Adverse reactions : תופעות לוואי

4.8   Undesirable Effects
MDS
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most Common Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the decitabine Arm: 
• Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.

• Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.

• Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.

Discussion of Adverse Reactions Information

The safety of decitabine was studied in 3 single-arm studies (N = 66, N = 98, N= 99) and 1 controlled  supportive care study (N = 83 decitabine, N = 81 supportive care). The data described below reflect exposure to decitabine in 83 patients in the MDS trial. In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine cycles was 3 (range 0 to 9).

Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care.


Table 1 Adverse Events Reported in ≥ 5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS

Decitabine       Supportive Care
N = 83 (%)           N = 81 (%)
Blood and lymphatic system disorders
Neutropenia                75 (90)              58 (72)
Thrombocytopenia           74 (89)              64 (79)
Anemia NOS                 68 (82)              60 (74)
Febrile neutropenia        24 (29)              5 (6)
Leukopenia NOS             23 (28)              11 (14)
Lymphadenopathy            10 (12)              6 (7)
Thrombocythemia            4 (5)                1 (1)
Cardiac disorders
Pulmonary edema NOS        5 (6)                0 (0)
Eye disorders
Vision blurred             5 (6)                0 (0)
Gastrointestinal disorders
Nausea                     35 (42)              13 (16)
Constipation               29 (35)              11 (14)
Diarrhea NOS               28 (34)              13 (16)
Vomiting NOS               21 (25)              7 (9)
Abdominal pain NOS         12 (14)              5 (6)
Oral mucosal petechiae     11 (13)              4 (5)
Stomatitis                 10 (12)              5 (6)
Dyspepsia                  10 (12)              1 (1)
Ascites                    8 (10)               2 (2)
Gingival bleeding          7 (8)                5 (6)
Hemorrhoids                7 (8)                3 (4)
Loose stools               6 (7)                3 (4)
Tongue ulceration          6 (7)                2 (2)
Dysphagia                  5 (6)                2 (2)
Oral soft tissue disorder  5 (6)                1 (1)
NOS
Lip ulceration             4 (5)                3 (4)
Abdominal distension       4 (5)                1 (1)
Abdominal pain upper       4 (5)                1 (1)
Gastro-esophageal reflux 4 (5)                  0 (0)
Disease
Glossodynia                4 (5)                0 (0)
General disorders and administrative site disorders
Pyrexia                      44 (53)           23 (28)
Edema peripheral             21 (25)           13 (16)
Rigors                       18 (22)           14 (17)
Edema NOS                    15 (18)           5 (6)
Pain NOS                     11 (13)           5 (6)
Lethargy                     10 (12)           3 (4)
Tenderness NOS               9 (11)            0 (0)
Fall                         7 (8)             3 (4)
Chest discomfort             6 (7)             3 (4)
Intermittent pyrexia         5 (6)             3 (4)
Malaise                      4 (5)             1 (1)
Crepitations NOS             4 (5)             1 (1)
Catheter site erythema       4 (5)             1 (1)
Catheter site pain           4 (5)             0 (0)
Injection site swelling      4 (5)             0 (0)
Hepatobiliary Disorders
Hyperbilirubinemia           12 (14)           4 (5)
Infections and Infestations
Pneumonia NOS                18 (22)           11 (14)
Cellulitis                   10 (12)           6 (7)
Candidal infection NOS       8 (10)            1 (1)
