Dabrafenib

Registered South African indications:

• Unresectable or metastatic melanoma
  - Used in combination with trametinib for the treatment of patients with a BRAF V600 mutation
• Advanced non-small cell adenocarcinoma
  - Used in combination with trametinib for the treatment of patients with BRAF V600 mutation

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

Cautions

• Severe renal impairment
• Moderate to severe hepatic impairment
• Hypertension
• Diabetes or hyperglycamia
• Previous or current cancer associated with RAS mutations
• Family history of cutaneous squamous cell carcinoma
• Haemorrhagic disorders
• Patients with impaired left ventricular function
• Pre-existing interstitial lung disease
• History of muscle disorders or drug-induced rhabdomyolysis
• History of/ risk for pancreatitis
• History of thrombo-embolic disorders/ coagulopathy
• Pre-existing gastrointestinal disorders (perforation)
• Glucose-6-phosphate dehydrogenase deficiency
• May impair ability to drive and operate machinery

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

Used for the treatment of

• Unresectable or metastatic melanoma
  - Used in combination with trametinib for the treatment of patients with a BRAF V600 mutation
• Advanced non-small cell adenocarcinoma
  - Used in combination with trametinib for the treatment of patients with BRAF V600 mutation

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Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for dabrafenib monotherapy

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• Animal studies have shown reproductive toxicity and embryo-foetal developmental toxicities, including teratogenic effects. Dabrafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus
• If the patient becomes pregnant while taking dabrafenib, the patient should be informed of the potential hazard to the foetus
• Please see trametinib monograph  when used in combination with trametinib
• Women of childbearing potential must use effective methods of contraception during therapy and for 2 weeks following discontinuation of dabrafenib and 16 weeks following the last dose of trametinib when given in combination with dabrafenib
• Dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception should be used

Breastfeeding

• Contraindication
• It is not known whether dabrafenib is excreted in human milk. Because many medicinal products are excreted in human milk, a risk to the breast-feeding child cannot be excluded.Breastfeeding is not recommended and a decision should be made whether to discontinue breast-feeding or discontinue dabrafenib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman

Fertility

• There are no data in humans for dabrafenib as monotherapy or in combination with trametinib. Dabrafenib may impair male and female fertility as adverse effects on male and female reproductive organs have been seen in animals.Male patients should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please see trametinib monograph when used in combination with trametinib

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available 

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no information available

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted- No warnings

Adverse reactions reported in dabrafenib monotherapy

Central Nervous System Disorders

• Headache
• Fatigue

Respiratory Disorders

• Cough

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Pancreatitis

Genitourinary Disorders

• Renal failure
• Nephritis

Endocrine and Metabolic Disorders

• Hypophosphataemia
• Hyperglycaemia
• Hypophosphataemia

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Papilloma
• Cutaneous squamous cell carcinoma
• Seborrhoeic keratosis
• Acrochordon (skin tags)
• Basal cell carcinoma
• New primary melanoma
• Hyperkeratosis
• Alopecia
• Rash
• Palmar-plantar erthrodysaesthesia syndrome
• Dry skin
• Pruritus
• Actinic keratosis
• Skin lesion
• Erythema
• Photosensitivity
• Panniculitis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity

Sensory Disorders

• Uveitis

Others

• Pyrexia
• Chills
• Asthenia
• Influenza-like illness
• Decreased appetite
• Weight increase or decrease

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Adverse reactions reported in dabrafenib & trametinib combination therapy 

Central Nervous System Disorders

• Headache
• Fatigue
• Dizziness

Cardiovascular Disorders

• Left ventricular ejection fraction reduction/left ventricular dysfunction
• Hypertension
• Hypotension
• Bradycardia
• Myocarditis

Respiratory Disorders

• Cough
• Interstitial lung disease/pneumonitis
• Pulmonary embolism
• Nasopharyngitis
• Dyspnoea
• Pneumonitis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Dry mouth
• Pancreatitis
• Colitis
• Gastrointestinal perforation
• Abdominal pain
• Stomatitis

Hepatobiliary Disorders

• Hepatic abnomalities

Genitourinary Disorders

• Renal failure
• Nephritis
• Urinary tract infection

Endocrine and Metabolic Disorders

• Hypophosphataemia
• Hyperglycaemia
• Dehydration
• Hyponatraemia
• Hypophosphataemia
• Hypercalcaemia

