Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of Xospata was evaluated in 319 patients with relapsed or refractory AML who have received at least one dose of 120 mg gilteritinib.

The most frequent adverse reactions with gilteritinib were alanine aminotransferase (ALT) increased (82.1%), aspartate aminotransferase (AST) increased (80.6%), blood alkaline phosphatase increased (68.7%), blood creatine phosphokinase increased (53.9%), diarrhoea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral oedema (24.1%), dyspnea (24.1%), dizziness (20.4%), hypotension (17.2%), pain in extremity (14.7%), asthenia (13.8%), arthralgia (12.5%) and myalgia (12.5%).
The most frequent serious adverse reactions were acute kidney injury (6.6%), diarrhoea (4.7%), ALT increased (4.1%), dyspnea (3.4%), AST increased (3.1%) and hypotension (2.8%). Other clinically significant serious adverse reactions included differentiation syndrome (2.2%), electrocardiogram QT prolonged (0.9%) and posterior reversible encephalopathy syndrome (0.6%).

Tabulated list of adverse reactions

Adverse reactions observed during clinical studies are listed below by frequency category.
Frequency categories are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions
All      Grades    Frequency
Grades      ≥3       category
Adverse drug reaction                             %         %
Immune system disorders
Anaphylactic reaction                               1.3    1.3       Common Nervous system disorders
Dizziness                                          20.4    0.3     Very common Posterior reversible encephalopathy syndrome                                            0.6    0.6      Uncommon Cardiac disorders
Electrocardiogram QT prolonged                      8.8    2.5      Common Pericardial effusion                                4.1    0.9      Common Pericarditis                                        1.6     0       Common Cardiac failure                                     1.3    1.3      Common Vascular disorders
Hypotension                                        17.2    7.2     Very common Respiratory, thoracic and mediastinal disorders
Cough                                              28.2    0.3     Very common Dyspnoea                                           24.1    4.4     Very common Differentiation syndrome                            3.4    2.2       Common Gastrointestinal disorders
Diarrhoea                                          35.1    4.1     Very common Nausea                                             29.8    1.9     Very common Constipation                                       28.2    0.6     Very common Hepatobiliary disorders
Alanine aminotransferase increased*                82.1   12.9     Very common Aspartate aminotransferase increased*              80.6   10.3     Very common Musculoskeletal and connective tissue disorders
Blood creatine phosphokinase increased*            53.9    6.3     Very common Blood alkaline phosphatase increased*              68.7    1.6     Very common Pain in extremity                                  14.7    0.6     Very common Arthralgia                                         12.5    1.3     Very common Myalgia                                            12.5    0.3     Very common Musculoskeletal pain                                4.1    0.3       Common Renal and urinary disorders
Acute kidney injury                                 6.6    2.2      Common General disorders and administration site conditions
Fatigue                                            30.4    3.1     Very common Peripheral oedema                                  24.1    0.3     Very common Asthenia                                           13.8    2.5     Very common Malaise                                             4.4     0        Common * Frequency is based on central laboratory values.
Description of selected adverse reactions
Differentiation syndrome
Of 319 patients treated with Xospata in the clinical studies, 11 (3%) experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and clinical findings of differentiation syndrome in patients treated with Xospata included fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as one day and up to 82 days after Xospata initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of Xospata. For recommendations in case of suspected differentiation syndrome see sections 4.2 and 4.4.

PRES
Of the 319 patients treated with Xospata in the clinical studies, 0.6% experienced posterior reversible encephalopathy syndrome (PRES). PRES is a rare, reversible, neurological disorder, which can present with rapidly evolving symptoms including seizure, headache, confusion, visual and neurological disturbances, with or without associated hypertension.
Symptoms have resolved after discontinuation of treatment (see sections 4.2 and 4.4).

QT prolongation
Of the 317 patients treated with gilteritinib at 120 mg with a post-baseline QTC value in clinical studies, 4 patients (1%) experienced a QTcF >500 msec. Additionally, across all doses, 12 patients (2.3%) with relapsed/refractory AML had a maximum post-baseline QTcF interval >500 msec (see sections 4.2, 4.4 and 5.1).

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 http://sideeffects.health.gov.il