Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The safety profile from pivotal clinical studies at the recommended doses of nelarabine in adults (1,500 mg/m2) and children (650 mg/m2) is based on data from 103 adults and 84 paediatric patients respectively. The most frequently occurring adverse events were fatigue; gastrointestinal disorders; haematological disorders; respiratory disorders; nervous system disorders (somnolence, peripheral neurological disorders [sensory and motor], dizziness, hypoaesthesia, paraesthesia, headache); and pyrexia. Neurotoxicity is the dose-limiting toxicity associated with nelarabine therapy (see section 4.4).

Tabulated list of adverse reactions

ATR API AUG21 V1                                                                                EU SmPC 11.20 The following convention has been utilised for the classification of frequency: 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)

Adverse reactions            Adults (1,500 mg/m2)          Children (650 mg/m2) N=103                         N=84
Infections and infestations
Infection (including but not Very common: 40 (39%)     Very common: 13 (15%) limited to; sepsis,
bacteraemia, pneumonia,
fungal infection)
Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour lysis syndrome (see Common: 1 (1%)              N/A also data from compassionate use programme and non-pivotal studies)
Blood and lymphatic system disorders
Febrile neutropenia          Very common: 12 (12%)     Common: 1 (1%) Neutropenia                  Very common: 83 (81%)     Very common: 79 (94%) Leukopenia                   Common: 3 (3%)            Very common: 32 (38%) Thrombocytopenia             Very common: 89 (86%)     Very common: 74 (88%) Anaemia                      Very common: 102 (99%)    Very common: 80 (95%) Metabolism and nutrition disorders
Hypoglycaemia                N/A                       Common: 5 (6%) Hypocalcaemia                Common: 3 (3%)            Common: 7 (8%) Hypomagnesaemia              Common: 4 (4%)            Common: 5 (6%) Hypokalaemia                 Common: 4 (4%)            Very common: 9 (11%) Anorexia                     Common: 9 (9%)            N/A
Psychiatric disorders
Confusional state            Common: 8 (8%)            Common: 2 (2%) Nervous system disorders
Seizures (including          Common: 1 (1%)            Common: 5 (6%) convulsions, grand mal convulsions, status epilepticus)
Amnesia                      Common: 3 (3%)            N/A
Somnolence                   Very common: 24 (23%)     Common: 6 (7%) Peripheral neurological      Very common: 22 (21%)     Very common: 10 (12%) disorders (sensory and motor)
Hypoesthesia                 Very common: 18 (17%)     Common: 5 (6%) Paraesthesia                 Very common: 15 (15%)     Common: 3 (4%) Ataxia                       Common: 9 (9%)            Common: 2 (2%) Balance disorder             Common: 2 (2%)            N/A
Tremor                       Common: 5 (5%)            Common: 3 (4%) Dizziness                    Very common: 22 (21%)     N/A

ATR API AUG21 V1                                                                              EU SmPC 11.20 Adverse reactions          Adults (1,500 mg/m2)        Children (650 mg/m2) N=103                       N=84
Headache                   Very common: 15 (15%)       Very common: 14 (17%) Dysgeusia                  Common: 3 (3%)              N/A
Eye disorders
Blurred vision             Common: 4 (4%)              N/A
Vascular disorders
Hypotension                Common: 8 (8%)              N/A
Respiratory, thoracic and mediastinal disorders
Pleural effusion           Common: 10 (10%)            N/A
Wheezing                   Common: 5 (5%)              N/A
Dyspnoea                   Very common: 21 (20%)       N/A
Cough                      Very common: 26 (25%)       N/A
Gastrointestinal disorders
Diarrhoea                  Very common: 23 (22%)       Common: 2 (2%) Stomatitis                 Common: 8 (8%)              Common: 1 (1%) Vomiting                   Very common: 23 (22%)       Common: 8 (10%) Abdominal pain             Common: 9 (9%)              N/A
Constipation               Very common: 22 (21%)       Common: 1 (1%) Nausea                     Very common: 42 (41%)       Common: 2 (2%) Hepatobiliary disorders
Hyperbilirubinaemia        Common: 3 (3%)              Common: 8 (10%) Transaminases increased    N/A                         Very common: 10 (12%) Aspartate aminotransferase Common: 6 (6%)              N/A increased
Musculoskeletal and connective tissue disorders
Muscle weakness            Common: 8 (8%)              N/A
Myalgia                    Very common: 13 (13%)       N/A
Arthralgia                 Common: 9 (9%)              Common: 1 (1%) Back pain                  Common: 8 (8%)              N/A
Pain in extremity          Common: 7 (7%)              Common: 2 (2%) Rhabdomyolysis, blood      Rare: N/A                   Rare: N/A creatine phosphokinase increased (see “Post– marketing data”)
Renal and urinary disorders
Blood creatinine increased Common: 2 (2%)              Common: 5 (6%) General disorders and administration site conditions
Oedema                     Very common: 11 (11%)       N/A
Gait abnormal              Common: 6 (6%)              N/A
Oedema peripheral          Very common: 15 (15%)       N/A
Pyrexia                    Very common: 24 (23%)       Common: 2 (2%) Pain                       Very common: 11 (11%)       N/A
Fatigue                    Very common: 51 (50%)       Common: 1 (1%) Asthenia                   Very common: 18 (17%)       Common: 5 (6%) 
ATR API AUG21 V1                                                               EU SmPC 11.20 Description of selected adverse reactions

Infection and infestations

There was a single additional report of biopsy confirmed progressive multifocal leukoencephalopathy in the adult population.
There have been reports of sometimes fatal opportunistic infections in patients receiving nelarabine therapy.

Nervous system disorders

There have been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Two paediatric patients had fatal neurological events.

Data from NCI studies/compassionate use programme and phase I studies 
In addition to the adverse reactions seen in the pivotal clinical studies, there are also data from 875 patients from NCI studies/compassionate use programme (694 patients) and Phase I (181 patients) studies of nelarabine. The following additional adverse reactions were seen: 
Neoplasms benign and malignant (including cysts and polyps)
Tumour lysis syndrome – 7 cases (see sections 4.2 and 4.4)

Post-marketing data
Rhabdomyolysis and increased blood creatine phosphokinase have been identified during post-approval use of nelarabine. This includes spontaneous case reports as well as serious adverse events from ongoing studies.

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/).