Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
AML
The safety evaluation of Rydapt (50 mg twice daily) in patients with newly diagnosed FLT3-mutated AML is based on a phase III, randomised, double-blind, placebo-controlled study with 717 patients.
The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the Rydapt plus standard chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus standard chemotherapy arm. For the 205 patients (120 in Rydapt arm and 85 in placebo arm) who entered the maintenance phase, the median duration of exposure in maintenance was 11 months for both arms (16 to 520 days for patients in the Rydapt arm and 22 to 381 days in the placebo arm).

The most frequent adverse reactions (ARs) in the Rydapt arm were febrile neutropenia (83.4%), nausea (83.4%), exfoliative dermatitis (61.6%), vomiting (60.7%), headache (45.9%), petechiae (35.8%) and pyrexia (34.5%). The most frequent Grade 3/4 ARs were febrile neutropenia (83.5%), lymphopenia (20.0%), device-related infection (15.7%), exfoliative dermatitis (13.6%), hyperglycaemia (7.0%) and nausea (5.8%). The most frequent laboratory abnormalities were haemoglobin decreased (97.3%), ANC decreased (86.7%), ALT increased (84.2%), AST increased (73.9%) and hypokalaemia (61.7%). The most frequent Grade 3/4 laboratory abnormalities were ANC decreased (85.8%), haemoglobin decreased (78.5%), ALT increased (19.4%) and hypokalaemia (13.9%).

Serious ARs occurred at similar rates in patients in the Rydapt versus the placebo arm. The most frequent serious AR in both arms was febrile neutropenia (16%).

Discontinuation due to any adverse reaction occurred in 3.1% of patients in the Rydapt arm versus 1.3% in the placebo arm. The most frequent Grade 3/4 adverse reaction leading to discontinuation in the Rydapt arm was exfoliative dermatitis (1.2%).

Safety profile during maintenance phase
While Table 3 provides the incidence for ARs over the total duration of the study, when the maintenance phase (single agent Rydapt or placebo) was assessed separately, a difference in the type and severity of ARs was observed. The overall incidence of ARs during the maintenance phase was generally lower than during the induction and consolidation phase. Incidences of ARs were, however, higher in the Rydapt arm than in the placebo arm during the maintenance phase. ARs occurring more often in the midostaurin arm versus placebo during maintenance included: nausea (46.4% versus 17.9%), hyperglycaemia (20.2% versus 12.5%), vomiting (19% versus 5.4%) and QT prolongation (11.9% versus 5.4%).

Most of the haematological abnormalities reported occurred during the induction and consolidation phase when the patients received Rydapt or placebo in combination with chemotherapy. The most frequent Grade 3/4 haematological abnormalities reported in patients during the maintenance phase with Rydapt were ANC decrease (20.8% versus 18.8%) and leukopenia (7.5% versus 5.9%).

ARs reported during the maintenance phase led to discontinuation of 1.2% of patients in the Rydapt arm and none in the placebo arm.

Advanced SM
The safety of Rydapt (100 mg twice daily) as a single agent in patients with advanced SM was evaluated in 142 patients in two single-arm, open-label, multicentre studies. The median duration of exposure to Rydapt was 11.4 months (range: 0 to 81 months).



The most frequent ARs were nausea (82%), vomiting (68%), diarrhoea (51%), peripheral oedema (35%) and fatigue (31%). The most frequent Grade 3/4 ARs were fatigue (8.5%), sepsis (7.7%), pneumonia (7%), febrile neutropenia (7%), and diarrhoea (6.3%). The most frequent non-haematological laboratory abnormalities were hyperglycaemia (93.7%), total bilirubin increased (40.1%), lipase increased (39.4%), aspartate aminotransferase (AST) increased (33.8%), and alanine aminotransferase (ALT) increased (33.1%), while the most frequent haematological laboratory abnormalities were absolute lymphocyte count decreased (73.2%) and ANC decreased (58.5%). The most frequent Grade 3/4 laboratory abnormalities were absolute lymphocyte count decreased (45.8%), ANC decreased (26.8%), hyperglycaemia (19%), and lipase increased (17.6%).

