Prescription Drug Information: Decitabine

DECITABINE- decitabine injection, powder, lyophilized, for solution
BluePoint Laboratories

1 INDICATIONS AND USAGE

Decitabine for Injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Pre-Medications and Baseline Testing

Consider pre-medicating for nausea with antiemetics
Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.

Decitabine for Injection Regimen Options

Three Day Regimen

Administer Decitabine for Injection at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/µL and platelets at least 50,000/µL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)].

Five Day Regimen

Administer Decitabine for Injection at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)]. Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/µL and platelets at least 50,000/µL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.

Patients with Renal or Severe Hepatic Impairment

Treatment with Decitabine for Injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with Decitabine for Injection.

2.2 Dosage Modifications for Adverse Reactions

Hematologic Toxicity

If hematologic recovery from a previous Decitabine for Injection treatment cycle requires more than 6 weeks, delay the next cycle of Decitabine for Injection therapy and reduce Decitabine for Injection dose temporarily by following this algorithm:

Recovery requiring more than 6, but less than 8 weeks – delay Decitabine for Injection dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/m2 every 8 hours (33 mg/m2 /day, 99 mg/m2 /cycle)) upon restarting therapy.
Recovery requiring more than 8, but less than 10 weeks – Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay Decitabine for Injection dosing up to 2 more weeks and reduce the dose to 11 mg/m2 every 8 hours (33mg/m2 /day, 99mg/m2 /cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated.

Non-Hematologic Toxicity

Delay subsequent Decitabine for Injection treatment for any the following non-hematologic toxicities and do not restart until toxicities resolve:

Serum creatinine greater than or equal to 2 mg/dL
Alanine transaminase (ALT), total bilirubin greater than or equal to 2 times upper limit of normal (ULN)
Active or uncontrolled infection

2.3 Preparation and Administration

Decitabine for Injection is a cytotoxic drug. Follow special handling and disposal procedures1.

Aseptically reconstitute Decitabine for Injection with room temperature (20o C to 25 o C) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted Decitabine for Injection solution is 5 mg/mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.

For Administration Within 15 Minutes of Preparation

If Decitabine for Injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20o C — 25 o C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Discard unused portion.

For Delayed Administration

If Decitabine for Injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2o C to 8o C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1mg/mL to 1 mg/mL. Store at 2o C to 8 o C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation. Discard unused portion.

Use the diluted, refrigerated solution within 4 hours from the time of preparation or discard.

Parental drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.

3 DOSAGE FORMS AND STRENGTHS

For Injection: 50mg of decitabine as a sterile, white to almost white lyophilized powder, in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Fatal and serious myelosuppression occurs in Decitabine for Injection-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of Decitabine for Injection dose reduction, delay and discontinuation. Neutropenia of any grade occurred in 90% of Decitabine for Injection-treated patients with grade 3 or 4 occurring in 87% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration (2.2)]. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

5.2 Embryo-Fetal Toxicity

Based on findings from human data, animal studies and its mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection, and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Myelosuppression [see Warnings and Precautions (5.1)]

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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