Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety of trametinib monotherapy has been evaluated in the integrated safety population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with trametinib 2 mg once daily in studies MEK114267, MEK113583, and MEK111054. Of these patients, 211 were treated with trametinib for BRAF V600 mutant melanoma in the randomised open label Phase III study MEK114267 (METRIC) (see section 5.1). The most common adverse reactions (incidence ≥20%) for trametinib were rash, diarrhoea, fatigue, oedema peripheral, nausea, and dermatitis acneiform.

The safety of trametinib in combination with dabrafenib has been evaluated in the integrated safety population of 1,076 patients with BRAF V600 mutant unresectable or metastatic melanoma Stage III BRAF V600 mutant melanoma following complete resection (adjuvant treatment) and advanced NSCLC treated with trametinib 2 mg once daily and dabrafenib 150 mg twice daily. Of these patients, 559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase III studies, MEK115306 (COMBI-d) and MEK116513 (COMBI-v), 435 were treated with the combination in the adjuvant treatment of Stage III BRAF V600 mutant melanoma after complete resection in a randomised Phase III study BRF115532 (COMBI-AD) and 82 were treated with the combination for BRAF V600 mutant NSCLC in a multi-cohort, non-randomised Phase II study BRF113928 (see section 5.1).

The most common adverse reactions (incidence ≥ 20 %) for trametinib in combination with dabrafenib were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.
The safety of trametinib when administered with dabrafenib was also 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 (see section 5.1) Patients received trametinib 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 trametinib 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 of 0 and 60% had ECOG performance status of 1.
The adverse reaction profile among all patients in study BRF117019 was similar to that observed in other approved indications.
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Tabulated list of adverse reactions

Adverse reactions associated with trametinib obtained from clinical studies and post marketing surveillance are tabulated below for trametinib monotherapy (Table 6) and trametinib in combination with dabrafenib (Table 7).

Adverse reactions are listed below by MedDRA system organ class.
The following convention has been utilised for the classification of frequency: Very common        ≥1/10
Common             ≥1/100 to <1/10
Uncommon           ≥1/1,000 to <1/100
Rare               ≥1/10,000 to <1/1,000
Very rare          <1/10,000
Not known          (cannot be estimated from the available data)
Categories have been assigned based on absolute frequencies in the clinical trial data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 6. Adverse reactions with trametinib monotherapy

System Organ Class                Frequency (all           Adverse Reactions grades)
Folliculitis
Paronychia
Infections and infestations       Common
Cellulitis
Rash pustular
Blood and lymphatic system
Common                   Anaemia disorders
Immune system disorders           Common                   Hypersensitivitya Metabolism and nutrition
Common                   Dehydration disorders
Peripheral neuropathy (including sensory
Nervous system disorders          Common and motor neuropathy)
Vision blurred
Common                   Periorbital oedema
Visual impairment
Eye disorders                                              Chorioretinopathy Papilloedema
Uncommon
Retinal detachment
Retinal vein occlusion
Left ventricular dysfunction
Common                      Ejection fraction decreased
Cardiac disorders                                                 Bradycardia Uncommon                    Cardiac failure
Not known                   Atrioventricular blockb
Hypertension
Very common
Vascular disorders                                                Haemorrhagec Common                      Lymphoedema
Cough
Very common
Respiratory, thoracic and                                         Dyspnoea mediastinal disorders                 Common                      Pneumonitis Uncommon                    Interstitial lung disease
Diarrhoea
Nausea
Vomiting
Very common
Constipation
Gastrointestinal disorders                                        Abdominal pain Dry mouth
Common                      Stomatitis
Uncommon                    Gastrointestinal perforation
Colitis
Rash
Dermatitis acneiform
Very common                 Dry skin
Pruritus
Skin and subcutaneous tissue                                      Alopecia disorders                                                         Erythema Palmar-plantar erythrodysaesthesia
Common                      syndrome
Skin fissures
Skin chapped
Musculoskeletal and
Uncommon                    Rhabdomyolysis connective tissue disorders
Fatigue
Very common                 Oedema peripheral
General disorders and
Pyrexia administration site
Face oedema conditions
Common                      Mucosal inflammation
Asthenia
Very common                 Aspartate aminotransferase increased
Alanine aminotransferase increased
Investigations
Common                      Blood alkaline phosphatase increased
Blood creatine phosphokinase increased a
May present with symptoms such as fever, rash, increased liver transaminases, and visual disturbances.
b
Including atrioventricular block complete.
c
Events include but are not limited to: epistaxis, haematochezia, gingival bleeding, haematuria, and rectal, haemorrhoidal, gastric, vaginal, conjunctival, intracranial and post procedural haemorrhage.



