Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most common adverse drug reactions (≥ 20%) of VITRAKVI in order of decreasing frequency were increased ALT (35%), increased AST (32%), vomiting (29%),anaemia (28%), constipation (27%), diarrhoea (26%), nausea (23%), fatigue (22%), and dizziness (20%).
The majority of adverse reactions were grade 2 or 3. Grade 4 was the highest reported grade for adverse reactions neutrophil count decreased (2%) ALT increased (1%) , AST increased, leucocyte count decreased, platelet count decreased, muscular weakness and blood alkaline phosphatase increased (each in <1%).The highest reported grade was grade 3 for adverse reactions anaemia (6%), weight increased (4%), diarrhoea (3%), gait disturbance and vomiting (each 1%), and fatigue, dizziness, paraesthesia, nausea, myalgia, and constipation (each in < 1%).
Permanent discontinuation of VITRAKVI for treatment emergent adverse reactions occurred in 2% of patients (2 cases each of neutrophil count decreased, ALT increased, and AST increased, 1 case each of gait disturbance, and muscular weakness ). The majority of adverse reactions leading to dose reduction occurred in the first three months of treatment.

Tabulated list of adverse reactions

The safety of VITRAKVI was evaluated in 361 patients with TRK fusion-positive cancer in one of three on-going clinical trials, Studies 1, 2 (“NAVIGATE”), and 3 (“SCOUT”) and post-marketing.
The safety population, characteristics were comprised of patients with a median age of 39.0 years (range: 0, 90) with 37% of patients being paediatric patients. Median time on treatment for the overall safety population (n=361) was 13.1 months (range: 0.1, 76.4).
The adverse drug reactions reported in patients (n=361) treated with VITRAKVI are shown in Table 2 and Table 3.

The adverse drug reactions are classified according to the System Organ Class.
Frequency groups are defined by 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 available data).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness.


Table 2: Adverse drug reactions reported in TRK fusion-positive cancer patients treated with VITRAKVI at recommended dose (overall safety population n=361) and post-marketing System organ class     Frequency        All grades                 Grades 3 and 4 Blood and lymphatic Very common Anaemia system disorders                        Neutrophil count decreased
(Neutropenia)
Leukocyte count decreased
(Leukopenia)
Common           Platelet count decreased   Anaemia
(Thrombocytopenia)         Neutrophil count decreased
(Neutropenia)a
Leukocyte count decreased
(Leukopenia)a, b
Uncommon                                   Platelet count decreased
(Thrombocytopenia)a,b

Nervous system          Very common     Dizziness disorders
Common          Gait disturbance           Gait disturbance
Paraesthesia
Uncommon                                   Dizziness
Paraesthesia

Gastrointestinal        Very common     Nausea disorders                               Constipation
Vomiting
Diarrhoea
Common          Dysgeusiac                 Diarrhoea
Uncommon                                   Vomiting
Nausea
Constipation
Hepatobiliary             Not known     Liver injury   d
 disorders


Musculoskeletal and               Very common    Myalgia connective tissue disorders                         Common         Muscular weakness
Uncommon                                  Myalgia
Muscular weakness ,
a b


General disorders and Very common                Fatigue administration site conditions            Uncommon                                              Fatigue Investigations        Very common                Alanine aminotransferase (ALT) increased
Aspartate aminotransferase
(AST) increased
Weight increased (Abnormal weight gain)
Common         Blood alkaline phosphatase Alanine aminotransferase increased                  (ALT) increaseda
Aspartate aminotransferase
(AST) increaseda
Weight increased
(Abnormal weight gain)

Uncommon                                  Blood alkaline phosphatase increaseda, b
 a   grade 4 reactions were reported b each grade frequency was less than <1% cADR dysgeusia includes the preferred terms“dysgeusia” and “taste disorder” d includes   cases with ALT/AST ≥3x ULN and bilirubin ≥2x ULN


Table 3: Adverse drug reactions reported in TRK fusion-positive paediatric cancer patients treated with VITRAKVI at recommended dose (n=135); all grades


System organ     Frequency Infants and        Children           Adolescents         Paediatric class                      toddlers                                                  patients (n=43)a            (n=67)b            (n=25)c             (n=135)
Blood and        Very      Anaemia            Anaemia            Anaemia             Anaemia lymphatic        common    Neutrophil count   Neutrophil count   Neutrophil count    Neutrophil system disorders           decreased          decreased          decreased           count (Neutropenia)      (Neutropenia)      (Neutropenia)       decreased
Leukocyte count    Leukocyte count    Leukocyte count     (Neutropenia decreased          decreased          decreased           )
(Leukopenia)       (Leukopenia)       (Leukopenia)        Leukocyte
Platelet count                                            count decreased                                                 decreased
(Thrombocytope                                            (Leukopenia nia)                                                      )
Platelet count decreased
(Thrombocyt openia)

Common                      Platelet count Platelet count decreased      decreased
(Thrombocytope (Thrombocytopenia) nia)

Nervous system Very                                              Dizziness disorders      common
Common       Dizziness         Dizziness           Paraesthesia       Dizziness Paraesthesia        Gait disturbance   Paraesthesia
Gait disturbance                       Gait disturbance
Gastrointestinal Very       Nausea            Nausea             Nausea              Nausea disorders        common     Constipation      Constipation       Constipation        Constipation Vomiting          Vomiting           Vomiting            Vomiting
Diarrhoea         Diarrhoea          Diarrhoea           Diarrhoea

Common                      Dysgeusia                              Dysgeusia Musculoskeletal Very                          Myalgia            Myalgia             Myalgia and connective common tissue disorders

