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 0 and 60% had ECOG performance status 1.
The adverse reaction profile among all patients in study BRF117019was 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 3) and dabrafenib in combination with trametinib (Table 6). Adverse drug reactions are listed below by MedDRA system organ class 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 (including           Common cysts and 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
Nervous system disorders             Very common                Headache Eye disorders                        Uncommon                   Uveitis Respiratory, thoracic and
Very common                Cough mediastinal disorders
Nausea
Very common                Vomiting
Gastrointestinal disorders                                      Diarrhoea Common                     Constipation
Uncommon                   Pancreatitis
Skin and subcutaneous tissue                                    Hyperkeratosis Very common disorders                                                       Alopecia Rash
Palmar –plantar erythrodysaesthesia syndrome
Dry skin
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 disorders                        Common
Hypophosphataemia
Hyperglycaemia
Headache
Nervous system disorders         Very common
Dizziness
Eye disorders                    Common                      Vision blurred 
Visual impairment
Uveitis
Chorioretinopathy
Uncommon      Retinal detachment
Periorbital oedema

Common        Ejection fraction decreased
Cardiac disorders            Uncommon      Bradycardia
Not known     Myocarditis
Hypertension
Very common
Haemorrhagee
Vascular disorders
Hypotension
Common
Lymphoedema
Very common   Cough
Respiratory, thoracic and    Common        Dyspnoea mediastinal disorders
Uncommon      Pneumonitis
Abdominal painf
Constipation
Very common   Diarrhoea
Nausea
Vomiting
Gastrointestinal disorders                 Dry mouth
Common
Stomatitis
Pancreatitis
Uncommon
Colitis
Rare          Gastrointestinal perforation
Dry skin
Pruritus
Very common
Rash
Erythemag
Dermatitis acneiform
Actinic keratosis
Night sweats
Hyperkeratosis
Alopecia
Common        Palmar-plantar erythrodysaesthesia
Skin and subcutaneous syndrome disorders
Skin lesion
Hyperhidrosis
Panniculitis
Skin fissures
Photosensitivity
Stevens-Johnson syndrome
Drug reaction with eosinophilia and
Not known     systemic symptoms
Dermatitis exfoliative generalised
Musculoskeletal and          Very common   Arthralgia
connective tissue disorders                                          Myalgia Pain in extremity
Muscle spasmsh

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
Blood alkaline phosphatase increased
Investigations
Gamma-glutamyltransferase increased
Common
Blood creatine phosphokinase increased 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
Bleeding from various sites, including intracranial bleeding and fatal bleeding f
Abdominal pain upper and abdominal pain lower g
Erythema, generalised erythema h
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 population 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
Study CTMT212X2101 (X2101)
The safety of dabrafenib when administered with trametinib was evaluated in Study X2101, a multi-center, open-label, multiple 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 – 17 years).
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 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 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
TAFINLAR plus Trametinib
(n=48)
Adverse Reactions
All Grades                 Grade 3 or 4
(%)                        (%)
General
Pyrexia                                 75                         17 Fatigueb                                48                          0 Skin
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
Cough                                   44                          0 Nervous system
Headache                                35                          0 Vascular disorders
Hemorrhagef                             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.
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                      TAFINLAR 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 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.

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/).