Trametinib


Generic Medicine Info
Indications and Dosage
Oral
Metastatic melanoma, Unresectable melanoma
Adult: As monotherapy or in combination with dabrafenib in patients with BRAF V600E or BRAF V600K mutation-positive cases: 2 mg once daily, continue until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Melanoma
Adult: As adjuvant treatment in combination with dabrafenib in patients with Stage III cases and BRAF V600E or BRAF V600K mutation-positive cases, following complete resection: 2 mg once daily for 12 months in the absence of disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Advanced non-small cell lung cancer, Locally advanced anaplastic thyroid carcinoma, Metastatic anaplastic thyroid carcinoma, Metastatic non-small cell lung carcinoma
Adult: In combination with dabrafenib in patients with BRAF V600E mutation-positive cases: 2 mg once daily, continue until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Administration
Should be taken on an empty stomach. Take at least 1 hr before or 2 hr after meals.
Special Precautions
Patient with diabetes mellitus or hyperglycaemia, impaired left ventricular function or conditions that impair left ventricular function; hypertension, risk factors for gastrointestinal perforation (e.g. history of diverticulitis, metastases to the gastrointestinal tract); suspected interstitial lung disease (ILD), pneumonitis. Moderate to severe hepatic and severe renal impairment. Pregnancy and lactation. Not recommended for treatment in patients with history of retinal vein occlusion (RVO). Not intended for the treatment of patient who progressed on prior BRAF inhibitor therapy.
Adverse Reactions
Significant: Neutropenia; cardiac events (e.g. heart failure, left ventricular dysfunction, decreased left ventricular ejection fraction); dermatological toxicity (e.g. rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, erythema); serious febrile reactions; fever with rigors/chills, hypotension, dehydration; elevated LFT, hyperglycaemia, hypertension; malignancies; retinal pigment epithelial detachments, RVO; ILD, pneumonitis; rhabdomyolysis.
Blood and lymphatic system disorders: Anaemia, leucopenia, lymphocytopenia, thrombocytopenia.
Cardiac disorders: Bradycarida, dyspnoea.
Eye disorders: Blurred vision, periorbital oedema, visual impairment.
Gastrointestinal disorders: Diarrheoa, stomatitis, abdominal pain, nausea, vomiting, constipation, dry mouth.
General disorders and administration site conditions: Fatigue, asthenia, mucosal inflammation.
Hepatobiliary disorders: Hypoalbuminemia, pancreatitis.
Infections and infestations: Folliculitis, rash pustular, cellulitis.
Investigations: Increased serum creatinine.
Metabolism and nutrition disorders: Peripheral oedema, hyponatremia, hypophosphataemia, decreased appetite.
Musculoskeletal and connective tissue disorders: Chills, arthralgia, myalgia.
Nervous system disorders: Headache, dizziness.
Renal and urinary disorders: Renal failure.
Respiratory, thoracic and mediastinal disorders: Cough.
Skin and subcutaneous tissue disorders: Paronychia, pruritus, xeroderma, alopecia, dry skin, fissures.
Vascular disorders: Lymphoedema.
Potentially Fatal: Gastrointestinal perforation, colitis, haemorrhage (intracranial, subarachnoid, retroperitoneal, gastrointestinal); venous thromboembolic events (e.g. DVT, pulmonary embolism), severe cutaneous reactions (e.g. Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms).
Patient Counseling Information
This drug may cause fatigue, dizziness or eye problems, if affected, do not drive or operate machinery.
MonitoringParameters
Confirm BRAF V600K or V600E mutation status prior to initiation of therapy. Monitor LFT at baseline and periodically thereafter; blood pressure, CBC, metabolic panel, serum albumin. Evaluate left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan at baseline then 1 month after initiation, and then at 2 to 3-month intervals. Perform pregnancy test prior to initiation of therapy in females of child-bearing age. Monitor for signs and symptoms of pulmonary toxicity (e.g. cough, dyspnoea, hypoxia, pleural effusion, or infiltrates); dermatologic toxicity and secondary skin infections; gastrointestinal toxicity (e.g. diarrhoea), bleeding. Perform ophthalmological evaluation periodically and in case of visual disturbances during treatment. For patients treated in combination with dabrafenib: Monitor blood glucose at baseline and periodically in patients with diabetes or hyperglycaemia. Perform dermatologic exams prior to therapy then every 2 months during combination therapy, and for up to 6 months following discontinuation of therapy. Monitor for signs and symptoms of malignancies.
Drug Interactions
May increase serum concentration with strong P-gp inhibitors (e.g. verapamil, ciclosporin, quinidine, itraconazole, ritonavir). May increase risk of haemorrhage with antiplatelet or anticoagulant therapy.
Food Interaction
Decreased absorption and exposure, and delays time to peak plasma concentration with high fat meal.
Action
Description: Trametinib reversibly inhibits mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2, which are components of extracellular signal-related kinase pathway that is often activated by mutated forms of protein kinase B-raf (BRAF) in melanoma and other cancers. Inhibition of MEK activation and kinase activity lead to decreased cellular proliferation, cell cycle arrest, and increased cell apoptosis.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Food, particularly high fat meal may decrease absorption. Bioavailability: 72%. Time to peak plasma concentration: 1.5 hours.
Distribution: Volume of distribution: 214 L. Plasma protein binding: Approx 97%.
Metabolism: Metabolised in the liver via deacetylation by hydrolytic enzymes alone or in combination with mono-oxygenation; further metabolised via glucuronidation.
Excretion: Mainly via faeces (>80%); urine (<20%; <0.1% as unchanged drug). Elimination half-life: Approx 4 to 5 days.
Chemical Structure

Chemical Structure Image
Trametinib

Source: National Center for Biotechnology Information. PubChem Database. Trametinib, CID=11707110, https://pubchem.ncbi.nlm.nih.gov/compound/Trametinib (accessed on May 28, 2020)

Storage
Store between 2-8°C. Protect from light and moisture.
ATC Classification
L01EE01 - trametinib ; Belongs to the class of mitogen-activated protein kinase (MEK) inhibitors. Used in the treatment of cancer.
References
Anon. Trametinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/04/2020.

Buckingham R (ed). Trametinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/04/2020.

Joint Formulary Committee. Trametinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 04/04/2020.

Mekinist Tablet, Film Coated (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 07/04/2020.

Disclaimer: This information is independently developed by MIMS based on Trametinib from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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