Adverse reactions : תופעות לוואי

4.8         Undesirable effects

Summary of the safety profile
The safety of dabrafenib monotherapy is based on the integrated safety population from five 
clinical trials, BRF113683 (BREAK-3), BRF113929 (BREAK-MB), BRF113710 (BREAK- 2), BRF113220, and BRF112680, which included 578 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with dabrafenib 150 mg twice daily. The most common adverse reactions (incidence ≥15%) reported with dabrafenib were hyperkeratosis, headache, pyrexia, arthralgia, fatigue, nausea, papilloma, alopecia, rash and vomiting.

The safety of dabrafenib in combination with trametinib has been evaluated in the integrated safety population of 1076 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 dabrafenib 150 mg twice daily and trametinib 2 mg once daily. Of these patients, 559 were treated with the combination for BRAF V600 mutant melanoma in two randomised Phase III clinical trials , 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 dabrafenib in combination with trametinib were: pyrexia, fatigue, nausea, chills, headache, diarrhoea, vomiting, arthralgia and rash.

The safety of dabrafenib when administered with trametinib 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 dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.
Among these 206 patients, 103 (50%) were exposed to dabrafenib for ≥ 1 year and 101 (49%) were exposed to trametinib 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.

Tabulated list of adverse reactions

Adverse reactions associated with dabrafenib obtained from clinical studies and post- marketing surveillance are tabulated below for dabrafenib monotherapy (Table 5) and dabrafenib in combination with trametinib (Table 6). Adverse reactions are listed below by MedDRA system organ class and ranked by frequency using the following convention: 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.



Table 5. Adverse reactions with dabrafenib monotherapy

System organ class                Frequency (all grades)   Adverse reactions Very common              Papilloma
Cutaneous squamous cell carcinoma
Neoplasms benign, malignant                                Seborrhoeic keratosis and unspecified (incl cysts and   Common polyps)                                                    Acrochordon (skin tags) Basal cell carcinoma
Uncommon                 New primary melanoma
Immune system disorders           Uncommon                 Hypersensitivity Very common              Decreased appetite
Metabolism and nutrition
Hypophosphataemia disorders                         Common
Hyperglycaemia
Very common              Headache
Nervous system disorders                                   Peripheral neuropathy (including Common sensory and motor neuropathy)
Eye disorders                     Uncommon                 Uveitis
Respiratory, thoracic and
Very common              Cough mediastinal disorders
Nausea
Very common              Vomiting
Gastrointestinal disorders                                 Diarrhoea
Common                   Constipation
Uncommon                 Pancreatitis
Hyperkeratosis
Alopecia
Very common              Rash
Palmar –plantar erythrodysaesthesia syndrome
Skin and subcutaneous tissue                               Dry skin disorders                                                  Pruritus
Actinic keratosis
Common
Skin lesion
Erythema
Photosensitivity
Uncommon                 Panniculitis
Arthralgia
Musculoskeletal and
Very common              Myalgia connective tissue disorders
Pain in extremity
Renal failure, acute renal failure
Renal and urinary disorders       Uncommon
Nephritis
Pyrexia
Fatigue
General disorders and             Very common
Chills administration site conditions
Asthenia
Common                   Influenza-like illness



Table 6 . Adverse reactions with dabrafenib in combination with trametinib 
System organ class             Frequency (all grades)      Adverse reactions 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
Common disorders                                                  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
Common sensory and motor neuropathy)
Vision blurred
Common                      Visual impairment
Uveitis
Eye disorders
Chorioretinopathy
Uncommon                    Retinal detachment
Periorbital oedema
Ejection fraction decreased
Common
Atrioventricular blocke
Cardiac disorders              Uncommon                    Bradycardia Not known                   Myocarditis
Hypertension
Very common
Haemorrhagef
Vascular disorders
Hypotension
Common
Lymphoedema
Very common                 Cough
Respiratory, thoracic and mediastinal disorders          Common                      Dyspnoea


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
Common        Palmar-plantar erythrodysaesthesia
Skin and subcutaneous tissue syndrome disorders
Skin lesion
Hyperhidrosis
Panniculitis
Skin fissures
Photosensitivity
Stevens-Johnson syndrome
Drug reaction with eosinophilia and
Not known     systemic symptoms
Dermatitis exfoliative generalised
Arthralgia
Myalgia
Musculoskeletal and
Very common   Pain in extremity connective tissue disorders
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
Investigations                 Very common
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Gamma-glutamyltransferase increased
Common
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 (cu SCC): 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
Atrioventricular block, atrioventricular block first degree, atrioventricular block second degree, 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
Cutaneous squamous cell carcinoma

For dabrafenib monotherapy in study MEK115306, cutaneous squamous cell carcinomas (including those classified as keratoacanthoma or mixed keratoacanthoma subtype) occurred in 10% of patients and approximately 70% of the events occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks. In the integrated safety population for dabrafenib in combination with trametinib, 2% of patients developed cuSCC and the events occurred later than with dabrafenib monotherapy with a median time to onset of 18-31 weeks.
All patients receiving dabrafenib as monotherapy or in combination with trametinib who developed cuSCC continued on treatment without dose modification.

