Decitabine: Package Insert and Label Information

DECITABINE — decitabine injection, powder, lyophilized, for solution
MSN LABORATORIES PRIVATE LIMITED

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, 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 for 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 nonhematologic 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 procedures.1
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 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 (2°C to 8°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 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. Discard unused portion.
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: 50 mg 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-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. 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 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 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 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:

6.1 Clinical Trails 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 Common Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the Decitabine Arm :

  • Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
  • Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
  • Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.


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 the Controlled Trial in MDS

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 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*

Decitabine N = 99 (%)
Blood and lymphatic system disorders
Anemia 31 (31)
Febrile neutropenia 20 (20)
Leukopenia 6 (6)
Neutropenia 38 (38)
Pancytopenia 5 (5)
Thrombocythemia 5 (5)
Thrombocytopenia 27 (27)
Cardiac disorders
Cardiac failure congestive 5 (5)
Tachycardia 8 (8)
Ear and labyrinth disorders
Ear pain 6 (6)
Gastrointestinal disorders
Abdominal pain 14 (14)
Abdominal pain upper 6 (6)
Constipation 30 (30)
Diarrhea 28 (28)
Dyspepsia 10 (10)
Dysphagia 5 (5)
Gastro-esophageal reflux 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)

* 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 reactions that occurred in patients receiving decitabine not previously reported in Tables 1 and 2 include:

  • Allergic Reaction: hypersensitivity (anaphylactic reaction)
  • Blood and Lymphatic System Disorders: myelosuppression, splenomegaly
  • Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia
  • Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage
  • General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage
  • Hepatobiliary Disorders: cholecystitis
  • Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection
  • Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage
  • Nervous System Disorders: intracranial hemorrhage
  • Psychiatric Disorders: mental status changes
  • Renal and Urinary Disorders: renal failure, urethral hemorrhage
  • Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass

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