MEKINIST SIDE EFFECTS

Generic Name: trametinib tablets
Brand Name: Mekinist
Drug Class: Antineoplastics MEK Inhibitors

Last updated on MDtodate: 10/7/2022

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

New Primary Malignancies
Hemorrhage
Colitis and Gastrointestinal Perforation
Venous Thromboembolism
Cardiomyopathy
Ocular Toxicities
Interstitial Lung Disease/Pneumonitis
Serious Febrile Reactions
Serious Skin Toxicities
Hyperglycemia

There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing information for additional information.

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 pooled safety populations described in the WARNINGS and PRECAUTIONS reflect exposure to MEKINIST as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054, and to MEKINIST administered with dabrafenib in 1087 patients enrolled in COMBI-d, COMBIv COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among the 329 patients who received MEKINIST as a single agent, 33% were exposed for 6 months or longer and 9% were exposed for at least one year. Among the 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year.

Unresectable Or Metastatic BRAF V600E Or V600K Mutation-Positive Melanoma

MEKINIST as a Single Agent

The safety of MEKINIST was evaluated in the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1000 mg/m² every 3 weeks or paclitaxel 175 mg/m² every 3 weeks) . 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. The median duration of treatment with MEKINIST was 4.3 months.

In this study, 9% of patients who received MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most frequent adverse reactions resulting in permanent discontinuation of MEKINIST were decreased 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 frequent reasons cited for dose reductions of MEKINIST. Tables 1 and 6 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as a single agent in the METRIC study.

Table 1. Select Adverse Reactions Occurring in ≥ 10% of Patients Who Received MEKINIST and at a Higher Incidence (≥ 5%) Than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions in METRIC

Adverse Reactions	MEKINIST N = 211		Chemotherapy N = 99
Adverse Reactions	All Grades^a (%)	Grades 3 and 4^b (%)	All Grades^a (%)	Grades 3 and 4^b (%)
Skin and subcutaneous tissue
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
Diarrhea	43	0	16	2
Stomatitis^c	15	2	2	0
Abdominal pain^d	13	1	5	1
Vascular
Lymphedema^e	32	1	4	0
Hypertension	15	12	7	3
Hemorrhage^f	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 ≤ 10% of patients (N = 329) who received MEKINIST were:

Cardiac: Bradycardia

Gastrointestinal: Dry mouth

Infections: Folliculitis, rash pustular, cellulitis

Musculoskeletal and Connective Tissue: Rhabdomyolysis

Nervous System: Dizziness, dysgeusia

Ocular: Blurred vision, dry eye

Table 2. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)^a]

Laboratory Abnormality	MEKINIST N = 211		Chemotherapy N = 99
Laboratory Abnormality	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 Only Grade 3 adverse reactions were reported in either treatment arm.

MEKINIST 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, the COMBI-d study (n = 209), a multicenter, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (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 LVEF, 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 glucose-6-phosphate dehydrogenase 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 lactate dehydrogenase (LDH) at baseline, and 0.5% had a history of brain metastases.

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

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

In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients who received MEKINIST plus dabrafenib; the most frequent 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 who received MEKINIST plus dabrafenib; the most frequent were pyrexia (18%), chills (7%), vomiting (6%), and decreased ejection fraction (4.8%).

Table 3 and Table 8 present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study.

Table 3. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d^a

Adverse Reactions	Pooled MEKINIST plus Dabrafenib N = 559		COMBI-d Study
	Pooled MEKINIST plus Dabrafenib N = 559		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
Pyrexia	54	5	57	7	33	1.9
Chills	31	0.5	31	0	17	0.5
Peripheral edema^b	21	0.7	25	1.4	11	0.5
Gastrointestinal
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 pain^c	18	0.9	26	1.0	14	2.4
Skin
Rash^d	32	1.1	42	0	27	1.4
Vascular
Hypertension	26	11	25	6	16	6
Hemorrhage^e	18	2.0	19	1.9	15	1.9
Nervous system
Dizziness	11	0.2	14	0	7	0
*≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. ^a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. ^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 Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. ^e 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).

