Trametinib (Mekinist) is a MEK 1 and MEK 2 inhibitor. It stops the growth and spread of the tumor cells in patients with melanoma, lung, and thyroid cancers.

Indications of Trametinib (Mekinist):

• Melanoma:

  • It is used in combination with dabrafenib in patients with BRAF V600E or BRAF V600K mutations, lymph node involvement, following complete resection OR
  • The treatment of unresectable or metastatic melanoma in patients as a single agent or combination therapy.

• Metastatic Non-small cell lung cancer:

  • It is indicated as combination therapy for the treatment of metastatic non-small cell lung cancer in patients with BRAF V600E mutation.

• Locally advanced or metastatic anaplastic thyroid cancer:

  • It is used in combination for treating locally advanced or metastatic anaplastic thyroid malignancy with BRAF V600E mutation and with no satisfactory locoregional treatment options.

Trametinib (Mekinist) dose Adults

Note: BRAF V600 mutation status should be verified before treatment.

Trametinib (Mekinist) dose for the treatment Melanoma as adjuvant therapy (with BRAF V600E or BRAF V600K mutations):

• 2 mg  per oral once daily (in combination with dabrafenib);
• continue for ≤1 year in the absence of disease progression or unacceptable toxicity.

Trametinib (Mekinist) dose for the treatment of metastatic or unresectable Melanoma (with BRAF V600E or BRAF V600K mutations):

• 2 mg per oral once daily (monotherapy or in combination with dabrafenib),
• continue until disease progression or unacceptable toxicity.

Trametinib (Mekinist) dose for the treatment of metastatic Non-small cell lung cancer (with BRAF V600E mutation):

• 2 mg per oral once daily (in combination with dabrafenib);
• continue until disease progression or unacceptable toxicity.

Trametinib (Mekinist) dose for the treatment of locally advanced or metastatic Anaplastic Thyroid cancer (with BRAF V600E mutation):

• 2 mg per oral once daily (in combination with dabrafenib); continue until disease progression or unacceptable toxicity.

Missed doses:

• Do not take a missed dose within 12 hours of the next dose.

FDA prescribing information is available in PDF.

Use in Children:

The safety and efficacy of the drug in children have not been established.

Pregnancy Risk Category D

• Studies on animal reproduction showed that fetal harm was evident.
• Effective contraceptives should be used by both males and females with reproductive potential during trametinib treatment and for at least 4 months following the last trametinib dosage.

Use while breastfeeding

• It is not known if Trametinib is excreted in breast milk.
• Due to serious side effects, the manufacturer does not recommend breastfeeding during trametinib therapy or for at least 4 months after the last dose.

Trametinib (Mekinist) Dose adjustment in renal disease:

• Mild to moderate impairment (GFR ≥30 mL/minute/1.73 m²):

  • No dosage adjustment necessary.

• Severe impairment (GFR <30 mL/minute/1.73 m²):

  • There are no dosage adjustments provided in the manufacturer's labeling.

Trametinib (Mekinist) Dose adjustment in liver disease:

• Mild impairment bilirubin ≤ upper normal limit and AST > upper normal limit or bilirubin >1 to 1.5 times upper normal limit with any AST:

  • No dosage adjustment necessary.

• Moderate bilirubin >1.5 to 3 times upper normal limit and any AST to severe bilirubin >3 to 10 times upper normal limit and any AST impairment:

  • There are no dosage adjustments provided in the manufacturer's labeling (an appropriate dose has not been established).

Common Side Effects of Trametinib (Mekinist) monotherapy:

• Cardiovascular:

  • Hypertension
  • Cardiomyopathy

• Dermatologic:

  • Skin Toxicity
  • Skin Rash
  • Acneiform Eruption
  • Xeroderma

• Endocrine & Metabolic:

  • Hypoalbuminemia

• Gastrointestinal:

  • Diarrhea
  • Stomatitis
  • Abdominal Pain

• Hematologic & Oncologic:

  • Anemia
  • Lymphedema
  • Hemorrhage

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase

Rare Side Effects of Trametinib (Mekinist):

• Cardiovascular:

  • Decreased Left Ventricular Ejection Fraction
  • Bradycardia

• Central Nervous System:

  • Dizziness

• Dermatologic:

  • Paronychia
  • Pruritus
  • Cellulitis
  • Folliculitis
  • Pustular Rash

• Gastrointestinal:

  • Dysgeusia
  • Xerostomia

• Neuromuscular & Skeletal:

  • Rhabdomyolysis

• Ophthalmic:

  • Blurred Vision
  • Dry Eye Syndrome

• Respiratory:

  • Interstitial Pulmonary Disease
  • Pneumonitis

Side effects reported with dual therapy (trametinib plus dabrafenib):

Common Side Effects of Trametinib (Mekinist):

• Cardiovascular:

  • Hypertension
  • Peripheral Edema
  • Prolonged Q-T Interval On ECG

• Central Nervous System:

  • Fatigue
  • Headache
  • Chills
  • Dizziness

• Dermatologic:

  • Skin Toxicity
  • Skin Rash
  • Xeroderma

• Endocrine & Metabolic:

  • Hyperglycemia
  • Hyponatremia
  • Hypoalbuminemia
  • Hypophosphatemia
  • Exacerbation Of Diabetes Mellitus

