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 Dacogen 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 Dacogen was studied in 3 single-arm studies (N = 66, N = 98, N= 99) and 1 controlled supportive care study (N = 83 Dacogen, N = 81 supportive care ). The data described below reflect exposure to Dacogen 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 Dacogen 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 Dacogen group and at a rate greater than supportive care.


Table 1 Adverse Events Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS
Dacogen                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) Dacogen 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* Dacogen
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 Dacogen 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 Dacogen. 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 Dacogen 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 Dacogen 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 Dacogen are summarised 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 DACOGEN 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                   Not known         Not known malignant and                      syndrome 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
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                          11                 3 disorders                       common             abnormal
Common             hyperbilirubinaemiag                      5                 <1 Skin and                        Uncommon           acute febrile neutrophilic                <1                NA subcutaneous tissue                                dermatosis (Sweet’s disorders                                          syndrome)
General disorders               Very               pyrexia                                   48                 9 and administration              common site 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 Dacogen 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 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