Decitabine (Page 2 of 5)

6.1 Clinical Trials 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.

The safety of Decitabine for Injection was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 Decitabine for Injection, N = 81 supportive care). The data described below reflect exposure to Decitabine for Injection 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 for Injection cycles was 3 (range 0 to 9).

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 for Injection 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.

Table 1 presents all adverse reactions occurring in at least 5% of patients in the Decitabine for Injection group and at a rate greater than supportive care.

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

Decitabine for Injection N = 83 (%)

Supportive Care 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 NOS

5 (6)

1 (1)

Lip ulceration

4 (5)

3 (4)

Abdominal distension

4 (5)

1 (1)

Abdominal pain upper

4 (5)

1 (1)

Gastro-esophageal reflux disease

4 (5)

0 (0)

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 NOS

6 (7)

1 (1)

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 phosphatase NOS increased

9 (11)

7 (9)

Aspartate aminotransferase increased

8 (10)

7 (9)

Blood urea increased

8 (10)

1 (1)

Blood lactate dehydrogenase increased

7 (8)

5 (6)

Blood albumin decreased

6 (7)

0 (0)

Blood bicarbonate increased

5 (6)

1 (1)

Blood chloride decreased

5 (6)

1 (1)

Protein total decreased

4 (5)

3 (4)

Blood bicarbonate decreased

4 (5)

1 (1)

Blood bilirubin decreased

4 (5)

1 (1)

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 discomfort

5 (6)

0 (0)

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 for Injection was dosed at 20 mg/m2 intravenously, infused over one hour daily for 5 consecutive days of a 4-week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients.

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

Decitabine for Injection 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 disease

5 (5)

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 infection

10 (10)

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)

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 reactions that occurred in patients receiving Decitabine for Injection, not previously reported in Tables 1 and 2include:

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.

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