Catheter related infection 7 (8)               0 (0)
Urinary tract infection      6 (7)             1 (1)
NOS
Staphylococcal infection 6 (7)                 0 (0)
Oral candidiasis             5 (6)             2 (2)
Sinusitis NOS                4 (5)             2 (2)
Bacteremia                   4 (5)             0 (0)
Injury, poisoning and procedural complications
Transfusion reaction         6 (7)             3 (4)
Abrasion NOS                 4 (5)             1 (1)
Investigations
Cardiac murmur NOS           13 (16)           9 (11)
Blood              alkaline 9 (11)             7 (9) phosphatase
NOS increased
Aspartate                    8 (10)            7 (9) aminotransferase increased
Blood urea increased         8 (10)            1 (1)
Blood                lactate 7 (8)             5 (6) dehydrogenase Increased
Blood albumin decreased 6 (7)                  0 (0)
Blood           bicarbonate 5 (6)              1 (1) increased
Blood chloride decreased 5 (6)                 1 (1)
Protein total decreased      4 (5)             3 (4)
Blood           bicarbonate 4 (5)              1 (1) decreased
Blood           bilirubin    4 (5)             1 (1) decreased
Metabolism and nutrition disorders
Hyperglycemia NOS            27 (33)           16 (20)
Hypoalbuminemia           20 (24)               14 (17)
Hypomagnesemia            20 (24)               6 (7)
Hypokalemia               18 (22)               10 (12)
Hyponatremia              16 (19)               13 (16)
Appetite decreased NOS 13 (16)                  12 (15)
Anorexia                  13 (16)               8 (10)
Hyperkalemia              11 (13)               3 (4)
Dehydration               5 (6)                 4 (5)
Musculoskeletal and connective tissue disorders
Arthralgia                17 (20)               8 (10)
Pain in limb              16 (19)               8 (10)
Back pain                 14 (17)               5 (6)
Chest wall pain           6 (7)                 1 (1)
Musculoskeletal           5 (6)                 0 (0) discomfort
Myalgia                   4 (5)                 1 (1)
Nervous system disorders
Headache                  23 (28)               11 (14)
Dizziness                 15 (18)               10 (12)
Hypoesthesia              9 (11)                1 (1)
Psychiatric disorders
Insomnia                  23 (28)               11 (14)
Confusional state         10 (12)               3 (4)
Anxiety                   9 (11)                8 (10)
Renal and urinary disorders
Dysuria                   5 (6)                 3 (4)
Urinary frequency         4 (5)                 1 (1)
Respiratory, thoracic and Mediastinal disorders
Cough                     33 (40)               25 (31)
Pharyngitis               13 (16)               6 (7)
Crackles lung             12 (14)               1 (1)
Breath sounds decreased 8 (10)                  7 (9)
Hypoxia                   8 (10)                4 (5)
Rales                     7 (8)                 2 (2)
Postnasal drip            4 (5)                 2 (2)
Skin and subcutaneous tissue disorders
Ecchymosis                18 (22)               12 (15)
Rash NOS                  16 (19)               7 (9)
Erythema                  12 (14)               5 (6)
Skin lesion NOS           9 (11)                3 (4)
Pruritis                  9 (11)                2 (2)
Alopecia                  7 (8)                 1 (1)
Urticaria NOS             5 (6)                 1 (1)
Swelling face             5 (6)                 0 (0)
Vascular disorders
Petechiae                 32 (39)               13 (16)
Pallor                    19 (23)               10 (12)
Hypotension NOS           5 (6)                 4 (5)
Hematoma NOS              4 (5)                 3 (4)

