Trametinib

Registered South African indications:

• Unresectable or metastatic melanoma
  - Used in combination with dabrafenib is indicated for the treatment of patients with unresectable ormetastatic melanoma with a BRAF V600 mutation
• Advanced non-small cell adenocarcinoma
  - Used in combination with dabrafenib is indicated for the treatment of patients with advanced nonsmall cell adenocarcinoma with BRAF V600 mutation

Contraindications

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

Cautions

• Severe renal impairment
• Moderate or severe hepatic impairment
• Heart failure 
• Lung or breathing problems
• Hypertension
• Uncontrolled glaucoma or ocular hypertension
• Uncontrolled diabetes mellitus
• Hyperviscosity or hypercoagubility syndromes
• Diverticulitis
• Family history of cutaneous squamous cell carcinoma
• Haemorrhagic disorders
• Porphyria
• Concomitant use of antiplatelet or anticoagulant therapy
• Patients with impaired left ventricular function
• Pre-existing interstitial lung disease
• History of muscle disorders or drug-induced rhabdomyolysis
• History of / risk of pancreatitis
• History of thrombo-embolic disorders / coagulopathy
• Pre-existing gastrointestinal disorders (perforation)

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

Used for the treatment of

• Unresectable or metastatic melanoma
  - Used in combination with dabrafenib is indicated for the treatment of patients with unresectable ormetastatic melanoma with a BRAF V600 mutation
• Advanced non-small cell adenocarcinoma
  - Used in combination with dabrafenib is indicated for the treatment of patients with advanced nonsmall cell adenocarcinoma with BRAF V600 mutation

Patients must have confirmation of BRAF V600 mutation using a validated test

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• There are no adequate and well-controlled studies of trametinib in pregnant women. Animal studies have shown reproductive toxicity. Trametinib should not be administered to pregnant women. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus
• Female patients of reproductive potential must be advised to use effective methods of contraception during treatment with trametinib and for 16 weeks after cessation of treatment
• Use with dabrafenib may render hormonal contraceptives less effective and therefore an alternative method of contraception, such as a barrier method, should be used

Breastfeeding

• Contraindicated
• It is not known if trametinib is excreted in human milk. Because many medicinal products are excreted in human milk, risk during breastfeeding cannot be excluded. Trametinib should not be administered to breast-feeding mothers. A decision should be made whether to discontinue breast-feeding or discontinue trametinib. Take into account the benefit of breast-feeding for the child and the benefit of therapy for the woman

Fertility

• There is no data in humans for trametinib as monotherapy or in combination with dabrafenib 
• In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs
• Trametinib may impair fertility in humans
• Men taking trametinib in combination with dabrafenib:
  Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Refer to the dabrafenib monograph for further information

Renal Impairment

• Mild to moderate: No dosage adjustment recommended
• Severe: Caution; no information available _1,2,3

Hepatic Impairment

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

Elderly

• No initial dose adjustment recommended, however more frequent dose adjustments may be required

Porphyria Information

• Not yet classified (NC)

Adverse reactions reported in trametinib monotherapy 

Cardiovascular Disorders 

• Hypertension
• Haemorrhage
• Left ventricular dysfunction  
• Decreased ejection fraction  
• Bradycardia  
• Cardiac failure  

Respiratory Disorders 

• Cough  
• Dyspnoea  
• Pneumonitis  
• Interstitial lung disease

Gastrointestinal Disorders 

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

Endocrine and Metabolic Disorders 

• Dehydration  

Musculoskeletal Disorders

• Rhabdomyolysis  

Skin and Subcutaneous Tissue Disorders

• Chapped skin 
• Cellulitis 
• Rash pustular 
• Aloplecia 
• Erythema 
• Palmar-plantar erythrodysaesthesia syndrome 
• Skin fissures 
• Folliculitis 
• Paronychia 
• Rash 
• Dermititis acneiform 
• Dry skin 
• Pruritis 

Immune, Blood and Lymphatic System Disorders 

• Anaemia  
• Hypersensitivity  
• Lymphoedema  

Sensory Disorders

• Papilloedema
• Retinal vein occlusion (RVO)
• Blurred vision
• Periorbital oedema 
• Impaired vision  
• Chorioretinopathy  
• Retinal detatchment

