What Is Trametinib (Mekinist)? FDA Approval, Licensing and Reimbursement in Turkey

• FDA Approved: Yes (Initial approval date: May 29, 2013)
• Brand Name: Mekinist
• Active Ingredient: Trametinib
• Route of Administration: Oral, tablet form
• Class: Signal transduction inhibitor, MEK inhibitor
• Category: Targeted agent
• Manufacturer: Novartis
• Distribution in Turkey: Novartis
• Approved Cancers: Inoperable or metastatic melanoma with a BRAF V600E or V600K mutation; non-small cell lung cancer with a BRAF V600E mutation; anaplastic thyroid cancer with a BRAF V600E mutation; and BRAF V600E-mutated solid tumors for which satisfactory treatment options have been exhausted.

What Is Mekinist, Containing Trametinib?

Mekinist, containing trametinib, is a biological treatment agent that reversibly inhibits the MEK1 and MEK2 enzymes in certain cancers with a BRAF V600E or V600K mutation. It stops cell growth and proliferation by targeting signal transduction pathways, thereby helping prevent cancer progression.

Today, trametinib is most commonly used with Tafinlar, containing the anti-BRAF drug dabrafenib, as a combination treatment.

How Does It Work?

• Mekinist reversibly blocks two specific enzymes called MEK1 and MEK2, which play important roles in cell growth and proliferation.
• Blocking these enzymes stops downstream steps in the ERK (extracellular signal-regulated kinase) pathway, which transmits signals from outside the cell. This prevents uncontrolled cell growth and proliferation.
• It is particularly effective in stopping the growth of melanoma cells carrying a BRAF-V600 mutation.

FDA (US Food and Drug Administration) Approval History

• March 16, 2023: Novartis's Tafinlar + Mekinist combination received FDA approval for pediatric patients with low-grade gliomas carrying a BRAF V600E mutation.
• June 22, 2022: Novartis's Tafinlar + Mekinist combination received its first tumor-agnostic indication approval for BRAF V600E-mutated solid tumors.
• May 4, 2018: The FDA approved Tafinlar + Mekinist for BRAF-positive anaplastic thyroid cancer.
• April 30, 2018: Novartis received FDA approval for Tafinlar + Mekinist as adjuvant treatment for melanoma with a BRAF V600 mutation.
• June 22, 2017: Novartis's targeted combination therapy Tafinlar + Mekinist received FDA approval for BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC).
• January 9, 2014: GSK received accelerated FDA approval for the combination of Mekinist (trametinib) and Tafinlar (dabrafenib).
• May 29, 2013: The FDA approved Mekinist (trametinib) for advanced melanoma.
• May 1, 2013: The PDUFA (Prescription Drug User Fee Act) approval date for trametinib in the US was extended to September 3, 2013.

Licensing in Turkey

Mekinist's licensed uses and therapeutic indications in Turkey are listed as follows:

Therapeutic Indications:

• Indicated in combination with dabrafenib until progression in patients with locally recurrent or metastatic BRAF V600 mutation-positive malignant melanoma who have not previously received a RAF pathway inhibitor, have an ECOG performance score of 0-1, have progressed after local treatments and cannot receive further local treatment. After disease progression, trametinib may not be continued as a single agent or in combination.
• Trametinib in combination with dabrafenib is indicated as adjuvant treatment following complete resection in adult patients with stage III melanoma and a BRAF V600 E mutation. Adjuvant treatment may be used for a maximum of 12 months. It may not be used in patients who develop progression during this period. After disease progression, trametinib may not be continued as a single agent or in combination.
• Indicated with dabrafenib until progression in patients with locally advanced or metastatic non-small cell lung cancer who have a BRAF V600 E mutation identified in an accredited laboratory; absent or unknown EGFR or ALK mutation status; an ECOG performance score of 0-1; adequate bone marrow reserve (neutrophil count above 1500 and platelet count above 100000); adequate liver and kidney function (ALT, AST, bilirubin and serum creatinine no more than 1.5 times normal); and a left ventricular ejection fraction within normal limits. Starting trametinib alone for these indications is not appropriate. If dabrafenib is discontinued because of dabrafenib-related complications, trametinib may be continued as monotherapy.

Is Trametinib Reimbursed in Turkey?

Mekinist is covered by Turkey's Social Security Institution (SGK) in the following treatment settings:

• Reimbursement is provided for use with dabrafenib until progression in patients with locally recurrent or metastatic BRAF V600 mutation-positive malignant melanoma who have not previously received a RAF pathway inhibitor, have an ECOG performance score of 0-1, have progressed after local treatments and cannot receive further local treatment.
• Reimbursement is provided for trametinib with dabrafenib as adjuvant treatment for 12 months after complete resection in adult patients with stage III melanoma and a BRAF V600 E mutation, until progression.