In a single-arm MDS study (N=99) decitabine was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse events regardless of causality occurring in at least 5% of patients.


Table 2 Adverse Events Reported in ≥ 5% of Patients in a Single-arm Study* 

Decitabine
N = 99 (%)
Blood and lymphatic system disorders
Anemia                      31 (31)
Febrile neutropenia         20 (20)
Leukopenia                  6 (6 )
Neutropenia                 38 (38)
Pancytopenia                5 (5 )
Thrombocythemia             5 (5 )
Thrombocytopenia            27 (27 )
Cardiac disorders
Cardiac failure congestive  5 (5 )
Tachycardia                 8 (8)
Ear and labyrinth disorders
Ear pain                    6 (6 )
Gastrointestinal disorders
Abdominal pain              14 (14 )
Abdominal pain upper        6 (6 )
Constipation                30 (30 )
Diarrhea                    28 (28 )
Dyspepsia                   10 (10 )
Dysphagia                   5 (5 )
Gastro-esophageal reflux    5 (5 ) disease
Nausea                      40 (40 )
Oral pain                   5 (5 )
Stomatitis                  11 (11 )
Toothache                   6 (6 )
Vomiting                    16 (16 )
General disorders and administration site conditions
Asthenia                    15 (15 )
Chest pain                  6 (6 )
Chills                      16 (16 )
Fatigue                     46 (46 )
Mucosal inflammation        9 (9 )
Edema                       5 (5 )
Edema peripheral            27 (27 )
Pain                        5 (5 )
Pyrexia                     36 (36)
Infections and infestations
Cellulitis                  9 (9 )
Oral candidiasis            6 (6 )
Pneumonia                   20 (20 )
Sinusitis                    6 (6 )
Staphylococcal bacteremia    8 (8 )
Tooth abscess                5 (5 )
Upper respiratory tract      10 (10 ) infection
Urinary tract infection      7 (7)
Injury, poisoning and procedural complications
Contusion                    9 (9 )
Investigations
Blood bilirubin increased    6 (6 )
Breath sounds abnormal       5 (5 )
Weight decreased             9 (9 )
Metabolism and nutrition disorders
Anorexia                     23 (23 )
Decreased appetite           8 (8 )
Dehydration                  8 (8 )
Hyperglycemia                6 (6 )
Hypokalemia                  12 (12 )
Hypomagnesemia               5 (5 )
Musculoskeletal and connective tissue disorders
Arthralgia                   17 (17 )
Back pain                    18 (18 )
Bone pain                    6 (6 )
Muscle spasms                7 (7 )
Muscular weakness            5 (5 )
Musculoskeletal pain         5 (5 )
Myalgia                      9 (9 )
Pain in extremity            18 (18 )
Nervous system disorders
Dizziness                    21 (21 )
Headache                     23 (23 )
Psychiatric disorders
Anxiety                      9 (9 )
Confusional state            8 (8 )
Depression                   9 (9 )
Insomnia                     14 (14 )
Respiratory, thoracic and mediastinal disorders
Cough                        27 (27 )
Dyspnea                      29 (29 )
Epistaxis                    13 (13 )
Pharyngolaryngeal pain       8 (8 )
Pleural effusion             5 (5 )
Sinus congestion             5 (5 )
Skin and subcutaneous tissue disorders
Dry skin                     8 (8 )
Ecchymosis                   9 (9 )
Erythema                     5 (5 )
Night sweats                 5 (5 )
Petechiae                    12 (12 )
Pruritus                     9 (9 )
Rash                         11 (11 )
Skin lesion                  5 (5 )
                           Vascular disorders
Hypertension                    6 (6)
Hypotension                     11 (11 )

* In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events.


No overall difference in safety was detected between patients >65 years of age and younger patients in these MDS trials. No significant differences in safety were detected between males and females.
Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non White patients were available to draw conclusions in these clinical trials.


Serious Adverse Events that occurred in patients receiving decitabine not previously reported in Tables 1 and 2 include:

•    Allergic Reaction: hypersensitivity (anaphylactic reaction).

• Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.

• Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.

• Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.

• General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.

• Hepatobiliary Disorders: cholecystitis.

• Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.

• Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.

• Nervous System Disorders: intracranial hemorrhage.

• Psychiatric Disorders: mental status changes.

• Renal and Urinary Disorders: renal failure, urethral hemorrhage.

• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.

Post marketing Experience

The following adverse reactions have been identified during post approval use of decitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Sweet’s syndrome (acute febrile neutrophilic dermatosis).

•     Differentiation syndrome

AML
Summary of the safety profile

The most common adverse drug reactions (≥ 35%) reported are pyrexia, anemia and thrombocytopenia.

The most common Grade 3/4 adverse drug reactions (≥ 20%) included pneumonia, thrombocytopenia, neutropenia, febrile neutropenia and anaemia.

In clinical studies, 30% of patients treated with decitabine and 25% of patients treated in the comparator arm had adverse events with an outcome of death during treatment or within 30 days after the last dose of study drug.

In the decitabine treatment group, there was a higher incidence of treatment discontinuation due to adverse events in women compared to men (43% versus 32%).

Tabulated list of adverse drug reactions

Adverse drug reactions reported in 293 AML patients treated with decitabine are summarized in Table 3. The following table reflects data from AML clinical studies and from post-marketing experience. The adverse drug reactions are listed 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 (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.


