These highlights do not include all the information needed to use DECITABINE FOR INJECTION safely and effectively. See full prescribing information for DECITABINE FOR INJECTION. DECITABINE for injection, for intravenous useInitial U.S. Approval: 2006

Decitabine by

Drug Labeling and Warnings

Decitabine by is a Prescription medication manufactured, distributed, or labeled by Sandoz Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DECITABINE- decitabine injection, powder, lyophilized, for solution 
Sandoz Inc

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DECITABINE FOR INJECTION safely and effectively. See full prescribing information for DECITABINE FOR INJECTION.

DECITABINE for injection, for intravenous use
Initial U.S. Approval: 2006

INDICATIONS AND USAGE

Decitabine for Injection is a nucleoside metabolic inhibitor 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. (1)

DOSAGE AND ADMINISTRATION

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 cycle every 6 weeks (2.1).

Five Day Regimen

Administer decitabine for injection at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks (2.2).

DOSAGE FORMS AND STRENGTHS

For Injection: 50 mg of decitabine as a lyophilized powder in a single-dose vial for reconstitution. (3)

CONTRAINDICATIONS

None (4)

WARNINGS AND PRECAUTIONS

  • Neutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. (5.1)
  • Embryo-fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.2,8.1, 8.3)

ADVERSE REACTIONS

Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2019

FULL PRESCRIBING INFORMATION

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 Starting Dosage

Pre-Medications and Baseline Testing

  • Consider pre-medicating for nausea with antiemetics.
  • Conduct baseline laboratory testing: 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 Dose Modifications for Toxicity).

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 Dose Modifications for Toxicity). 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.

2.2 Dose Modifications for Toxicity

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 the decitabine for injection dose up to 2 more weeks and reduce the dose to 11 mg/m2 every 8 hours (33 mg/m2/day, 99 mg/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
  • SGPT, total bilirubin greater than or equal to 2 times ULN
  • Active or uncontrolled infection

2.3 Instructions for Intravenous Administration

Decitabine for injection is a cytotoxic drug and caution should be exercised when handling and preparing decitabine1.

Aseptically reconstitute decitabine for injection with room temperature (20°C to 25°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 (20°C to 25°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL- 1 mg/mL.

For Delayed Administration

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

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

Parenteral 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: Decitabine for injection is supplied as a sterile, lyophilized white to almost white powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Fatal and serious myelosuppression occurs in decitabine-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of decitabine dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade 3 or 4 occurring in 87% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% 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

Decitabine can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, decitabine alters DNA synthesis and is expected to result in adverse reproductive effects [see Clinical Pharmacology (12.1)]. In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Advise women of childbearing potential to avoid becoming pregnant while taking decitabine and for 6 months following the last dose. Advise men with female partners of childbearing potential to avoid fathering a child while receiving treatment with decitabine, and for 3 months following the last dose, Counsel patients of childbearing potential to use effective contraception during this time [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

6.1 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.  

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). Most Commonly Occurring 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 Phase 3 Trials 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.

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

Table 1 Adverse Reactions Reported in ≥5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in Phase 3 MDS Trial
Decitabine
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 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 reactions occurring in at least 5% of patients.

Table 2 Adverse Reactions Reported in ≥5% of Patients in a Single-arm Study*
Decitabine
N =99 (%)
  • * 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.
    		•

    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 myelodysplasia trials. No significant gender differences in safety or efficacy were detected. 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 regardless of causality, not previously reported in Tables 1 and 2 include:

    • 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.
    • Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine has been reported in a Phase 2 trial.

    6.2 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.

    Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.

    7 DRUG INTERACTIONS

    Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on findings from human data, animal studies, and the mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

    Limited published data on decitabine use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes and was teratogenic, fetotoxic, and embryotoxic starting at doses approximately 7% of the recommended human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.

    Data

    Human Data

    A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated.

    Animal Data

    In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring.

    In mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs.

    In rats given a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2.

    The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

    8.2 Lactation

    Risk Summary

    There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine in a nursing child, advise lactating women to avoid breastfeeding during treatment with decitabine and for at least 1 week after the last dose.

    8.3 Females and Males of Reproductive Potential

    Pregnancy Testing

    Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine.

    Contraception

    FemalesAdvise females of reproductive potential to avoid pregnancy and use effective contraception while receiving decitabine and for 6 months following the last dose. Males Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose [see Nonclinical Toxicology (13.1)].

    Infertility

    Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine [see Nonclinical Toxicology (13.1)].

    8.4 Pediatric Use

    The safety and effectiveness of decitabine in pediatric patients have not been established.

    8.5 Geriatric Use

    Of the total number of patients exposed to decitabine in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

    10 OVERDOSAGE

    There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.