New primary melanoma

New primary melanomas have been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib in melanoma studies. Cases were managed with excision and did not require treatment modification (see section 4.4). No new primary melanoma was reported from the Phase II NSCLC study (BRF113928).

Non-cutaneous malignancy

Activation of MAP kinase signalling in BRAF wild-type cells which are exposed to BRAF inhibitors may lead to increased risk of non-cutaneous malignancies, including those with RAS mutations (see section 4.4). Non-cutaneous malignancies were reported in 1% (6/586) of patients in the integrated safety population of dabrafenib monotherapy, and <1% (8/1076) of patients in the integrated safety population of dabrafenib in combination with trametinib.
Cases of RAS-driven malignancies have been seen with dabrafenib as monotherapy and in combination with trametinib. Patients should be monitored as clinically appropriate.

Haemorrhage

Haemorrhagic events, including major haemorrhagic events and fatal haemorrhages, have occurred in patients taking dabrafenib in combination with trametinib. Please refer to the trametinib Prescribing Information.

LVEF reduction/Left ventricular dysfunction

Decreased LVEF has been reported in 6% (65/1076) of patients in the integrated safety population of dabrafenib in combination with trametinib. Most cases were asymptomatic and reversible. Patients with LVEF lower than the institutional lower limit of normal were not included in clinical trials with dabrafenib. Dabrafenib in combination with trametinib should be used with caution in patients with conditions that could impair left ventricular function.
Please refer to the trametinib Prescribing Information.

Pyrexia

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib; the incidence and severity of pyrexia are increased with the combination therapy (see section 4.4). For patients who received dabrafenib in combination with trametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy and approximately one-third of the patients had 3 or more events. In 1% of patients receiving dabrafenib as monotherapy in the integrated safety population, serious non-infectious febrile events were identified as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency or pre-renal origin in subjects with normal baseline renal function. The onset of these serious non-infectious febrile events was typically within the first month of therapy. Patients with serious non- infectious febrile events responded well to dose interruption and/or dose reduction and supportive care (see sections 4.2 and 4.4).
Hepatic events

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with trametinib. Please refer to the trametinib Prescribing Information.

Hypertension

Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, 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.

Arthralgia

Arthralgia was reported very commonly in the integrated safety populations of dabrafenib monotherapy (25%) and dabrafenib in combination with trametinib (25%) although these were mainly Grade 1 and 2 in severity with Grade 3 occurring uncommonly (<1%) and no Grade 4 occurrences being reported.

Hypophosphataemia

Hypophosphataemia has been reported commonly in the integrated safety population of dabrafenib monotherapy (7%) and of dabrafenib in combination with trametinib (4%). It should be noted that approximately half of these occurrences with dabrafenib monotherapy (4%) and 1% with dabrafenib in combination with trametinib were Grade 3 in severity.



Pancreatitis

Pancreatitis has been reported in dabrafenib monotherapy and in combination with trametinib.
Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when re-starting dabrafenib after an episode of pancreatitis (see section 4.4).

Renal failure

Renal failure due to pyrexia-associated pre-renal azotaemia or granulomatous nephritis was uncommon; however, dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x ULN). Caution should be used in this setting (see section 4.4).