Table 3:        Adverse Drug Reactions Identified with Decitabine 2

System Organ Class      Frequency      Adverse Drug Reaction            Frequency (all Grades)                                 All       Grades 3-4a a
Grades          (%)
(%)

Infections and                  Very                pneumonia*                                  24                    20 infestations                    common              urinary tract infection*                    15                    7 All other infections (viral,                63                    39 bacterial, fungal)* b,c,d
Common              septic shock*                             6                    4 sepsis*                                   9                    8 sinusitis                                 3                    1
Neoplasms benign,               Not known           differentiation syndrome              Not known            Not known malignant and unspecified (incl.
cysts and polyps)
Blood and lymphatic             Very                febrile neutropenia*                        34                    32 disorders                       common              neutropenia*                                32                    30 thrombocytopeniab*e                         41                    38 anaemia                                     38                    31 leukopenia                                  20                    18
Uncommon            Pancytopenia*                               <1                    <1 Immune system                   Common              Hypersensitivity including                   1                    <1 disorders                                           anaphylactic reaction c.f Metabolism and                  Very                hyperglycaemia                              13                    3 nutrition disorders             common
Nervous system                  Very                headache                                    16                    1 disorders                       common
Cardiac disorders               Uncommon            Cardiomyopathy                             <1                     <1 Respiratory, thoracic           Very                epistaxis                                  14                      2 and mediastinal                 common disorders                       Not known           interstitial lung disease             Not known            Not known Gastrointestinal                Very                diarrhoea                                 31                    2 disorders                       common              vomiting                                  18                    1 nausea                                    33                   <1
Common              stomatitis                                 7                    1 Not known           Enterocolitis, including              Not known            Not known neutropaenic colitis,
caecitis*
Hepatobiliary                   Very                hepatic function abnormal                   11                    3 disorders                       common
Common              hyperbilirubinaemiag                         5                    <1 Skin and                        Uncommon            acute febrile neutrophilic                  <1                    NA subcutaneous tissue                                 dermatosis (Sweet’s disorders                                           syndrome)
General disorders and Very                          pyrexia                                     48                    9 administration site   common conditions a
Worst National Cancer Institute Common Terminology Criteria for Adverse Events Grade b
Excluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis.
c
The most frequently reported "other infections" in study DACO-016 were: oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis.
d
Including enterocolitis infectious.
e
Including haemorrhage associated with thrombocytopaenia, including fatal cases.
f
Including preferred terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.
    g
In clinical studies in AML and myelodysplastic syndrome (MDS), the reporting frequency for hyperbilirubinaemia was 11% for All Grades and 2% for Grade 3-4.


*Includes events with a fatal outcome
NA=Not applicable


Description of selected adverse drug reactions

Hematologic adverse drug reactions

The most commonly reported hematologic adverse drug reactions associated with decitabine treatment included febrile neutropenia, thrombocytopenia, neutropenia, anemia and leukopenia.
Serious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as central nervous system (CNS) hemorrhage (2%) and gastrointestinal (GI) hemorrhage (2%), in the context of severe thrombocytopenia, were reported in patients receiving decitabine.
Hematological adverse drug reactions should be managed by routine monitoring of complete blood counts and early administration of supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia and transfusions for anemia or thrombocytopenia according to institutional guidelines. For situations where decitabine administration should be delayed, see section 4.2.


Infections and infestations adverse drug reactions
Serious infection related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving decitabine.
Gastrointestinal disorders
Occurrences of enterocolitis, including neutropenic colitis, cecities have been reported during treatment with decitabine. Enterocolitis may lead to septic complications and may be associated with fatal outcome.
Respiratory, thoracic and mediastinal disorders
Cases of interstitial lung disease (including pulmonary infiltrates, organizing pneumonia and pulmonary fibrosis) without signs of infectious etiology have been reported in patients receiving decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction. Differentiation syndrome may occur with or without concomitant leucocytosis.
Capillary leak syndrome and coagulopathy can also occur (see section 4.4).


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