    11 DESCRIPTION

    Decitabine for Injection contains decitabine (5-aza-2’deoxycitidine), an analogue of the natural nucleoside 2’-deoxycytidine. Decitabine is a fine, white to almost white powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:

    structure

    Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide (DMSO).

    Decitabine for Injection is a white to almost white sterile lyophilized powder supplied in a clear colorless glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide.  

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.  

    12.2 Pharmacodynamics

    Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.

    12.3 Pharmacokinetics

    Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.

    Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine

    DoseCmax
    (ng/mL)     		AUC 0-∞
    (ng∙h/mL)     		T1/2
    (h)     		CL
    (L/h/m2)     		AUCCumulative*
    (ng∙h/mL)
  • * N=35 Cumulative AUC per cycle
  • † N=14
  • ‡ N=11
    		•

    15 mg/m2

    3-hr infusion every 8 hours for 3 days
    (Option 1)†

    73.8
    (66)

    163
    (62)

    0.62
    (49)

    125
    (53)

    1332
    (1010-1730)

    20 mg/m 2

    1-hr infusion daily for 5 days
    (Option 2)‡

    147
    (49)

    115
    (43)

    0.54
    (43)

    210
    (47)

    570
    (470-700)

    The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.  

    Specific Populations

    Patients with Renal Impairment

    There are no data on the use of decitabine in patients with renal impairment; therefore, if decitabine is administered to these patients, monitor them frequently for excessive toxicity.

    Patients with Hepatic Impairment

    There are no data on the use of decitabine in patients with hepatic impairment; therefore, if decitabine is administered to these patients, monitor them frequently for excessive toxicity.

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity studies with decitabine have not been conducted.

    The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.

    In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥0.3 mg/m2. In females mated to males dosed with ≥0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

    14 CLINICAL STUDIES

    14.1 Controlled Trial in Myelodysplastic Syndrome

    A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine therapy plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4.

    Table 4 Baseline Demographics and Other Patient Characteristics (ITT)
    Demographic or Other Patient Characteristic Decitabine
    N = 89     		Supportive Care
    N= 81

    Age (years)
    Mean (±SD)
    Median (IQR)
    (Range: min-max)


    69±10
    70 (65-76)
    (31-85)


    67±10
    70 (62-74)
    (30-82)

    Gender n (%)
    Male
    Female


    59 (66)
    30 (34)


    57 (70)
    24 (30)

    Race n (%)
    White
    Black
    Other


    83 (93)
    4 (4)
    2 (2)


    76 (94)
    2 (2)
    3 (4)

    Weeks Since MDS Diagnosis
    Mean (±SD)
    Median (IQR)
    (Range: min-max)


    86±131
    29 (10-87)
    (2-667)


    77±119
    35 (7-98)
    (2-865)

    Previous MDS Therapy n (%)
    Yes
    No


    27 (30)
    62 (70)


    19 (23)
    62 (77)

    RBC Transfusion Status n (%)
    Independent
    Dependent


    23 (26)
    66 (74)


    27 (33)
    54 (67)

    Platelet Transfusion Status n (%)
    Independent
    Dependent


    69 (78)
    20 (22)


    62 (77)
    19 (23)

    IPSS Classification n (%)
    Intermediate-1
    Intermediate-2
    High Risk


    28 (31)
    38 (43)
    23 (26)


    24 (30)
    36 (44)
    21 (26)

    FAB Classification n (%)
    RA
    RARS
    RAEB
    RAEB-t
    CMML


    12 (13)
    7 (8)
    47 (53)
    17 (19)
    6 (7)


    12 (15)
    4 (5)
    43 (53)
    14 (17)
    8 (10)

    Patients randomized to the decitabine arm received decitabine intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5:  

    Table 5 Response Criteria for Phase 3 MDS Trial*
  • * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

    • Complete Response (CR)
    ≥8 weeks

    Bone Marrow

    On repeat aspirates:

    • <5% myeloblasts
    • No dysplastic changes

    Peripheral Blood

    In all samples during response:

    • Hgb >11 g/dL (no transfusions or erythropoietin
    • ANC ≥1500/μL (no growth factor)
    • Platelets ≥100,000/μL (no thrombopoietic agent)
    • No blasts and no dysplasia

    Partial Response (PR)
    ≥8 weeks

    Bone Marrow

    On repeat aspirates:

    • ≥50% decrease in blasts over pretreatment values OR
    • Improvement to a less advanced MDS FAB classification

    Peripheral Blood

    Same as for CR

    The overall response rate (CR+PR) in the ITT population was 17% in decitabine-treated patients and 0% in the SC group (p<0.001). (See Table 6) The overall response rate was 21% (12/56) in decitabine-treated patients considered evaluable for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Decitabine treatment did not significantly delay the median time to AML or death versus supportive care.