Special populations

Paediatric
Pediatric Safety Pool
The pediatric pooled safety population reflects exposure to weight-based dabrafenib orally, twice daily administered in combination with trametinib 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, multiple 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 dabrafenib administered with trametinib, 84% were exposed for 6 months or longer and 70% 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 dabrafenib when administered with trametinib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n=48) with refractory or recurrent solid tumors (see section 5.1). The median duration of exposure to dabrafenib in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.9 months, respectively.
The median duration of exposure to trametinib in Parts C and D was 20.8 and 24.4 months, respectively. The median age of pediatric patients who received dabrafenib with trametinib was 9 years (range: 1 to 17).
Serious adverse reactions occurred in 46% of patients who received dabrafenib in combination with trametinib. 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 7 and Table 8.
Table 7 summarizes the adverse reactions in Study X2101.
Table 7. Adverse Reactions (>20%) in Pediatric Patients Treated With Dabrafenib Plus Trametinib in Study X2101a
Dabrafenib plus Trametinib
(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 d
Dermatitis acneiform                    40                         0
Gastrointestinal
Vomiting                                52                        4.2 Diarrhea                                42                        2.1 e
Abdominal pain                          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 TAFINLAR in Study X2101 observed in less than 20% of patients (N=48) who received TAFINLAR in combination with trametinib were: atrioventricular block (2.1%).
Table 8 summarizes the laboratory abnormalities in Study X2101.
Table 8. Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Pediatric Patients Treated With Dabrafenib Plus Trametinib in Study X2101 Laboratory Abnormality                      Dabrafenib plus Trametiniba 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 dabrafenib in combination with trametinib 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 dabrafenib plus trametinib (n=73) or carboplatin plus vincristine (n=33). Nine patients crossed over from the carboplatin plus vincristine arm to the dabrafenib and trametinib arm. Pediatric patients received weight based dabrafenib orally twice daily administered in combination with trametinib 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 dabrafenib plus trametinib (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 dabrafenib due to an adverse reaction occurred in 4% of patients. Adverse reactions which resulted in permanent discontinuation of dabrafenib included chills, fatigue, pyrexia, weight increased, and headache.
Dosage interruptions of dabrafenib due to an adverse reaction occurred in 73% of patients.
Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (53%).
Dose reductions of dabrafenib due to an adverse reaction occurred in 48% of patients.
Adverse reactions which required dose reductions in > 2% of patients included rash (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 9 summarizes the adverse reactions in Study G2201.
Table 9. Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received Dabrafenib in Combination with Trametinib in Study G2201a
Dabrafenib plus Trametinib        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 h
Dizziness                  15                   0              9                 3 Peripheral
7                   0             45                 6
Neuropathyi
Vascular
Hemorrhagej                25                   0             12                 0 Skin and subcutaneous tissue
Rashk                     51                  2.7            18                 3 Dry skin                  26                   0             3                  0 Dermatitis
22                   0              0                 0 acneiforml
Alopecia                   3                   0             24                 0 Musculoskeletal And Connective Tissue
Musculoskeletal
34                   0             30                 0
Painm
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

Dabrafenib plus Trametinib                    Carboplatin plus Vincristine Adverse Reactions                            N=73                                           N=33 
All grades            Grade ≥ 3             All grades               Grade ≥ 3 (%)                  (%)                    (%)                     (%) Upper Respiratory
15              0                                       6                       0 Tract Infection
Injury, Poisoning And Procedural Complications
Infusion Related
0              0                                       15                      3 Reaction
Investigations
Weight Increased           15              7                                       0                       0 a NCI   CTCAE version 4.03.
b Includes diarrhea, colitis, enterocolitis, and enteritis.
c Includes abdominal pain and upper abdominal pain.
d Includes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis.
e Includes pyrexia and body temperature increased.
f Includes fatigue and asthenia.
g Includes headache and migraine with aura.
h Includes dizziness and vertigo.
i Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia,  hypoaesthesia, and peripheral sensory neuropathy.
j Includes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage  intracranial.
k Includes 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.
l Includes dermatitis acneiform, acne, and acne pustular.
m Includes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and  musculoskeletal stiffness.

Table 10 summarizes the laboratory abnormalities in Study G2201.


Table 10. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received Dabrafenib in Combination with Trametinib in Study G2201a
Dabrafenib plus Trametinib            Carboplatin plus Vincristine
N=73                                   N=33
Laboratory Abnormality                All Grades         Grade 3 or 4       All Grades        Grade 3 or 4 (%)               (%)                 (%)              (%)

Hepatic
Increased alkaline
55                  0                 13               0 phosphatase
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
0                  0                 44               0 glucose
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

Of the total number of patients in the integrated safety population of dabrafenib monotherapy (n=578), 22% were 65 years of age and older, and 6% were 75 years of age and older.
Compared with younger subjects (<65), more subjects ≥65 years old had adverse reactions that led to study drug dose reductions (22% versus 12%) or interruptions (39% versus 27%).
In addition, older patients experienced more serious adverse reactions compared to younger patients (41% versus 22%). No overall differences in efficacy were observed between these subjects and younger subjects.

In the integrated safety population of dabrafenib in combination with trametinib (n=1076), 265 patients (25%) were ≥65 years of age, 62 patients (6%) were ≥75 years of age. The proportion of patients experiencing AEs was similar in those aged <65 years and those aged ≥65 years in all clinical trials. Patients ≥65 years were more likely to experience SAEs and AEs leading to permanent discontinuation of medicinal product, dose reduction and dose interruption than those <65 years.
Of the 26 patients with ATC who received dabrafenib in Study BRF117019, 77% were aged 65 years and older, and 31% were aged 75 years and older (see section 5.1). This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

Dabrafenib in combination with trametinib in patients with brain metastases 
The safety and efficacy of the combination of dabrafenib and trametinib 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