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Mekinist

"The U.S. Food and Drug Administration today approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin "...

Mekinist

Mekinist Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Mekinist (trametinib) is a kinase inhibitor used to treat patients with melanoma with BRAF V600E or V600K mutations that are metastatic or unable to be removed by surgery (unresectable). Common side effects include acne, rosacea, dry skin, itching, infection of the skin around a fingernail or toenail, diarrhea, inflammation of the lining of the mouth, abdominal pain, fluid retention and swelling of the limbs, high blood pressure, or bleeding.

The recommended dose of Mekinist is 2 mg orally once daily. Take at least 1 hour before or 2 hours after a meal. Mekinist may interact with other drugs. Tell your doctor all medications and supplements you use. Mekinist can cause fetal harm and is not recommended during pregnancy. Tell your doctor if you become pregnant during treatment. It is unknown if this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants, consult your doctor before breastfeeding.

Our Mekinist (trametinib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Mekinist FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in another section of the label:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to MEKINIST as a single agent and in combination with dabrafenib. MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, > 99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST. The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with MEKINIST.

The safety of MEKINIST in combination with dabrafenib was evaluated in Trial 2 and other trials consisting of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received MEKINIST 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 202 patients, 68 (34%) were exposed to MEKINIST and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to MEKINIST and 40 (20%) were exposed to dabrafenib for greater than one year. The median age was 54 years, 57% were male and > 99% were white.

Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m² every 3 weeks or paclitaxel 175 mg/m² every 3 weeks) [see Clinical Studies]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with MEKINIST was 4.3 months. In Trial 1, 9% of patients receiving MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of MEKINIST were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most common reasons cited for dose reductions of MEKINIST.

Table 3: Selected Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKINIST and at a Higher Incidence ( ≥ 5%) Than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions

Adverse Reactions MEKINIST
N = 211
Chemotherapy
N = 99
All Gradesa Grades 3 and 4b All Gradesa Grades 3 and 4b
Skin and subcutaneous tissue disorders
  Rash 57 8 10 0
  Dermatitis acneiform 19 <1 1 0
  Dry skin 11 0 0 0
  Pruritus 10 2 1 0
  Paronychia 10 0 1 0
Gastrointestinal disorders
  Diarrhea 43 0 16 2
  Stomatitisc 15 2 2 0
  Abdominal paind 13 1 5 1
Vascular disorders
  Lymphedemae 32 1 4 0
  Hypertension 15 12 7 3
  Hemorrhagef 13 < 1 0 0
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.15
b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm.
c Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation.
d Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
e Includes the following terms: lymphedema, edema, and peripheral edema.
f Includes the following terms: epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.

Other clinically important adverse reactions observed in ≤ 10% of patients (N = 329) treated with MEKINIST were:

Cardiac Disorders: Bradycardia.

Gastrointestinal Disorders: Xerostomia.

Infections and Infestations: Folliculitis, rash pustular, cellulitis.

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Nervous System Disorders: Dizziness, dysgeusia.

Ocular Disorders: Vision blurred, dry eye.

Table 4: Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in Patients Treated With MEKINIST in Trial 1 (Between-Arm Difference of ≥ 5% [All Grades] or ≥ 2% [Grades 3 or 4]a)

Test MEKINIST
N = 211
Chemotherapy
N = 99
All Grades Grades 3 and 4 All Grades Grades 3 and 4
Increased aspartate aminotransferase (AST) 60 2 16 1
Increased alanine aminotransferase (ALT) 39 3 20 3
Hypoalbuminemia 42 2 23 1
Anemia 38 2 26 3
Increased alkaline phosphatase 24 2 18 3
a No Grade 4 events were reported in either treatment arm.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), MEKINIST 1 mg once daily in combination with dabrafenib 150 mg twice daily (N = 54), and dabrafenib as a single agent 150 mg twice daily (N = 53) [see Clinical Studies]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history of RVO, or RPED, QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both MEKINIST (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both MEKINIST (1-mg once-daily treatment group) and dabrafenib when used in combination, and 6.1 months for dabrafenib as a single agent.