Dose modifications (interruption or adjustment) due to ARs occurred in 31% of patients. The most frequent ARs that led to dose modification (incidence ≥5%) were nausea and vomiting.

ARs that led to treatment discontinuation occurred in 9.2% of patients. The most frequent (incidence ≥1%) were febrile neutropenia, nausea, vomiting and pleural effusion.

Tabulated lists of adverse reactions

ARs are listed according to MedDRA system organ class. Within each system organ class, the ARs are ranked by frequency, with the most frequent reactions first, using the following convention (CIOMS III): 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 the order of decreasing seriousness.

AML
Table 3 presents the frequency category of ARs reported in the phase III study in patients with newly diagnosed FLT3-mutated AML and during post marketing experience.

Table 3      Adverse reactions observed in AML

All grades       Grades 3/4
Rydapt +         Rydapt +
Adverse reaction                               chemo            chemo           Frequency category n=2291           n=3451
%               %
Infections and infestations
Device-related infection                          24               15.7        Very common Upper respiratory tract infection                 5.2              0.6         Common Neutropenic sepsis                                0.9              3.5         Uncommon Blood and lymphatic system disorders
Febrile neutropenia                               83.4             83.5        Very common Petechiae                                         35.8             1.2         Very common Lymphopenia                                       16.6              20         Very common Immune system disorders
Hypersensitivity                                  15.7             0.6         Very common Metabolism and nutrition disorders
Hyperuricaemia                                    8.3              0.6         Common Psychiatric disorders
Insomnia                                          12.2              0          Very common Nervous system disorders
Headache                                          45.9             2.6         Very common Syncope                                            5.2             4.6         Common Tremor                                             3.9              0          Common 

Eye disorders
Eyelid oedema                                  3.1       0     Common Cardiac disorders
Hypotension                                   14.4      5.5    Very common Sinus tachycardia                              9.6      1.2    Common Hypertension                                   7.9      2.3    Common Pericardial effusion                           3.5      0.6    Common Respiratory, thoracic and mediastinal disorders
Epistaxis                                     27.5      2.6    Very common Laryngeal pain                                11.8      0.6    Very common Interstitial lung disease/Pneumonitis2        11.4      4.9    Very common Dyspnoea                                      10.9      5.5    Very common Pleural effusion                               5.7      0.9    Common Nasopharyngitis                                8.7       0     Common Acute respiratory distress syndrome            2.2      2.3    Common Gastrointestinal disorders
Nausea                                        83.4      5.8    Very common Vomiting                                      60.7      2.9    Very common Stomatitis                                    21.8      3.5    Very common Abdominal pain upper                          16.6       0     Very common Haemorrhoids                                  15.3      1.4    Very common Anorectal discomfort                            7       0.9    Common Abdominal discomfort                           3.5       0     Common Skin and subcutaneous tissue disorders
Dermatitis exfoliative                        61.6      13.6   Very common Hyperhidrosis                                 14.4       0     Very common Dry skin                                        7        0     Common Keratitis                                      6.6      0.3    Common Acute febrile neutrophilic dermatosis3          -        -     Not known Musculoskeletal and connective tissue disorders
Back pain                                     21.8      1.4    Very common Arthralgia                                     14       0.3    Very common Bone pain                                      9.6      1.4    Common Pain in extremity                              9.6      1.4    Common Neck pain                                      7.9      0.6    Common General disorders and administration site conditions
Pyrexia                                       34.5      3.2    Very common Catheter-related thrombosis                    3.5       2     Common 


