensitivity
  - Haemorrhage

Coadministration with CYP3A inhibitors

• Strong CYP3A inhibitors
  - Cobimetinib is metabolized by CYP3A and cobimetinib AUC increased approximately 7 fold in the presence of a strong CYP3A inhibitor in healthy subjects. The magnitude of interaction could potentially be lower in patients. Avoid concurrent use of strong CYP3A inhibitors during treatment with cobimetinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. For strong CYP3A inhibitors used short-term (7 days or less), consider interrupting cobimetinib therapy during the duration of inhibitor use
• Moderate CYP3A inhibitors
  - Caution should be exercised if cobimetinib is coadministered with moderate CYP3A inhibitors. When cobimetinib is coadministered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety
• Mild CYP3A inhibitors
  - Cobimetinib can be coadministered with mild inhibitors of CYP3A without dose adjustment

Coadministration with CYP3A inducers

• Moderate and strong CYP3A inducers
  - Coadministration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study; however, a reduction in cobimetinib exposure is likely. Therefore, concomitant use of moderate and strong CYP3A inducers should be avoided. Alternative agents with no or minimal CYP3A induction should be considered. Given that cobimetinib concentrations are likely to be significantly reduced when coadministered with moderate to strong CYP3A inducers, patient's efficacy may be compromised

Use in non-Caucasian patients

• The safety and efficacy of cobimetinib in non-Caucasian patients have not been established

Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node.

In the preclinical models, the combination of cobimetinib and vemurafenib showed that by simultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the combination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a stronger inhibition of intracellular signalling and decreased tumour cell proliferation.

Tablet 20mg

• Cotellic (Roche) originator