May 1, 2016
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Mekinist

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Mekinist

Side Effects
Interactions

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 to 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 Administered As A Single Agent

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.

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
  Acneiform dermatitis 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.
b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm.
c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation.
d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
e Includes lymphedema, edema, and peripheral edema.
f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.

Other clinically important adverse reactions observed in less than or equal to 10% of patients (N = 329) treated with MEKINIST were:

Cardiac Disorders: Bradycardia

Gastrointestinal Disorders: Dry mouth.

Infections and Infestations: Folliculitis, rash pustular, cellulitis.

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Nervous System Disorders: Dizziness, dysgeusia.

Ocular Disorders: Blurred vision, 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
Hypoalbuminemia 42 2 23 1
Increased alanine aminotransferase (ALT) 39 3 20 3
Anemia 38 2 26 3
Increased alkaline phosphatase 24 2 18 3
a No Grade 4 events were reported in either treatment arm.

MEKINIST Administered With Dabrafenib

The safety of MEKINIST, administered with dabrafenib, was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received Mekinist in two trials, Trial 2 (n = 209) multicenter, double-blind, randomized (1:1), active-controlled trial and Trial 3 (n = 350) a multicenter, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of G6PD deficiency.

Among these 559 patients, 197 (35%) were exposed to MEKINIST for > 6 months to 12 months while 185 (33%) were exposed to MEKINIST for > 1 year. The median age was 55 years (range: 18 to 91), 57% were male, and 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline, and 0.5% had a history of brain metastases.

The most commonly occurring adverse reactions ( ≥ 20%) for MEKINIST in patients receiving MEKINIST plus dabrafenib were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.

The demographics and baseline tumor characteristics of patients enrolled in Trial 2 are summarized in Clinical Studies [see Clinical Studies]. Patients receiving MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients receiving MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for > 6 months to 12 months while 46% were exposed to MEKINIST for > 1 year.

In Trial 2, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (18%), chills (7%), vomiting (6%) and decreased ejection fraction (4.8%).

Table 5 and Table 6 present selected adverse drug reactions and laboratory abnormalities, respectively, of MEKINIST observed in Trial 2.

Table 5: Incidence of Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in Trial 2a

Adverse Reactions Pooled MEKINIST plus Dabrafenib
N = 559
Trial 2
MEKINIST plus Dabrafenib
N =209
Dabrafenib
N = 211
All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%)
General disorders and administrative site conditions
  Pyrexia 54 5 57 7 33 1.9
  Chills 31 0.5 31 0 17 0.5
  Edema peripheralb 21 0.7 25 1.4 11 0.5
Gastrointestinal disorders
  Nausea 35 0.4 34 0.5 27 1.4
  Diarrhea 31 1.3 30 1.4 16 0.9
  Vomiting 27 1.1 25 1.0 14 0.5
  Abdominal painc 18 0.9 26 1.0 14 2.4
Nervous system disorders
  Dizziness 11 0.2 14 0 7 0
Vascular disorders
  Hypertension 26 11 25 6 16 6
  Hemorrhaged 18 2.0 19 1.9 15 1.9
Skin and subcutaneous tissue disorders
  Rashe 32 1.1 42 0 27 1.4
* ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.
b Includes peripheral edema, edema, lymphedema, localized edema , and generalized edema.
c Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort.
d Most common events ( ≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm).
e Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash.

Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients receiving MEKINIST in combination with dabrafenib (N = 559) were:

Cardiac Disorders: bradycardia

Musculoskeletal Disorders: rhabdomyolysis

Table 6: Treatment-Emergent Laboratory Abnormalities Occurring at ≥ 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in Trial 2

Test Pooled MEKINIST plus Dabrafenib
N = 559a
Trial 2
MEKINIST plus Dabrafenib
N = 209b
Dabrafenib
N = 211b
All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%) All Grades (%) Grades 3 and 4c (%)
Hematology
  Neutropenia 46 7 50 6 16 1.9
  Anemia 43 2.3 43 2.4 38 4.3
  Lymphopenia 32 8 38 9 28 7
  Thrombocytopenia 21 0.7 19 0.5 10 0.5
Liver Function Tests
  Increased AST 59 4.1 60 4.3 21 1.0
  Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5
  Increased ALT 48 4.5 44 3.8 28 1.0
Chemistry
  Hyperglycemia 60 4.7 65 6 57 4.3
  Hypoalbuminemia 48 1.1 53 1.4 27 0
  Hyponatremia 25 8 24 6 14 2.9
* ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent
AST = Aspartate aminotransferase; ALT = Alanine aminotransferase.
a For these laboratory tests the denominator is 556.
b For these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm.
c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, hyperglycemia (each n = 1) in the Trial 2 combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm.

Read the Mekinist (trametinib tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/22/2016

Side Effects
Interactions

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