Price: As of August 2025, the pharmacy retail price of Mekinist 2mg, 30 tablets, is 90397.34 TL, and Mekinist 0.5 mg, 30 tablets, costs 22681.82 TL.

What Is the Status of Pazopanib on the List of Off-Label Drugs That May Be Used Without Additional TİTCK Approval?

MALIGNANT MELANOMA: Its use as adjuvant treatment is appropriate in patients with stage III disease who are BRAF V600K-positive.

STAGE IV COLORECTAL CANCER: In BRAF V600E-positive disease, dabrafenib and trametinib may be used with cetuximab or panitumumab in the 2nd line and beyond.

GBM (GLIOBLASTOMA MULTIFORME): Its use is appropriate in BRAF (V600E) mutation-positive patients whose disease has progressed after CRT and temozolomide.

STAGE IV BILIARY TRACT CANCER: In the presence of a BRAF V600E mutation, dabrafenib and trametinib may be used with cetuximab or panitumumab in the 2nd line and beyond.

Mechanisms of Resistance

• Upregulation or activation of the PI3K/AKT pathway: This cellular pathway supports cell growth and survival. It may become more active to overcome Mekinist's effects.
• Reactivation of the MAPK signaling pathway: Mekinist suppresses the MAPK pathway. However, some cells may reactivate it and develop resistance.
• Development of MEK2 mutations: MEK2 is one of Mekinist's targets. Mutations in this enzyme may reduce the drug's effect.
• The presence of NRAS mutations: NRAS mutations affect pathways controlling cell growth signals and may lead to Mekinist resistance.
• Increased activity or expression of the HER2-neu pathway: Activation of this pathway may reduce Mekinist's effects on cells and cause treatment resistance.

Absorption

Oral bioavailability is approximately 70%. Maximum plasma concentration is reached after 1.5 hours. Taking it with high-fat food reduces Cmax, Tmax and AUC.

Distribution

Trametinib binds extensively (97.4%) to plasma proteins.

Metabolism

Trametinib is metabolized in the liver, mainly through deacetylation or glucuronidation biotransformation pathways. Excretion is predominantly fecal (more than 80%), with less than 20% excreted through the kidneys. The average terminal half-life is 4-5 days.

Dose Range

• For Adults: The recommended dose, alone or with dabrafenib, is 2 mg once daily. It should be taken at least 1 hour before or 2 hours after food.
• For Pediatric Patients: Dosage is based on body weight and specified in the package insert.

Drug Interactions

No significant drug interaction has been reported.

Precautions

1. Monitoring Cardiac Function: LVEF (left ventricular ejection fraction) should be assessed at baseline and periodically during treatment. Approximately 10% of patients may develop cardiomyopathy after an average of 63 days. Treatment should be interrupted if LVEF falls by 10% from its pretreatment level. Treatment should be permanently discontinued in patients with symptomatic cardiomyopathy or a persistent, asymptomatic LVEF reduction that does not resolve within 4 weeks.
2. Visual Disturbances: Patients should be informed of the possibility of visual disturbances.
3. Eye Examinations: Careful eye examinations should be performed at baseline and when new visual changes occur to rule out retinal detachment or retinal vein occlusion.
4. Monitoring Lung Symptoms: Treatment should be interrupted in patients with new or worsening lung symptoms and discontinued in patients diagnosed with treatment-related pneumonia or interstitial lung disease (ILD).
5. Skin Toxicity and Infections: Patients should be monitored for severe skin toxicity and secondary infections. Skin toxicity develops after an average of 15 days and resolves after an average of 48 days.
6. BRAF Testing: An FDA-approved diagnostic test should be performed to confirm the presence of BRAF-V600E or BRAF-V600K mutations. This test is necessary to identify which patients should receive trametinib.
7. Hepatic Impairment: No dose adjustment is recommended in mild hepatic impairment, but caution is required in moderate or severe hepatic impairment.
8. Renal Impairment: No dose adjustment is recommended in mild or moderate renal impairment, but caution is required in severe renal impairment.
9. Pregnancy and Breastfeeding: Trametinib may harm the fetus. Women of reproductive potential should use effective contraception during treatment and for 4 months after the last dose. Breastfeeding is not recommended during treatment or for 4 months after the last dose.

Side Effects

• Cardiac Toxicity: Cardiomyopathy.
• Ophthalmologic Side Effects: Retinal detachment and retinal vein occlusion.
• Pulmonary Toxicity: ILD symptoms (cough, dyspnea, hypoxia).
• Skin Toxicity: Skin rash, dermatitis, hand-foot syndrome, erythema and pruritus.
• Gastrointestinal Side Effects: Diarrhea, mucositis and abdominal pain.
• Hypertension
• Lymphedema