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

Cardiac: Bradycardia

Immunologic: Sarcoidosis

Musculoskeletal:Rhabdomyolysis

Table 4. Laboratory Abnormalities Worsening From Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d

Laboratory Abnormality	Pooled MEKINIST plus Dabrafenib N = 559^a		COMBI-d Study
	Pooled MEKINIST plus Dabrafenib N = 559^a		MEKINIST plus Dabrafenib N = 209^b		Dabrafenib N = 211^b
	All Grades (%)	Grades 3 and 4^c (%)	All Grades (%)	Grades 3 and 4^c (%)	All Grades (%)	Grades 3 and 4^c (%)
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
Hepatic
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
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
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. *≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. ^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 COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm.

Adjuvant Treatment Of BRAF V600E Or V600K Mutation-Positive Melanoma

The safety of MEKINIST when administered with dabrafenib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily for 12 months. The trial excluded patients with abnormal LVEF; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO.

Patients who received MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients who received MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months. The median age of patients who received MEKINIST in combination with dabrafenib was 50 years (range: 18 to 89), 56% were male, 99% were white, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status 1.

The most common adverse reactions (≥ 20%) in patients who received MEKINIST in combination with dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most frequent for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most frequent were pyrexia and decreased ejection fraction.

Table 5 summarizes adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib.

Table 5. Adverse Reactions Occurring in ≥ 20% of Patients in COMBI-ADa Adverse Reactions

Adverse Reactions	MEKINIST plus Dabrafenib N = 435		Placebo N = 432
Adverse Reactions	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
General
Pyrexia^b	63	5	11	<1
Fatigue^c	59	5	37	<1
Chills	37	1	4	0
Gastrointestinal
Nausea	40	< 1	20	0
Diarrhea	33	< 1	15	< 1
Vomiting	28	< 1	10	0
Nervous system
Headache^d	39	1	4	0
Skin
Rash^e	37	< 1	16	< 1
Musculoskeletal
Arthralgia	28	< 1	14	0
Myalgia^f	20	< 1	14	0
^a NCI CTCAE version 4.0. ^b Includes pyrexia and hyperpyrexia. ^c Includes fatigue, asthenia, and malaise. ^d Includes headache and tension headache. ^e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. ^f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain.

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received MEKINIST in combination with dabrafenib were: blurred vision (6%), decreased ejection fraction (5%), rhabdomyolysis (< 1%), and sarcoidosis (< 1%).

The laboratory abnormalities are summarized in Table 6.

Table 6. Laboratory Abnormalities Worsening From Baseline Occurring in ≥ 20% of Patients in COMBI-AD

Laboratory Abnormality	MEKINIST plus Dabrafenib^a N = 435		Placebo^a N = 432
Laboratory Abnormality	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Chemistry
Hyperglycemia	63	3	47	2
Hypophosphatemia	42	7	10	<1
Hypoalbuminemia	25	<1	<1	0
Hepatic
Increased AST	57	6	11	<1
Increased ALT	48	5	18	<1
Increased blood alkaline phosphatase	38	1	6	<1
Hematology
Neutropenia	47	6	12	<1
Lymphopenia	26	5	6	<1
Anemia	25	<1	6	<1
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. ^a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428).

MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428).

Trial COMBI-APlus (Pyrexia Management Study)

COMBI-APlus evaluated the impact of pyrexia related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F.

Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients.

Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer

The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of ILD or pneumonitis, or history or current RVO.

Among these 93 patients, 53 (57%) were exposed to MEKINIST and dabrafenib for > 6 months and 27 (29%) were exposed to MEKINIST and dabrafenib for ≥ 1 year. The median age was 65 years (range: 41 to 91), 46% were male, 85% were white; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.

