Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions (≥20%) were fatigue, constipation, dysgeusia, oedema, dizziness, diarrhoea, nausea, dysaesthesia, dyspnoea, anaemia, increased weight, increased blood creatinine, pain, cognitive disorders, vomiting, cough, and pyrexia. The most frequent serious adverse reactions (≥2%) were lung infection (5.2%), dyspnoea (4.6%), cognitive impairment (3.8%), pleural effusion (3.0%) and fractures (3.8%). Permanent discontinuation due to an adverse reaction occurred in 4.6% of patients.

Tabulated list of adverse reactions

Table 4 summarise the adverse drug reactions (ADRs) occurring in adult and paediatric patients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, STARTRK-2) and one clinical trial in pediatric patients (STARTRK-NG). The median duration of exposure was 5.5 months.

Adverse drug reactions are listed by MedDRA system organ class. The following categories of frequency have been used: very common ≥1/10, common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each system organ class, the adverse reactions are presented in order of decreasing frequency.


Table 4: Adverse drug reactions occurring in adult and paediatric patients treated with Rozlytrek in clinical trials (N=504)

Frequency
System organ                                       All grades                     Grade ≥3 Adverse reaction                           category class                                             (%)                           (%) (all grades)
Infections and        Lung infection1                   13.1      Very common            6.0* infestations          Urinary tract infection           12.7      Very common            2.6 Blood and             Anaemia                           28.2      Very common            9.7 lymphatic system disorders             Neutropenia2                      11.3      Very common            4.4 Weight increased                  26.4      Very common            7.3 Metabolism and        Decreased appetite                11.9      Very common            0.2 nutritional           Hyperuricemia                     9.1         Common               1.8 disorders             Dehydration                       7.9         Common               1.0 Tumour lysis syndrome             0.2        Uncommon              0.2* Dysgeusia                         42.3      Very common            0.4 Dizziness3                        39.7      Very common            1.2 Dysaesthesia4                     29.0      Very common            0.2 Cognitive disorders5              24.2      Very common            4.4 Headache                          17.5      Very common            1.0 Nervous system
Peripheral sensory disorders                                               15.7      Very common            1.0 neuropathy6
Ataxia7                           15.7      Very common            0.8 Sleep disturbances8               13.5      Very common            0.4 Mood disorders9                   9.1         Common               0.6 Syncope                           4.6         Common               3.0 Eye disorders         Vision blurred10                  11.9      Very common            0.4 Congestive heart
3.0         Common               2.2 failure11
Cardiac disorders
Electrocardiogram QTc
2.0         Common               0.6 prolonged
Vascular
Hypotension12                     16.5      Very common            2.4 disorders
Respiratory,          Dyspnoea                          27.0      Very common            5.8* thoracic and          Cough                             21.4      Very common             0.6 mediastinal disorders             Pleural effusion                  6.9         Common               2.8 Constipation                      42.9      Very common            0.4 Diarrhoea                         33.5      Very common            2.6 Gastrointestinal      Nausea                            32.1      Very common            0.8 disorders             Vomiting                          23.2      Very common            1.2 Abdominal pain                    11.1      Very common            0.6 Dysphagia                         10.1      Very common            0.4 Hepatobiliary         AST increased                     17.5      Very common            3.6 disorders             ALT increased                     16.1      Very common            3.4 Skin and              Rash13                            11.5      Very common            1.4 subcutaneous
Photosensitivity reaction         2.8         Common                0 tissue disorders
Myalgia                           19.6      Very common            0.6 Musculoskeletal
Arthralgia                        19.0      Very common            0.6 and connective
Muscular weakness                 12.3      Very common            1.2 tissue disorders
Fractures14,15                    10.5      Very common            3.3 Blood creatinine
Renal and urinary                                       25.4      Very common            0.6 increased disorders
Urinary retention16               10.9      Very common            0.6 Frequency
System organ                                                   All grades                                      Grade ≥3 Adverse reaction                                         category class                                                         (%)                                            (%) (all grades)
General disorders             Fatigue17                               45.0              Very common                    5.0 and                           Oedema18                                37.3              Very common                    1.4 administration                Pain19                                  24.4              Very common                    1.6 site conditions               Pyrexia                                 20.0              Very common                    0.8 * Grades 3 to 5, inclusive of fatal adverse reactions (including 2 reactions of pneumonia, 2 reactions of dyspnoea, and 1 reaction of tumour lysis syndrome).
1
Lung infection (bronchitis, lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection, upper respiratory tract infection)
2
Neutropenia (neutropenia, neutrophil count decreased)
3
Dizziness (dizziness, vertigo, dizziness postural)
4
Dysaesthesia (paresthesia, hyperesthesia, hypoesthesia, dysesthesia)
5
Cognitive disorders (cognitive disorder, confusional state, disturbance in attention, memory impairment, amnesia, mental status changes, hallucination, delirium, ‘visual hallucination’ and mental disorder) 6
Periphery sensory neuropathy (neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy)
7
Ataxia (ataxia, balance disorder, gait disturbances)
8
Sleep disturbances (hypersomnia, insomnia, sleep disorder, somnolence) 9
Mood disorders (anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered, mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation) 10
Vision blurred (diplopia, vision blurred, visual impairment)
11
Congestive heart failure (acute right ventricular failure, cardiac failure, cardiac failure congestive, chronic right ventricular failure, ejection fraction decreased, pulmonary oedema)
12
Hypotension (hypotension, orthostatic hypotension)
13
Rash (rash, rash maculopapular, rash pruritic, rash erythematous, rash papular) 14
Fractures (ankle fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, fracture, humerus fracture, jaw fracture, lower limb fracture, pathological fracture, rib fracture, spinal compression fracture, spinal fracture, stress fracture, tibia fracture, wrist fracture)
15
Data based on 798 safety evaluable patients from 02 Aug 2022 data cut-off 16
Urinary retention (urinary retention, urinary incontinence, urinary hesitation, micturition disorder, micturition urgency) 17
Fatigue (fatigue, asthenia)
18
Oedema (face oedema, fluid retention, generalised oedema, localized oedema, oedema, oedema peripheral, peripheral swelling)
19
Pain (back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity) 
Description of selected adverse reactions