Table 7. Adverse reactions with trametinib in combination with dabrafenib 

System Organ Class             Frequency (all           Adverse Reactions grades)
Very common              Nasopharyngitis
Urinary tract infection
Infections and infestations                             Cellulitis
Common                   Folliculitis
Paronychia
Rash pustular
Cutaneous squamous cell carcinomaa
Neoplasms benign,              Common                   Papillomab malignant and unspecified                               Seborrhoeic keratosis (incl cysts and polyps)                                 New primary melanomac Uncommon
Acrochordon (skin tags)
Neutropenia
Blood and lymphatic system                              Anaemia disorders                      Common                   Thrombocytopenia Leukopenia
Hypersensitivityd
Uncommon
Immune system disorders                                 Sarcoidosis
Rare                     Haemophagocytic lymphohistiocytosis
Very common              Decreased appetite
Dehydration
Metabolism and nutrition                                Hyponatraemia Common disorders                                               Hypophosphataemia Hyperglycaemia
Not known                Tumour lysis syndrome
Headache
Very common
Dizziness
Nervous system disorders
Peripheral neuropathy (including sensory
Common and motor neuropathy)
Vision blurred
Common                   Visual impairment
Uveitis
Eye disorders
Chorioretinopathy
Uncommon                 Retinal detachment
Periorbital oedema
Common                   Ejection fraction decreased
Cardiac disorders                                       Atrioventricular blocke Uncommon
Bradycardia
Not known                Myocarditis
Hypertension
Very common
Haemorrhagef
Vascular disorders
Hypotension
Common
Lymphoedema



Very common              Cough
Respiratory, thoracic and
Common                   Dyspnoea mediastinal disorders
Uncommon                 Pneumonitis
Abdominal paing
Constipation
Very common              Diarrhoea
Nausea
Vomiting
Gastrointestinal disorders
Dry mouth
Common
Stomatitis
Pancreatitis
Uncommon
Colitis
Rare                     Gastrointestinal perforation
Dry skin
Pruritus
Very common
Rash
Erythemah
Dermatitis acneiform
Actinic keratosis
Night sweats
Hyperkeratosis
Alopecia
Palmar-plantar erythrodysaesthesia
Skin and subcutaneous tissue   Common                   syndrome disorders                                               Skin lesion
Hyperhidrosis
Panniculitis
Skin fissures
Photosensitivity
Uncommon                 Acute febrile neutrophilic dermatosis
Stevens-Johnson syndrome
Drug reaction with eosinophilia and
Not Known systemic symptoms
Dermatitis exfoliative generalised



