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: 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 3 and Table 4.

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                                             Leukocyte count decreased (Leukopenia) Very common       Dizziness
Nervous system 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 disorders   Not known         Liver injuryd

Musculoskeletal and       Very common       Myalgia connective tissue disorders                Common            Muscular weakness
Uncommon                                          Myalgia
Muscular weaknessa, 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% c
ADR 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     Frequenc Infants and          Children           Adolescents    Paediatric class            y        toddlers                                               patients (n=43)a              (n=67)b          (n=25)c          (n=135)
Blood and        Very     Anaemia              Anaemia          Anaemia          Anaemia lymphatic system common Neutrophil count       Neutrophil count Neutrophil count Neutrophil count disorders                 decreased            decreased        decreased        decreased (Neutropenia)        (Neutropenia)    (Neutropenia)    (Neutropenia)
Leukocyte count      Leukocyte count Leukocyte count Leukocyte count decreased            decreased        decreased        decreased
(Leukopenia)         (Leukopenia)     (Leukopenia)     (Leukopenia)
Platelet count                                         Platelet count decreased                                              decreased
(Thrombocytope                                         (Thrombocytope nia)                                                   nia)
Common                        Platelet count decreased        Platelet count
(Thrombocytope decreased nia)             (Thrombocytope 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                                                                     Muscular Common                       Muscular          Muscular           weakness weakness          weakness
General            Very     Fatigue            Fatigue             Fatigue           Fatigue disorders and      common administration site conditions
Investigations     Very     Alanine            Alanine            Alanine          Alanine common   aminotransferase   aminotransferase   aminotransferase aminotransferase (ALT) increased    (ALT) increased    (ALT) increased  (ALT) increased Aspartate          Aspartate          Aspartate        Aspartate aminotransferase   aminotransferase   aminotransferase aminotransferase (AST) increased    (AST) increased    (AST) increased  (AST) increased Weight                                Weight increased Weight increased increased          Weight             (Abnormal weight (Abnormal
(Abnormal          increased          gain)            weight gain) weight gain)       (Abnormal          Blood alkaline   Blood alkaline Blood alkaline    weight gain)       phosphatase      phosphatase phosphatase       Blood alkaline     increased        increased increased         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 and 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 authorization 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