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Pain in extremity
• Muscle spasms
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Papilloma
• Cutaneous squamous cell carcinoma
• Seborrhoeic keratosis
• Acrochordon (skin tags)
• Basal cell carcinoma
• New primary melanoma
• Hyperkeratosis
• Alopecia
• Rash
• Palmar-plantar erthrodysaesthesia syndrome
• Dry skin
• Pruritus
• Actinic keratosis
• Skin lesion
• Erythema
• Photosensitivity
• Panniculitis
• Stevens-Johnson syndrome
• Cellulitis
• Folliculitis
• Paronychia
• Rash pustular
• Dermatitis acneiform
• Actinic keratosis
• Hyperhidrosis
• Skin fissures
• Generalised dermatitis exfoliative

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Pyrexia
• Chills
• Night sweats
• Haemorrhage
• Deep vein thrombosis
• Eosinophilia and systemic symptoms (DRESS)
• Neutropenia
• Anaemia
• Leukopenia
• Thrombocytopenia
• Lymphoedema
• Peripheral oedema

Sensory Disorders

• Uveitis
• Iridocyclitis
• Iritis
• Blurred vision
• Retinal pigment epithelial dystrophy
• Retinal vein occlusion
• Visual impairment
• Chorioretinopathy
• Retinal detachment
• Periorbital oedema

Others

• Influenza-like illness
• Decreased appetite
• Weight increase or decrease
• Mucosal inflammation
• Face oedema
• Asthenia
• Alanine aminotransferase increased
• Aspartate aminotransferase increased 
• Blood alkaline phosphatase increased
• Gamma-glutamyltransferase increased 
• Blood creatine phosphokinase increased

• CYP2CB inhibitors
• CYP2CB inducers
• CYP3A4 inhibitors
• CYP3A4 inducers
• CYP3A4 substrates
• CYP2C9 substrates
• OATP and BCRP substrates (e.g. rosuvastatin)
• Agents that alter pH of upper gastrointestinal tract (e.g. H2-receptor antagonists, Antacids, Proton pump inhibitors)
• Analgesics (e.g. fentanyl, methadone)
• Antibiotics (e.g. clarithromycin, doxycycline)
• Anticancer agents (e.g. cabazitaxel)
• Anticoagulants (e.g. acenocoumarol, warfarin)
• Antiepileptic (e.g. carbamazepine, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin)
• Corticosteroids (e.g. dexamethasone, methylprednisolone)
• HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)
• Hormonal contraceptives
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus)
• Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)

• Renal function
• Hepatic function
• Skin examination (dermatologic toxicity and secondary infections)
• Eye and vision test
• Serum glucose (particularly in patients with pre-existing diabetes mellitus or hyperglycemia)
• Electrolytes
• Signs/symptoms of hemolytic anemia
• Left ventricular ejection fraction (by echocardiogram or MUGA scan)
• Head and neck examination (minimally visual inspection of oral mucosa and lymph node palpation)
• Chest/abdomen CT scan

• Dabrafenib should be taken at least one hour before or at least two hours after a meal at similar times each day with an interval of approximately 12 hours between doses
• If a dose of dabrafenib is missed, it should not be taken if there is less than six hours until the next scheduled dose
• The capsules are to be swallowed whole with water. They should not be chewed or opened and should not be mixed with food or liquids due to chemical instability of dabrafenib
• Male patients must use a condom during intercourse and not to father a child during therapy and for 4 months following discontinuation.

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Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for dabrafenib monotherapy

Dabrafenib is a potent, selective, ATP-competitive inhibitor of RAF kinases with IC50 values of 0.65, 0.5 and 1.84 nM for BRAFV600E, BRAFV600K and BRAFV600D enzymes, respectively. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumour cell growth. BRAF mutations have been identified. Dabrafenib also inhibits wild-type BRAF and CRAF enzymes with IC50 values of 3.2 and 5.0 nM, respectively. Dabrafenib inhibits BRAF V600 mutant melanoma cell growth in vitro and in vivo. In patients with BRAF V600 mutant melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline

Combination with trametinib

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of dabrafenib with trametinib has shown anti-tumour activity in BRAF V600 mutation positive melanoma cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts.

Capsule 50 mg

• Rafinlar (Novartis) originator

Capsule 75 mg

• Rafinlar (Novartis) originator