Arthralgia
Musculoskeletal and                                          Myalgia
Very common connective tissue disorders                                  Pain in extremity Muscle spasmsi
Renal failure
Renal and urinary disorders       Uncommon
Nephritis
Fatigue
Chills
Asthenia
General disorders and             Very common
Oedema peripheral administration site                                          Pyrexia conditions
Influenza-like illness
Mucosal inflammation
Common
Face oedema
Alanine aminotransferase increased
Very common
Aspartate aminotransferase increased
Investigations                                               Blood alkaline phosphatase increased Common                     Gamma-glutamyltransferase increased
Blood creatine phosphokinase increased
The safety profile from MEK116513 is generally similar to that of MEK115306 with the following exceptions: 1) The following adverse reactions have a higher frequency category as compared to MEK115306: muscle spasm (very common); renal failure and lymphoedema (common); acute renal failure (uncommon); 2) The following adverse reactions have occurred in MEK116513 but not in MEK115306: cardiac failure, left ventricular dysfunction, interstitial lung disease (uncommon); 3) The following adverse reaction has occurred in MEK116513 and BRF115532 but not in MEK115306 and BRF113928: rhabdomyolysis (uncommon).
a
Cutaneous squamous cell carcinoma (cuSCC): SCC, SCC of the skin, SCC in situ (Bowen’s disease) and keratoacanthoma b
Papilloma, skin papilloma c
Malignant melanoma, metastatic malignant melanoma, and superficial spreading melanoma Stage III d
Includes drug hypersensitivity e
Including atrioventricular block complete f
Bleeding from various sites, including intracranial bleeding and fatal bleeding g
Abdominal pain upper and abdominal pain lower h
Erythema, generalised erythema i
Muscle spasms, musculoskeletal stiffness

Description of selected adverse reactions

New malignancies
New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib. Please refer to the dabrafenib Prescribing Information.

Haemorrhage

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, occurred in patients taking trametinib as monotherapy and in combination with dabrafenib. The majority of bleeding events were mild. Fatal intracranial haemorrhages occurred in the integrated safety population of trametinib in combination with dabrafenib in <1% (8/1076) of patients. The median time to onset of the first occurrence of haemorrhagic events for the combination of trametinib and dabrafenib was 94 days in the melanoma Phase III studies and 75 days in the NSCLC study for the patients who had received prior anti-cancer therapy.

The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy. If haemorrhage occurs, treat as clinically indicated (see section 4.4).
LVEF reduction/Left ventricular dysfunction

Trametinib has been reported to decrease LVEF when used as monotherapy or in combination with dabrafenib. In clinical trials, the median time to first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease was between 2 to 5 months. In the integrated safety population of trametinib in combination with dabrafenib, decreased LVEF has been reported in 6% (65/1076) of patients, with most cases being asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with trametinib. Trametinib should be used with caution in patients with conditions that could impair left ventricular function (see sections 4.2 and 4.4).

Pyrexia

Pyrexia has been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib; however, the incidence and severity of pyrexia are increased with the combination therapy. Please refer to sections 4.4 and 4.8 of the dabrafenib Prescribing Information.

Hepatic events

Hepatic adverse reactions have been reported in clinical trials with trametinib as monotherapy and in combination with dabrafenib. Of the hepatic adverse reactions, increased ALT and AST were the most common events and the majority were either Grade 1 or 2. For trametinib monotherapy, more than 90% of these liver events occurred within the first 6 months of treatment. Liver events were detected in clinical trials with monitoring every four weeks. It is recommended that patients receiving treatment with trametinib monotherapy or in combination with dabrafenib have liver function monitored every four weeks for 6 months. Liver monitoring may be continued thereafter as clinically indicated (see section 4.4).

Hypertension

Elevations in blood pressure have been reported in association with trametinib as monotherapy and in combination with dabrafenib, in patients with or without pre-existing hypertension. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate (see section 4.4).

Interstitial lung disease (ILD)/Pneumonitis

Patients treated with trametinib or combination with dabrafenib may develop ILD or pneumonitis.
Trametinib should be withheld in patients with suspected ILD or pneumonitis, including patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnoea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. For patients diagnosed with treatment-related ILD or pneumonitis trametinib should be permanently discontinued (see sections 4.2 and 4.4).

Visual impairment

Disorders associated with visual disturbances, including RPED and RVO, have been observed with trametinib. Symptoms such as blurred vision, decreased acuity, and other visual disturbances have been reported in the clinical trials with trametinib (see sections 4.2 and 4.4).