The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of MEKINIST occurred in 19% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and decreased ejection fraction (5%).

Table 7 and Table 12 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF113928.

Table 7. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated With MEKINIST plus Dabrafenib in Study BRF113928a

Adverse Reactions	MEKINIST plus Dabrafenib N = 93
Adverse Reactions	All Grades (%)	Grades 3 and 4^b (%)
General
Pyrexia	55	5
Fatigue^b	51	5
Edema^c	28	0
Chills	23	1.1
Gastrointestinal
Nausea	45	0
Vomiting	33	3.2
Diarrhea	32	2.2
Decreased appetite	29	0
Skin
Dry skin	31	1.1
Rash^d	28	3.2
Vascular
Hemorrhagee	23	3.2
Respiratory system
Cough	22	0
Dyspnea	20	5
^a NCI CTCAE version 4.0. ^b Includes fatigue, malaise, and asthenia. ^c Includes peripheral edema, edema, and generalized edema. ^d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. ^e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

Table 8 : Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received MEKINIST plus Dabrafenib in Study BRF113928

Laboratory Abnormality	MEKINIST plus Dabrafenib N = 93
Laboratory Abnormality	All Grades (%)	Grades 3 and 4 (%)
Chemistrya
Hyperglycemia	71	9
Hyponatremia	57	17
Hypophosphatemia	36	7
Increased creatinine	21	1.1
Hepatica
Increased blood alkaline phosphatase	64	0
Increased AST	61	4.4
Increased ALT	32	6
Hematologyb
Leukopenia	48	8
Anemia	46	10
Neutropenia	44	8
Lymphopenia	42	14
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. ^a For these laboratory tests the denominator is 90. ^b For these laboratory tests the denominator is 91.

Advanced BRAF V600E-Mutation Positive Tumors

Study BRF117019

The safety of MEKINIST when administered with dabrafenib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). A total of 206 patients were enrolled in the trial, 36 of whom were enrolled in the ATC cohort, 105 were enrolled in specific solid tumor cohorts, and 65 in other malignancies. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity.

Among these 206 patients, 101 (49%) were exposed to MEKINIST for ≥ 1 year and 103 (50%) were exposed to dabrafenib for ≥ 1 year. The median age was 60 years (range: 18 to 89); 56% were male; 79% were white; and 34% had baseline ECOG performance status 0 and 60% had ECOG performance status 1.

Serious adverse reactions occurred in 45% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%). Fatal adverse reactions occurred in 3.9% of patients who received MEKINIST in combination with dabrafenib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%).

Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%).

Dosage interruptions due to an adverse reaction occurred in 55% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (22%), chills (9%), fatigue (6%), neutropenia, (6%), and nausea (5%).

Dose reductions due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (18%), chills (8%), and fatigue (6%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, are listed in Table 13 and Table 14.

Table 9 summarizes the adverse reactions in Study BRF117019.

Table 9 : Adverse Reactions (≥20%) in Adult Patients Treated With MEKINIST Plus Dabrafenib in Study BRF117019

Adverse Reactions	MEKINIST plus Dabrafenib^a (n=206)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)
General
Pyrexia	55	4.95
Fatigue^b	50	5
Chills	30	0.5
Edema peripheral^c	22	0
Gastrointestinal
Nausea	40	1.5
Constipation	27	0
Vomiting	27	1.5
Diarrhea	26	2.93
Skin
Rash^d	40	2.4
Nervous system
Headache	30	1.5
Vascular disorders
Hemorrhage^e	29	4.4
Respiratory
Cough^f	29	0
Musculoskeletal and Connective Tissue
Myalgia^g	24	0.5
Arthralgia	23	0.5
^a NCI CTCAE version 4.0. ^b Includes fatigue, asthenia, and malaise. ^c Includes edema peripheral and peripheral swelling. ^d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. ^e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melaena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. ^f Includes cough and productive cough. ^g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain.