Cognitive disorders
A variety of cognitive symptoms was reported across clinical trials (section 4.4). These included events reported as cognitive disorders (6.3%), confusional state (7.3%), disturbance in attention (3.8%), memory impairment (4.2%), amnesia (2.8%), mental status changes (1.2%), hallucination (1.0%), delirium (0.8%), visual hallucination (0.4%) and mental disorder (0.2%). Grade 3 cognitve disorders were reported in 4.4% of patients. Adult patients who had CNS disease at baseline had a higher frequency of these adverse reactions (29.7%) compared to those without CNS disease (23.1%).
The median time to onset for cognitive disorders was 0.92 months.

Fractures
Fractures were experienced by 9.0% (65/722) of adult patients and 25.0% (19/76) of paediatric patients. In general, there was inadequate assessment for tumour involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumour involvement were reported in some adult patients. In both adult and paediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft) and some fractures occurred in the setting of a fall or other trauma.

The median time to fracture was 8.1 months (range: 0.26 months to 45.34 months) in adults. Rozlytrek was interrupted in 26.2% of adults that experienced fractures. Seventeen adult patients had Rozlytrek treatment interrupted and none had treatment discontinued due to fractures.

A total of 47 fracture events were reported in the 19 paediatric patients. The median time to fracture was 4.3 months (range: 2.0 months to 28.65 months) in paediatric patients. Rozlytrek was interrupted 
in 15.8% (3/19) of paediatric patients who experienced fractures. Nine of the fractures were Grade 2 and 8 of the fractures were Grade 3. Six of the Grade 3 fractures were serious. There were no reports of tumour involvement at the site of the fracture.

Ataxia
Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.7% of patients. The median time to onset for ataxia was 0.4 months (range: 0.03 months to 28.19 months) and the median duration was 0.7 months (range: 0.03 months to 11.99 months). The majority of patients (67.1%) recovered from ataxia. Ataxia related adverse reactions were observed more frequently in elderly patients (23.8%) compared to patients below 65 years of age (12.8%).

Syncope
Syncope was reported in 4.6% of patients. In some patients, syncope was reported with concurrent hypotension, dehydration, or QTc prolongation and in other patients no other concurrent related conditions were reported.

QTc interval prolongation
Among the 504 patients who received entrectinib across clinical trials, 17 (4.0%) patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of >60 ms after starting entrectinib, and 12 (2.8%) patients had a QTcF interval of 500 ms (section 4.4).

Peripheral sensory neuropathy
Peripheral sensory neuropathy was reported in 15.7% of patients. The median time to onset was 0.49 months (range 0.03 months to 20.93 months) and the median duration was 0.8 months (range: 0.07 months to 6.01 months). The majority of patients (55.7%) recovered from peripheral neuropathy.

Eye disorders
Eye disorders reported across clinical trials included vision blurred (8.5%), diplopia (2.6%), and visual impairment (1.6%). The median time to onset for eye disorders was 1.9 months (range: 0.03 months to 21.59 months). The median duration of eye disorders was 1 month (range 0.03 months to 14.49 months). The majority of patients (61.7%) recovered from the eye disorder adverse reactions.

Elderly

Among the 504 patients who received entrectinib across clinical trials, 130 (25.8%) patients were 65 years or older and 34 (6.7%) were 75 years or older. The overall safety profile of entrectinib in the elderly patients is similar to the safety profile observed in patients younger than 65 years of age.
Adverse reactions occurring more frequently in the elderly compared to patients less than 65 years old were dizziness (48.5% vs 36.6%), blood creatinine increased (31.5% vs 23.3%), and hypotension (21.5% vs 14.7%), ataxia (23.8% vs 12.8%).

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