Rash

Rash has been observed in about 60% of patients when given as monotherapy and in about 24% of patients in trametinib and dabrafenib combination studies in the integrated safety population. The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions (see sections 4.2 and 4.4).

Rhabdomyolysis

Rhabdomyolysis has been reported in patients taking trametinib alone or in combination with dabrafenib. Signs or symptoms of rhabdomyolysis should warrant an appropriate clinical evaluation and treatment as indicated (see section 4.4).

Pancreatitis

Pancreatitis has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib Prescribing Information.

Renal failure

Renal failure has been reported with dabrafenib in combination with trametinib. Please see the dabrafenib Prescribing Information.

Special populations

Paediatric
Pediatric Safety Pool
The pediatric pooled safety population reflects exposure to weight-based trametinib orally, once daily administered in combination with dabrafenib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43) (see section 5.1). Among 166 patients who received trametinib administered with dabrafenib, 85% were exposed for 6 months and 69% were exposed for greater than one year. The most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%).
The most common (> 2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).


BRAF V600E Mutation-Positive Solid Tumors in Pediatric Patients
Study CTMT212X2101 (X2101)
The safety of trametinib when administered with dabrafenib was evaluated in Study X2101, a multi- center, open-label, multi-cohort study in pediatric patients (n=48) with refractory or recurrent solid tumors activation (see section 5.1) The median duration of exposure to trametinib 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 trametinib with dabrafenib was 9 years (range: 1 to 17).
Serious adverse reactions occurred in 46% of patients who received trametinib in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (25%) and decreased ejection fraction (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 increased ALT (6%), increased AST (4.2%) and decreased ejection fraction (4.2%).
Dose interruptions due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dose interruption in > 5% of patients included pyrexia (56%), vomiting (19%), neutropenia (13%), rash (13%), decreased ejection fraction (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 8 and Table 9.
Table 8 summarizes the adverse reactions in Study X2101.
Table 8. Adverse Reactions (>20%) in Pediatric Patients Treated with Trametinib Plus Dabrafenib in Study X2101
Trametinib plus Dabrafeniba
(N=48)
Adverse Reactions
All Grades                   Grade 3 or 4
(%)                           (%)
General
Pyrexia                                             75                                  17 Fatigueb                                            48                                   0 Skin and subcutaneous tissue
Rashc                                               73                                  2.1 Dry skin                                            48                                   0 Dermatitis acneiformd                               40                                   0 Gastrointestinal
Vomiting                                            52                                  4.2 Diarrhea                                            42                                  2.1 Abdominal paine                                     33                                  4.2 Nausea                                              33                                  2.1 Constipation                                        23                                   0 Respiratory system
Cough                                               44                                   0 Nervous system
Headache                                            35                                   0 Vascular
Hemorrhagef                                         33                                   0 Infections and infestations
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.
Clinically relevant adverse reactions for trametinib in Study X2101 observed in less than 20% of patients (N=48) who received trametinib in combination with dabrafenib were: atrioventricular block (2.1%).


Table 9 summarizes the laboratory abnormalities in Study X2101.
Table 9. Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Pediatric Patients Treated with Trametinib Plus Dabrafenib in Study X2101
Laboratory Abnormality                              Trametinib plus Dabrafeniba 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 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
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.