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Diarrhea
  • Decreased Appetite
  • Abdominal Pain
  • Constipation

• Hematologic & Oncologic:

  • Neutropenia
  • Leukopenia
  • Anemia
  • Lymphocytopenia
  • Hemorrhage
  • Thrombocytopenia
  • Malignant Neoplasm

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alanine Aminotransferase

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Cough
  • Dyspnea

• Miscellaneous:

  • Fever
  • Febrile Reaction

Rare Side Effects of Trametinib (Mekinist) (dual therapy):

• Cardiovascular:

  • Bradycardia
  • Cardiomyopathy
  • Reduced Ejection Fraction
  • Venous Thromboembolism
  • Hypertension

• Central Nervous System:

  • Intracranial Hemorrhage

• Gastrointestinal:

  • Gastrointestinal Hemorrhage
  • Pancreatitis

• Hematologic & Oncologic:

  • Basal Cell Carcinoma
  • Squamous Cell Carcinoma Of Skin

• Neuromuscular & Skeletal:

  • Rhabdomyolysis

• Ophthalmic:

  • Blurred Vision

• Respiratory:

  • Pneumonitis

Contraindication to Trametinib (Mekinist):

The US labeling of the manufacturer does not list any contraindications. Canadian labeling: Hypersensitivity of trametinib and any component of the formulation.

Warnings and precautions

• Suppression of bone marrow

  • When taken concurrently with dabrafenib, it can cause neutropenia.

• Cardiac events

  • This can lead to heart failure, or decreased left ventricular ejection percentage. Therefore, an echocardiogram and MUGA scan are required at regular intervals.
  • In severe cases, it may be necessary to reduce or stop the dose.

• Dermatologic toxicities:

  • In severe cases, drug therapy should be stopped.

• Febrile reactions

  • Combining trametinib with dabrafenib can cause fever, hypotension, rigors/chills or renal failure.
  • If the fever persists for more than 3 days or complications occur, corticosteroids are recommended.

• Events in the gastrointestinal tract:

  • It can lead to life-threatening colitis or GI perforation.

• Hemorrhage

  • Drug therapy can lead to fatal intracranial, retroperitoneal, and gastrointestinal hemorhages.

• Hepatotoxicity

  • Trametinib has been linked to liver dysfunction.

• Hyperglycemia

  • Combination therapy with trametinib/dabrafenib may cause hyperglycemia. Therefore, glucose monitoring or insulin therapy may be necessary.

• Hypertension

  • You should use it with caution as hypertension can result.

• Malignancy

  • Basal cell carcinoma and cutaneous squamous cells carcinoma can both be detected in single-agent therapy or dual therapy.
  • Dermatological exams should be done before treatment begins, every 2 months, during treatment, and up to 6 months after discontinuation.

• Ocular toxicities:

  • There are two possible outcomes: retinal vein occlusion and retinal pigment epithelial dissociation (RPED).
  • These can lead to macular edema, reduced visual function, neovascularization and glaucoma.
  • If a retinal vein occlusion occurs, the drug should immediately be stopped
  • If iritis or uveitis occurs, it should be treated immediately with mydriatic drops and ophthalmic steroids.

• Toxicity in the lungs:

  • Pneumonitis and interstitial lung disease can present with symptoms such as cough, dyspnea or hypoxia.

• Venous thromboembolism

  • You should be aware that it can lead to pulmonary embolism and fatal deep vein thrombosis.

Trametinib: Drug Interaction

Monitoring parameters:

• Blood glucose
• LFTs
• Echo and MUGA scan to assess LVF status
• BRAF V600K or V600E mutation status before treatment
• Pregnancy
• Ophthalmic exam
• Signs/symptoms of pulmonary/dermatological toxicity.
• Signs/symptoms of infection
• Signs/symptoms of cutaneous and noncutaneous malignancies

How to administer Trametinib (Mekinist):

• It should be taken orally at least one hour before or two hours after a meal.
• Dosage should be taken at the same time every day.
• Trametinib should not be given more than once a day.

Mechanism of action of Trametinib (Mekinist):

• Trametinib selectively inhibits mitogen-activated ex kinase 1 and 2 activation, kinase activity, leading to decreased cell proliferation, cell cycle arrest and increased apoptosis.
• Combining trametinib with dabrafenib causes MAPK pathway inhibition at a greater scale.
• This results in BRAF V600 melanoma cells dying. Combining dabrafenib with Trametinib results in synergistic inhibitions of cell growth in lung carcinoma cell lines that are BRAF V600E mutation.

Absorption:

• Rapid; decreased with a high-fat, high-calorie meal (1,000 calories)

Distribution:

• 214 L

Protein binding:

• 97% to plasma proteins

Metabolism:

• Predominantly deacetylation (via hydrolytic enzymes) alone or with monooxygenation or in combination with glucuronidation

Bioavailability:

• 72%

Half-life elimination:

• 4 to 5 days

Time to peak:

• 1.5 hours; delayed with a high-fat, high-calorie meal (1,000 calories)

Excretion:

• Feces (>80%)
• urine (<20% with <0.1% as unchanged drug)

International Brands of Trametinib:

• Mekinist

Trametinib Brand Names in Pakistan:

No Brands Available in Pakistan.