Clinically relevant adverse reactions in < 20% of adult patients who received MEKINIST in combination with dabrafenib included ejection fraction decreased (8.3%), uveitis (1.9%) and hypersensitivity (1.9%). Table 10 summarizes the laboratory abnormalities in Study BRF117019.

Table 10 : Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Adult Patients Treated With MEKINIST Plus Dabrafenib in Study BRF117019

Laboratory Abnormality	MEKINIST plus Dabrafenib^a
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hyperglycemia	61	8
Decreased sodium	35	10
Decreased magnesium	24	0
Increased creatinine	21	1.5
Hepatic
Increased alkaline phosphatase	51	5
Increased AST	51	4.6
Increased ALT	39	3
Hematology
Decreased hemoglobin	44	9
^a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value.

Study CTMT212X2101 (X2101)

The safety of MEKINIST when administered with dabrafenib was evaluated in Study X2101, a multi-center, open-label, multiple cohort study in pediatric patients (n=48) with refractory or recurrent solid tumors activation .The median duration of exposure to MEKINIST in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.4 months, respectively. The median duration of exposure to dabrafenib in Parts C and D was 20.8 and 24.9 months, respectively. The median age of pediatric patients who received MEKINIST with dabrafenib was 9 years (range: 1 – 17 years).

Serious adverse reactions occurred in 46% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (25%) and ejection fraction decreased (6%). Permanent treatment discontinuation due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 3% of patients included ALT increased (6%), AST increased (4.2%) and ejection fraction decreased (4.2%). Dosage interruptions due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (56%), vomiting (19%), neutropenia (13%), rash (13%), ejection fraction decreased (6%) and uveitis (6%).

Dose reductions due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (13%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, are listed in Table 15 and Table 16.

Table 11 summarizes the adverse reactions in Study X2101.

Table 11 : Adverse Reactions (≥20%) in Pediatric Patients Treated With MEKINIST Plus Dabrafenib

Adverse Reactions	MEKINIST plus Dabrafenib (n=48)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)
General
Pyrexia	75	17
Fatigue^b	48	0
Skin
Rash^c	73	2.1
Dry skin	48	0
Dermatitis acneiform^d	40	0
Gastrointestinal
Vomiting	52	4.2
Diarrhea	42	2.1
Abdominal pain^e	33	4.2
Nausea	33	2.1
Constipation	23	0
Respiratory
Cough	44	0
Nervous system
Headache	35	0
Vascular discorders
Hemorrhage^f	33	0
Infections
Paronychia	23	0
^a NCI CTCAE version 4.0. ^b Includes fatigue, asthenia and malaise. ^c Includes rash, rash maculo-papular, rash erythematous, rash papular, rash pustular, and rash macular. ^d Includes dermatitis acneiform and acne. ^e Includes abdominal pain and abdominal pain upper. ^f Includes epistaxis, hematuria, contusion, hematoma, petechiae, rectal hemorrhage, and red blood cell count decreased.

Table12 summarizes the laboratory abnormalities in Study X2101.

Table 12: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Pediatric Patients Treated With MEKINIST Plus Dabrafenib in Study X2101

Laboratory Abnormality	MEKINIST plus Dabrafenib^a
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hyperglycemia	65	2.2
Hypoalbuminemia	48	2.1
Hypocalcemia	40	2.1
Decreased phosphate	38	0
Decreased magnesium	33	2.1
Hypernatremia	27	0
Hypokalemia	21	2.1
Hepatic
Increased AST	55	4.2
Increased ALT	40	6
Increased alkaline phosphatase	28	6
Increased total bilirubin	21	2.1
Hematology
Decreased hemoglobin	60	6
Decreased neutrophils	49	28
^a The denominator used to calculate the rate varied from 39 to 48 based on the number of patients with a baseline value and at least one post-treatment value.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of MEKINIST in combination with dabrafenib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: SCAR (including DRESS and SJS)

SRC: NLM .

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