  Investigations
Haemoglobin decreased*                               97.3             78.5         Very common ANC decreased*                                       86.7             85.8         Very common ALT increased*                                       84.2             19.4         Very common AST increased*                                       73.9              6.4         Very common Hypokalaemia*                                        61.7             13.9         Very common Hyperglycaemia                                       20.1               7          Very common Hypernatraemia*                                       20               1.2         Very common Electrocardiogram QT prolonged3                      19.7              5.8         Very common Activated partial thromboplastin time prolonged                                            12.7              2.6         Very common Hypercalcaemia*                                       6.7              0.6         Common Weight increased                                      6.6              0.6         Common 1
For trial sites in North America, all grades were collected for 13 pre-specified adverse events. For all other adverse events, only grades 3 and 4 were collected. Therefore all grade AEs are summarised only for patients in non-North American trial sites, whereas Grades 3 and 4 are summarised for patients in all trial sites.
2
This AR was included after identification in the post-marketing setting. Interstitial lung disease has been derived from post-marketing experience with Rydapt via spontaneous case reports and literature cases. No cases of interstitial lung disease were reported in the phase III study.
3
These ARs were included after identification in the post-marketing setting.
* Frequency is based on laboratory values.

Advanced SM
Table 4 presents the frequency category of ARs based on pooled data from two studies in patients with advanced SM.

Table 4     Adverse reactions observed in advanced SM

Adverse reaction                           Rydapt (100 mg twice daily)         Frequency category N=142
All grades     Grades 3/4
%              %
Infections and infestations
Urinary tract infection                         13                2.8         Very common Upper respiratory tract infection               11                1.4         Very common Pneumonia                                       8.5               7.0         Common Sepsis                                          7.7               7.7         Common Bronchitis                                      5.6                0          Common Oral herpes                                     4.9                0          Common Cystitis                                        4.2                0          Common Sinusitis                                       4.2               0.7         Common Erysipelas                                      3.5               1.4         Common Herpes zoster                                   3.5               0.7         Common Blood and lymphatic system disorders
Febrile neutropenia                             7.7               7.0         Common Immune system disorders
Hypersensitivity                                2.1                0          Common Anaphylactic shock                              0.7               0.7         Uncommon Nervous system disorders
Headache                                        26                1.4         Very common Dizziness                                       13                 0          Very common Disturbance in attention                         7                 0          Common Tremor                                          6.3                0          Common Ear and labyrinth disorders
Vertigo                                    4.9                   0         Common Vascular disorders
Hypotension                                9.2                  2.1        Common Haematoma                                  6.3                  0.7        Common Respiratory, thoracic and mediastinal disorders
Dyspnoea                                   18                   5.6        Very common Cough                                      16                   0.7        Very common Pleural effusion                           13                   4.2        Very common Epistaxis                                  12                   2.8        Very common Oropharyngeal pain                         4.2                   0         Common Interstitial lung disease/Pneumonitis1     2.1                   0         Common 
Gastrointestinal disorders
Nausea                                         82                5.6        Very common Vomiting                                       68                5.6        Very common Diarrhoea                                      51                6.3        Very common Constipation                                   29                0.7        Very common Dyspepsia                                      5.6                0         Common Gastrointestinal haemorrhage                   4.2               3.5        Common General disorders and administration site conditions
Oedema peripheral                              35                3.5        Very common Fatigue                                        31                8.5        Very common Pyrexia                                        27                4.2        Very common Asthenia                                       4.9               0.7        Common Chills                                         4.9                0         Common Oedema                                         4.2               0.7        Common Investigations
Hyperglycaemia (non-fasting)*                 93.7              19.0        Very common Absolute lymphocyte decreased*                73.2              45.8        Very common ANC decreased*                                58.5              26.8        Very common Total bilirubin increased*                    40.1               4.9        Very common Lipase increased*                             39.4              17.6        Very common AST increased*                                33.8               2.8        Very common ALT increased*                                33.1               3.5        Very common Amylase increased*                            20.4               7.0        Very common Electrocardiogram QT prolonged1               10.6               0.7        Very common Weight increased                               5.6               2.8        Common Injury, poisoning and procedural complications
Contusion                                      6.3                0         Common Fall                                           4.2               0.7        Common * Frequency is based on laboratory values.
1
These ARs were included after identification in the post-marketing setting.

Description of selected adverse reactions

Gastrointestinal disorders
Nausea, vomiting and diarrhoea were observed in AML and advanced SM patients. In advanced SM patients these events led to dose adjustment or interruption in 26% and to discontinuation in 4.2% of the patients. Most of the events occurred within the first 6 months of treatment and were managed with supportive prophylactic medicinal products.



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