    Table 6 Analysis of Response (ITT)

    Parameter Decitabine
    N=89     		Supportive Care
    N=81
  • * In the statistical analysis plan, a p-value of ≤0.024 was required to achieve statistical significance.
  • † p-value <0.001 from two-sided Fisher's Exact Test comparing decitabine vs. Supportive Care.
    		•

    Overall Response Rate (CR+PR)*

    Complete Response (CR)
    Partial Response (PR)

    15 (17%)†
    8 (9%)
    7 (8%)

    0 (0%)
    0 (0%)
    0 (0%)

    Duration of Response
    Median time to (CR+PR) response - Days (range)
    Median Duration of (CR+PR) response - Days (range)



    93 (55-272)

    288 (116-388)



    NA

    NA

    All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.

    Responses occurred in patients with an adjudicated baseline diagnosis of AML.

    14.2 Single-arm Studies in Myelodysplastic Syndrome

    Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received decitabine by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1 to 5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8.

    Table 7 Baseline Demographics and Other Patient Characteristics (ITT)

    Demographic or Other Patient CharacteristicDecitabine
    N = 99

    Age (years)
    Mean (±SD)
    Median (Range: min-max)


    71±9
    72 (34-87)

    Gender n (%)
    Male
    Female


    71 (72)
    28 (28)

    Race n (%)
    White
    Black
    Asian
    Other


    86 (87)
    6 (6)
    4 (4)
    3 (3)

    Days From MDS Diagnosis to First Dose
    Mean (±SD)
    Median (Range: min-max)


    444±626
    154 (7-3079)

    Previous MDS Therapy n (%)
    Yes
    No


    27 (27)
    72 (73)

    RBC Transfusion Status n (%)
    Independent
    Dependent


    33 (33)
    66 (67)

    Platelet Transfusion Status n (%)
    Independent
    Dependent


    84 (85)
    15 (15)

    IPSS Classification n (%)
    Low Risk
    Intermediate-1
    Intermediate-2
    High Risk


    1 (1)
    52 (53)
    23 (23)
    23 (23)

    FAB Classification n (%)
    RA
    RARS
    RAEB
    RAEB-t
    CMML


    20 (20)
    17 (17)
    45 (45)
    6 (6)
    11 (11)
    Table 8 Analysis of Response (ITT)*
    ParameterDecitabine
    N=99
  • * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.
  • † indicates censored observation
    		•

    Overall Response Rate (CR+PR)

    16 (16%)

      Complete Response (CR)

    15 (15%)

      Partial Response (PR)

    1 (1%)

    Duration of Response

    Median time to (CR+PR) response - Days (range)

    162 (50-267)
    443 (72-722†)

    Median Duration of (CR+PR) response - Days (range)

    15 REFERENCES

    16 HOW SUPPLIED/STORAGE AND HANDLING

    Decitabine for injection is supplied as follows:

    •   NDC: 0781-3139-80, 50 mg single-dose vial individually packaged in a carton.

    Storage

    Store vials at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

    17 PATIENT COUNSELING INFORMATION

    Advise women of childbearing potential to avoid pregnancy and to use effective contraception while receiving decitabine for injection and for 6 months after last dose [see Warnings and Precautions (5.2)].

    Advise men not to father a child while receiving treatment with decitabine for injection, and for 3 months after the last dose. Advise men with female partners of childbearing potential to use effective contraception [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)].

    Advise patients to avoid breastfeeding while receiving decitabine for injection and for at 1 week after the last dose [see Use in Specific Populations (8.2)]. Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions (5.1)].

    Manufactured by

    Emcure Pharmaceuticals Ltd., Pune, India

    for Sandoz Inc., Princeton, NJ 08540

    Rev. February 2019

    PRINCIPAL DISPLAY PANEL

    NDC 0781-3139-80

    Decitabine for Injection

    50 mg per Vial

    FOR INTRAVENOUS USE ONLY

    WARNING: Cytotoxic Agent

    Single use sterile vial

    Store vials at 25°C (77°F); [See USP controlled room temperature]

    excursions permitted to 15°C to 30°C (59°F to 86°F)

    (see insert).

    Rx only

    SANDOZ

    Vial label
    DECITABINE 
    decitabine injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0781-3139
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DECITABINE (UNII: 776B62CQ27) (DECITABINE - UNII:776B62CQ27) DECITABINE50 mg  in 20 mL
    Inactive Ingredients
    Ingredient NameStrength
    POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0781-3139-801 in 1 CARTON08/28/201405/31/2019
    120 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20296908/28/201405/31/2019
    Labeler - Sandoz Inc (005387188)

    Revised: 10/2019
    Document Id: 10009401-9796-469a-a892-ca9ca47f396f
    Set id: 0b9599e8-9018-42ee-b247-e2a944c36510
    Version: 5
    Effective Time: 20191011
    Â
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