BRAF V600E Mutation-Positive Low-Grade Glioma in Pediatric Patients
Study CDRB436G2201 (G2201)
The safety of trametinib in combination with dabrafenib was evaluated in pediatric patients 1 to < 18 years of age in Study G2201. Patients with low-grade glioma (LGG) who required first systemic therapy were randomized (2:1) to trametinib plus dabrafenib (n = 73) or carboplatin plus vincristine (n = 33). Nine patients crossed over from the carboplatin plus vincristine arm to the trametinib and dabrafenib arm. Pediatric patients received weight-based trametinib orally once daily administered in combination with dabrafenib until disease progression or intolerable toxicity. Patients in the control arm received carboplatin and vincristine at doses of 175 mg/m2 and 1.5 mg/m2, respectively in 10- week induction course followed by eight 6-week cycles of maintenance therapy or until disease progression or intolerable toxicity. Among patients with low-grade glioma who were randomized to trametinib plus dabrafenib (n = 73), 95% were exposed for 6 months or longer and 71% were exposed for greater than one year.
The median age of these patients was 10 years (range: 1 to 17); 60% female; 75% White, 7% Asian, 2.7% Black or African American, 4% other race and 11% where race was unknown or not reported.
Serious adverse reactions occurred in 40% of these patients. Serious adverse reactions in > 3% of patients included pyrexia (14%) and vomiting (4%).
Permanent discontinuation of trametinib due to an adverse reaction occurred in 4% of patients.
Adverse reactions which resulted in permanent discontinuation of trametinib included chills, fatigue, pyrexia, weight increased, and headache.
Dosage interruptions of trametinib due to an adverse reaction occurred in 70% of patients. Adverse reactions which required a dosage interruption in > 5% of patients included pyrexia (52%).
Dose reductions of trametinib due to an adverse reaction occurred in 12% of patients. Adverse reactions which required dose reductions in > 2% of patients included weight increased (2.7%).
The most common (≥ 15%) adverse reactions were pyrexia (68%), rash (51%), headache (47%), vomiting (34%), musculoskeletal pain (34%), fatigue (33%), diarrhea (29%), dry skin (26%), nausea (25%), hemorrhage (25%), abdominal pain (25%), dermatitis acneiform (22%), dizziness (15%), upper respiratory tract infection (15%), and weight increased (15%).
The most common (≥ 20%) laboratory abnormalities that worsened from baseline were leukopenia (59%), increased alkaline phosphatase (55%), anemia (46%), decreased neutrophils (44%), increased AST (37%), decreased magnesium (34%), increased magnesium (32%), decreased platelets (30%), increased ALT (29%), and increased lymphocytes (24%).


Table 10 summarizes the adverse reactions in Study G2201.

Table 10. Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received Trametinib in Combination with Dabrafenib in Study G2201a
Trametinib plus Dabrafenib          Carboplatin plus Vincristine
Adverse Reactions                                        N = 73                          N = 33 
All Grades             Grade ≥ 3   All Grades       Grade ≥ 3
(%)                  (%)           (%)            (%)
Gastrointestinal
Vomiting                                  34                    1            48               3 Diarrheab                                 29                    0            18               6 Nausea                                    25                    0            45               0 c
Abdominal pain                            25                    0            24               0 Constipation                              12                    0            36               0 Stomatitisd                               10                    0            18               0 General
Pyrexiae                                  68                    8            18               3 Fatiguef                                  33                    0            39               0 Nervous system
Headacheg                                 47                    1            33               3 Dizzinessh                                15                    0            9                3 Peripheral neuropathyi                     7                    0            45               6 Vascular
Hemorrhagej                               25                    0            12               0 Skin and subcutaneous tissue
Rashk                                     51                    2.7          18               3 Dry skin                                  26                     0           3                0 Dermatitis acneiforml                     22                     0           0                0 Alopecia                                   3                     0           24               0 Musculoskeletal and connective tissue
Musculoskeletal painm                     34                    0            30               0 Pain in jaw                               1.4                   0            18               0 Metabolism and nutrition
Decreased appetite                         5                    0            24               0 Respiratory, thoracic and mediastinal
Oropharyngeal pain                        11                    0            18               0 Psychiatric
Anxiety                                   1.4                   0            15               3 Immune system
Hypersensitivity                           0                    0            15               3 Infections and infestations
Upper respiratory tract infection         15                    0            6                0 Injury, poisoning and procedural complications
Infusion related reaction                   0                    0            15               3 Investigations
Weight increased                           15                    7            0                0 