Others

• Peripheral oedema
• Facial oedema  
• Mucosal inflammation  
• Asthenia  
• Fatigue  
• Epistaxis
• Fever  
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased blood alkaline phosphotase
• Increased blood creatine phosphokinase  

Adverse reactions reported trametinib & dabrafenib combination therapy

Central Nervous System Disorders

• Dizziness 
• Headache 

Cardiovascular Disorders

• Hypertension
• Hypotension
• Haemorrhage
• Left ventricular dysfunction  
• Decreased ejection fraction  
• Bradycardia  
• Cardiac failure  
• Hypotension  
• Myocarditis
• Lymphoedema
• Pulmonary embolism

Respiratory Disorders 

• Cough  
• Dyspnoea  
• Pneumonitis  
• Interstitial lung disease

Gastrointestinal Disorders 

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

Genitourinary Disorders 

• Urinary tract infections
• Renal failure  
• Nephritis  

Endocrine and Metabolic Disorders 

• Dehydration  
• Decreased appetite  
• Hyperglycemia  
• Hyponatraemia
• Hypophosphotaemia
• Hypercalcaemia

Musculoskeletal Disorders

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

Skin and Subcutaneous Tissue Disorders

• Cellulitis 
• Rash pustular 
• Aloplecia 
• Erythema 
• Palmar-plantar erythrodysaesthesia syndrome 
• Skin fissures 
• Skin lesions
• Folliculitis 
• Paronychia 
• Rash 
• Dermititis acneiform 
• Dry skin 
• Pruritis 
• Actinic keratosis 
• Night sweats 
• Hyperkeratosis 
• Aloplecia 
• Hyperhidriosis  
• Panniculitis
• Stevens-Johnson syndrome
• Photosensitivity
• Drug reaction with eosinophilia and systemic symptoms
• Dermatitis exfoliative generalised

Immune, Blood and Lymphatic System Disorders 

• Anaemia  
• Hypersensitivity  
• Lymphoedema  
• Haemorrhage  
• Neutropenia
• Thrombocytopenia  
• Leukopenia 
• Drug reaction with eosinophilia (DRESS)

Sensory Disorders

• Blurred vision
• Periorbital oedema 
• Impaired vision  
• Chorioretinopathy  
• Retinal detatchment 
• Uveitis  

Neoplasms benign, malignantand unspecified (incl cysts and polyps)

• Cutaneous squamous cell carcinoma(SCC) including SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma  
• Papilloma including skin papilloma
• Seborrhoeic keratosis
• Acrochordon (skin tags)
• New primary melanoma 

Others

• Peripheral oedema
• Facial oedema  
• Mucosal inflammation  
• Asthenia  
• Fatigue  
• Fever  
• Influenza-like illness  
• Chills
• Nasopharyngitis
• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased blood alkaline phosphotase
• Increased blood creatine phosphokinase  
• Increased gamma-glutamyltransferase

• Strong hepatic P-gp inhibitors (in vitro)

• Liver function tests
• Left ventricular ejection fraction (LVEF) tests, 1 month after treatment initiation, then at 2-3 month intervals
• Eye and vision testing
• Pulmonary toxicity
• Skin toxicity and secondary skin infections
• Blood pressure
• Blood glucose (when taken in combination with dabrafenib)

• Trametinib should be taken without food, at least 1 hour before or 2 hours after a meal, with a full glass of water  
• The tablets should not be chewed or crushed  
• If a dose of Trametinib is missed, only take the dose if it is more than 12 hours until the next scheduled dose
• It is recommended that the dose of trametinib is taken at a similar time every day. When trametinib and dabrafenib are taken in combination, the once-daily dose of trametinib should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib
• If a patient vomits after taking trametinib, the patient should not retake the dose and should take the next scheduled dose
• Men taking trametinib must also use a condom during intercourse and not father a child during treatment and for 4 months afterwards to avoid exposure of trametinib to the foetus

Patients must have confirmation of BRAF V600 mutation using a validated test

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. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity. Trametinib inhibits growth of BRAF V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.

Combination with dabrafenib

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/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 trametinib with dabrafenib 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.

Tablet, film-coated 0.5mg

• Meqsel 0.5mg (Novartis) originator

Tablet, film-coated  2mg

• Meqsel 2mg (Novartis) originator