Common                      Muscular           Muscular weakness Muscular weakness                             weakness


General           Very      Fatigue           Fatigue            Fatigue             Fatigue disorders and     common administration site conditions


Investigations        Very           Alanine               Alanine               Alanine                   Alanine common         aminotransferase      aminotransferase      aminotransferase          aminotransfe (ALT) increased       (ALT) increased       (ALT) increased           rase (ALT) Aspartate             Aspartate             Aspartate                 increased aminotransferase      aminotransferase      aminotransferase          Aspartate (AST) increased       (AST) increased       (AST) increased           aminotransfe Weight                                      Weight increased          rase (AST) increased             Weight                (Abnormal weight          increased (Abnormal             increased             gain)                     Weight weight gain)          (Abnormal             Blood alkaline            increased Blood alkaline       weight gain)          phosphatase               (Abnormal Phosphatase         Blood alkaline        increased                 weight gain) increased           phosphatase                                     Blood increased                                       alkaline phosphatase increased a   Infant/toddlers (28 days to 23 months): 5 grade 4 Neutrophil count decreased (Neutropenia) reactions and 2 Blood alkaline phosphatase increased reported. Grade 3 reactions included 11 cases of Neutrophil count decreased (Neutropenia), 4 cases of ALT increased, 3 cases each of Anaemia, and Weight increased (Abnormal weight gain), and 2 cases each of Blood alkaline phosphatase increased, Diarrhoea, and Vomiting and 1 case of AST increased.
b   Children (2 to 11 years): 1 grade 4 Leucocytes count decreased reported. 8 reported grade 3 cases of Neutrophil count decreased (Neutropenia), 2 cases each of Anaemia, Diarrhoea, and Vomiting and 1 case each of ALT increased, AST increased, Gait disturbance, Weight increased (Abnormal weight gain), Paraesthesia and Myalgia c   Adolescents (12 to <18 years): no grade 4 reactions were reported. Grade 3 reactions were reported in 1 case each of ALT increased, AST increased, Fatigue, Gait disturbance, and Muscular weakness.

Description of selected adverse reactions

Neurologic reactions
In the overall safety database (n=361 ), the maximum grade neurologic adverse reaction observed was grade 3 or 4 which was observed in 10 ( 3%) patients and included gait disturbance (4 patients, 1%), dizziness (3 patients, <1%), and paraesthesia (3 patients, <1%). The overall incidence was 20% for dizziness, 6% for paraesthesia and 5% for gait disturbance. Neurologic reactions leading to dose modification or interruptions included dizziness (1%),gait disturbance (<1%), and paraesthesia (<1%).
One patient permanently discontinued the treatment due to grade 3 gait disturbance. In all cases except of one, patients with evidence of anti-tumour activity who required a dose reduction were able to continue dosing at a reduced dose and/or schedule (see section 4.4).

Hepatotoxicity
Abnormalities of liver function tests including ALT, AST, ALP and bilirubin have been observed in patients treated with VITRAKVI.
In the overall safety database (n=361), the maximum grade transaminase elevation observed was grade 4 ALT increase in 7 patients (2%) and AST increase in 4 patients (1%). Grade 3 ALT and AST increases in 25 (7%) and 22 (6%) of patients, respectively. Majority of grade 3 elevations were transient appearing in the first three months of treatment and resolving to grade 1 by months 3-4.
Grade 2 ALT and AST increases were observed in 35 (10%) and 32 (9%) of patients, respectively, and grade 1 ALT and AST increases were observed in 173 (48%) and 177 (49%) of patients, respectively.
ALT and AST increases leading to dose modifications or interruptions occurred in 24 (7%) patients and 21 (6%) patients, respectively (see section 4.4). Two patients permanently discontinued the treatment with 1 patient due to grade 3 ALT and grade 3 AST increases.
Cases of hepatotoxicity with increases in ALT and/or AST of grade 2, 3 or 4 severity and increases in bilirubin ≥ 2x ULN have been reported in adult patients. In some cases, the dose of VITRAKVI was withheld and restarted at a reduced dose, while in other cases treatment was permanently discontinued (see section 4.4).


Additional information on special populations

Paediatric patients
Of the 361 patients treated with VITRAKVI, 135 (37%) patients were from birth to <18 years of age (n=13 from birth to < 3 months, n=4 ≥ 3 months to < 6 months, n=17 ≥ 6 months to < 12 months, n=9≥ 12 months to < 2 years, n=31 ≥ 2 years to < 6 years, n=36 ≥ 6 years to < 12 years, n= 25 ≥ 12 years to < 18 years). The majority of adverse reactions were grade 1 or 2 in severity and were resolved without VITRAKVI dose modification or discontinuation. Adverse reactions of grade 3 or 4 in severity were generally observed more frequently in patients < 6 years of age. They were reported in 69% of patients from birth to < 3 months and in 44% of patients ≥ 3 months to < 6 years.
Decreased neutrophil count has been reported to have led to study drug discontinuation, dose modification and dose interruption.


Elderly
Of the 361 patients in the overall safety population who received VITRAKVI, 69 (19%) patients were 65 years or older and 22 (6%) patients were 75 years or older. The safety profile in elderly patients (≥ 65 years) is consistent with that seen in younger patients. The adverse reaction dizziness (30% versus 28% in all adults), anaemia (35% versus 27% in all adults), diarrhoea (25% versus 22% in all adults), muscular weakness (13% versus 10% in all adults), platelet count decreased (12% versus 6% in all adults), gait disturbance (9% versus 5% in all adults), and dysgeusia (9% versus 6% in all adults) were more frequent in patients of 65 years or older.

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