aNCI  CTCAE version 4.03.
bIncludes diarrhea, colitis, enterocolitis, and enteritis.
cIncludes abdominal pain and upper abdominal pain.
dIncludes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis.
eIncludes pyrexia and body temperature increased.
fIncludes fatigue and asthenia.
gIncludes headache and migraine with aura.
hIncludes dizziness and vertigo.
iIncludes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia, hypoaesthesia, and  peripheral sensory neuropathy.
jIncludes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage intracranial.
kIncludes rash, rash macular, rash maculo-papular, rash pustular, rash papular, rash erythematous, eczema, erythema multiforme, dermatitis,  dermatitis exfoliative, skin exfoliation, palmar-plantar erythrodysaesthesia syndrome, and dermatitis bullous.
lIncludes dermatitis acneiform, acne, and acne pustular.
mIncludes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness.

Table 11 summarizes the laboratory abnormalities in Study G2201.
Table 11. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received Trametinib in Combination with Dabrafenib in Study G2201a Trametinib plus Dabrafenib                  Carboplatin plus Vincristine N = 73                                  N = 33
Laboratory Abnormality
All Grades            Grade 3 or 4            All Grades           Grade 3 or 4 (%)                    (%)                   (%)                    (%) Hepatic
Increased alkaline phosphatase                             55                     0                     13                     0 Increased AST                                              37                    1.4                    55                     0 Increased ALT                                              29                     3                     61                     9 Chemistry
Decreased magnesium                                        34                    4.1                    76                     6 Increased magnesium                                        32                     0                     24                     3 Increased potassium                                        15                    4.2                    21                     6 Decreased calcium                                          14                    4.1                    22                     9 Decreased potassium                                        8                     1.4                    70                     0 Decreased phosphate                                        7                     2.7                    33                     3 Decreased sodium                                           5                     1.4                    27                     6 Increased serum fasting glucose                            0                      0                     44                     0 Hematology
Decreased leukocytes                                       59                     0                     91                    18 Decreased hemoglobin                                       46                     0                     94                    36 Decreased neutrophils                                      44                    17                     84                    75 Decreased platelets                                        30                     0                     73                    18 Increased lymphocytes                                      24                     0                     13                    3.1 Decreased lymphocytes                                      16                    1.4                    56                     6 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a
The denominator used to calculate the rate varied from 70 to 73 in D+T arm and 9 to 33 in C + V arm based on the number of patients with a baseline value and at least one post-treatment value.

Elderly

In the Phase III study with trametinib in patients with unresectable or metastatic melanoma (n = 211), 49 patients (23%) were ≥65 years of age, and 9 patients (4%) were ≥75 years of age. The proportion of subjects experiencing adverse reactions (AR) and serious adverse reactions (SAR) was similar in the subjects aged <65 years and those aged ≥65 years. Patients ≥65 years were more likely to experience ARs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
In the integrated safety population of trametinib in combination with dabrafenib (n=1,076) 265 patients (25%) were ≥65 years of age; 62 patients (6%) were ≥75 years of age. The proportion of patients experiencing ARs was similar in those aged <65 years and those aged ≥65 years in all studies.
Patients ≥65 years were more likely to experience SARs and ARs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
Of the 26 patients with ATC who received trametinib in Study BRF117019, 77% were aged 65 years and older and 31% were aged 75 years and older (see section 5.1). This study did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

Renal impairment

No dosage adjustment is required in patients with mild or moderate renal impairment (see section 5.2).
Trametinib should be used with caution in patients with severe renal impairment (see sections 4.2 and 4.4).

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment (see section 5.2).
Trametinib should be used with caution in patients with moderate or severe hepatic impairment (see sections 4.2 and 4.4)

Trametinib in combination with dabrafenib in patients with brain metastases 
The safety and efficacy of the combination of trametinib and dabrafenib have been evaluated in a multi-cohort, open-label, Phase II study in patients with BRAF V600 mutant melanoma with brain metastases. The safety profile observed in these patients appears to be consistent with the integrated safety profile of the combination.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il
And to Novartis using the following email address: safetydesk.israel@novartis.com