In Trial 2, 13% of patients receiving MEKINIST in combination with dabrafenib at the recommended dose experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with MEKINIST in combination with dabrafenib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions, and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of MEKINIST and dabrafenib when used in combination.17

Table 5: Common Adverse Drug Reactions Occurring in > 10% (All Grades) or ≥ 5% (Grades 3 or 4) of Patients Treated With MEKINIST in Combination With Dabrafenib in Trial 2

Adverse Reactions MEKINIST 2 mg plus Dabrafenib
N = 55
MEKINIST 1 mg plus Dabrafenib
N = 54
Dabrafenib
N = 53
All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4
General disorders and administrative site conditions
Pyrexia 71 5 69 9 26 0
Chills 58 2 50 2 17 0
Fatigue 53 4 57 2 40 6
Edema peripheralb 31 0 28 0 17 0
Skin and subcutaneous tissue disorders
Rashc 45 0 43 2 53 0
Night Sweats 24 0 15 0 6 0
Dry skin 18 0 9 0 6 0
Dermatitis acneiform 16 0 11 0 4 0
Actinic keratosis 15 0 7 0 9 0
Erythema 15 0 6 0 2 0
Pruritus 11 0 11 0 13 0
Gastrointestinal disorders
Nausea 44 2 46 6 21 0
Vomiting 40 2 43 4 15 0
Diarrhea 36 2 26 0 28 0
Abdominal paind 33 2 24 2 21 2
Constipation 22 0 17 2 11 0
Dry mouth 11 0 11 0 6 0
Nervous system disorders
Headache 29 0 37 2 28 0
Dizziness 16 0 13 0 9 0
Respiratory, thoracic, and mediastinal disorders
Cough 29 0 11 0 21 0
Oropharyngeal pain 13 0 7 0 0 0
Musculoskeletal, connective tissue, and bone disorders
Arthralgia 27 0 44 0 34 0
Myalgia 22 2 24 0 23 2
Back pain 18 5 11 0 11 2
Muscle spasms 16 0 2 0 4 0
Pain in extremity 16 0 11 2 19 0
Metabolism and nutritional disorders
Decreased appetite 22 0 30 0 19 0
Dehydration 11 0 6 2 2 0
Psychiatric disorders
Insomnia 18 0 11 0 8 2
Vascular disorders
Hemorrhagee 16 5 11 0 2 0
Infections and infestations
Urinary tract infection 13 2 6 0 9 2
Renal and urinary disorders
Renal failuref 7 7 2 0 0 0
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.
b Includes the following terms: peripheral edema, edema, and lymphedema.
c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.
d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.
f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in < 10% of patients treated with MEKINIST in combination with dabrafenib were:

Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6: Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4)] of Patients Treated With MEKINIST in Combination With Dabrafenib in Trial 2

Test MEKINIST 2 mg plus Dabrafenib
N = 55
MEKINIST 1 mg plus Dabrafenib
N = 54
Dabrafenib

N = 53
All Grades Grades 3 and 4 All Grades Grades 3 and 4 All Grades Grades 3 and 4a
Hematology
  Leukopenia 62 5 46 4 21 0
  Lymphopenia 55 22 59 19 40 6
  Neutropenia 55 13 37 2 9 2
  Anemia 55 4 46 7 28 0
  Thrombocytopenia 31 4 31 2 8 0
Liver Function Tests
  Increased AST 60 5 54 0 15 0
  Increased alkaline phosphatase 60 2 67 6 26 2
  Increased ALT 42 4 35 4 11 0
  Hyperbilirubinemia 15 0 7 4 0 0
Chemistry
  Hyperglycemia 58 5 67 6 49 2
  Increased GGT 56 11 54 17 38 2
  Hyponatremia 55 11 48 15 36 2
  Hypoalbuminemia 53 0 43 2 23 0
  Hypophosphatemia 47 5 41 11 40 0
  Hypokalemia 29 2 15 2 23 6
  Increased creatinine 24 5 20 2 9 0
  Hypomagnesemia 18 2 2 0 6 0
  Hyperkalemia 18 0 22 0 15 4
  Hypercalcemia 15 0 19 2 4 0
  Hypocalcemia 13 0 20 0 9 0
a No Grade 4 events were reported in dabrafenib arm.
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to > 500 msec occurred in 4% (2/55) of patients treated with MEKINIST in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with MEKINIST in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent.

Read the entire FDA prescribing information for Mekinist (Trametinib Tablets) »

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