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Dacogen (Eisai Inc.)

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INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 1 VIAL in 1 CARTON (62856-600-01) > 20 mL in 1 VIAL Label Information

Complete Dacogen Information

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use Dacogen safely and effectively. See full prescribing information for Dacogen.

    DACOGEN® (decitabine) for INJECTION
    Initial U.S. Approval: 2006

    INDICATIONS AND USAGE

    Dacogen is a nucleoside metabolic inhibitor indicated for treatment of 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

    There are two regimens for Dacogen administration. With either regimen it is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles.  (2)

    • Treatment Regimen – Option 1
      Administer Dacogen 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)
    • Treatment Regimen – Option 2
      Administer Dacogen 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

    Lyophilized powder in a single-dose vial, 50 mg/vial. (3)

    CONTRAINDICATIONS

    None (4)

    WARNINGS AND PRECAUTIONS

    • Neutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. (5.1)
    • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus (5.2, 8.1)
    • Women of childbearing potential and men with female partners of childbearing potential should use effective contraception and avoid pregnancy (5.3, 5.4)

    ADVERSE REACTIONS

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


    To report SUSPECTED ADVERSE REACTIONS, contact Eisai, Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 2/2014


  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

        Dacogen is indicated for treatment of 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

        There are two regimens for Dacogen administration. With either regimen it is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. 

        Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle.  Liver chemistries and serum creatinine should be obtained prior to initiation of treatment.

    2.1 Treatment Regimen – Option 1

        Dacogen is administered at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days.  This cycle should be repeated every 6 weeks.  Patients may be premedicated with standard anti-emetic therapy.

        If hematologic recovery (ANC â‰¥ 1,000/μL and platelets â‰¥ 50,000/μL) from a previous Dacogen treatment cycle requires more than 6 weeks, then the next cycle of Dacogen therapy should be delayed and dosing temporarily reduced by following this algorithm:

    • Recovery requiring more than 6, but less than 8 weeks − Dacogen dosing to be delayed for up to 2 weeks and the dose temporarily reduced to 11 mg/mevery 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy.
    • Recovery requiring more than 8, but less than 10 weeks − Patient should be assessed for disease progression (by bone marrow aspirates); in the absence of progression, the Dacogen dose should be delayed up to 2 more weeks and the dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy, then maintained or increased in subsequent cycles as clinically indicated.

    2.2 Treatment Regimen – Option 2

        Dacogen is administered at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days.  This cycle should be repeated every 4 weeks.  Patients may be premedicated with standard anti-emetic therapy.  

        If myelosuppression is present, subsequent treatment cycles of Dacogen should be delayed until there is hematologic recovery (ANC ≥ 1,000/μL platelets â‰¥ 50,000/μL ).

    2.3 Patients with Non-hematologic Toxicity

        Following the first cycle of Dacogen treatment, if any of the following non-hematologic toxicities are present, Dacogen treatment should not be restarted until the toxicity is resolved:  1) serum creatinine ≥ 2 mg/dL; 2) SGPT, total bilirubin ≥ 2 times ULN; 3) and active or uncontrolled infection.

    2.4 Instructions for Intravenous Administration

        Dacogen is a cytotoxic drug and caution should be exercised when handling and preparing Dacogen.  Procedures for proper handling and disposal of antineoplastic drugs should be applied.  Several guidances on this subject have been published.1-4.

        Dacogen should be aseptically reconstituted with 10 mL of Sterile Water for Injection (USP); upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3.  Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final drug concentration of 0.1 - 1.0 mg/mL.  Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2ËšC - 8ËšC) infusion fluids and stored at 2ËšC - 8ËšC (36ËšF - 46ËšF) for up to a maximum of 4 hours until administration.

        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

        Dacogen (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 Neutropenia and Thrombocytopenia

        Treatment with Dacogen is associated with neutropenia and thrombocytopenia.  Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.  After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted [see Dosage and Administration (2.1, 2.2)].  Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS.  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 Use in Pregnancy

        Dacogen can cause fetal harm when administered to a pregnant woman.  Based on its mechanism of action, Dacogen is expected to result in adverse reproductive effects.  In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. There are no adequate and well-controlled studies of Dacogen in pregnant women.  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.  Women of childbearing potential should be advised to avoid becoming pregnant while taking Dacogen [see Use in Specific Populations (8.1)]

    5.3 Use in Women of Childbearing Potential

        Women of childbearing potential should be advised to avoid becoming pregnant while receiving Dacogen and for 1 month following completion of treatment. Women of childbearing potential should be counseled to use effective contraception during this time [see Use in Specific Populations (8.1)]. Based on its mechanism of action, Dacogen can cause fetal harm if used during pregnancy.

    5.4 Use in Men

        Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months following completion of treatment [see Nonclinical Toxicology (13.1)]. Men with female partners of childbearing potential should use effective contraception during this time. Based on its mechanism of action, Dacogen alters DNA synthesis and can cause fetal harm.


  • 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.

    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 in the Phase 3 Trials 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
        
    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 Phase 3 MDS Trial
      Dacogen
    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)

        Discussion of Clinically Important Adverse Reactions
        
    In the controlled trial using Dacogen dosed at 15 mg/m2, administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%).  Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation.  Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment [See Warnings and Precautions (5.1)]. Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm.

        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 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.

        Discussion of Clinically Important Adverse Reactions
        
    In the single-arm study (N=99) when Dacogen was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%).  Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays were due to hematologic toxicities.  Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation.  Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment.  Nineteen of 99 patients permanently discontinued therapy for adverse events.

        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 Events that occurred in patients receiving Dacogen 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 Dacogen 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 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.

    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

        Dacogen can cause fetal harm when administered to a pregnant woman.  There are no adequate and well-controlled studies of Dacogen in pregnant women.

        The developmental toxicity of decitabine was examined 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.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.  Women of child bearing potential should be advised to avoid becoming pregnant while taking Dacogen.

    8.3 Nursing Mothers

        It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from Dacogen in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

    8.4 Pediatric Use

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

    8.5 Geriatric Use

        Of the total number of patients exposed to Dacogen 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.

    8.6 Renal Impairment

        There are no data on the use of Dacogen in patients with renal dysfunction; therefore, Dacogen should be used with caution in these patients.

    8.7 Hepatic Impairment

        There are no data on the use of Dacogen in patients with hepatic dysfunction; therefore, Dacogen should be used with caution in these patients.


  • 10 OVERDOSAGE

        There is no known antidote for overdosage with Dacogen.  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

        Dacogen (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:

    Dacogen structural formula

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

        Dacogen (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 forthe control of cellulardifferentiation 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
    Dose Cmax
    (ng/mL)
    AUC0-∞
    (ng·h/mL)
    T1/2
    (h)
    CL
    (L/h/m2)
    AUCCumulative***
    (ng·h/mL)
      *N=14, **N=11, ***N=35 Cumulative AUC per cycle
      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/m2 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.


  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis and 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 Escherichiacoli lac-I transgene in colonic DNA of decitabine-treated mice.  Decitabine caused chromosomal rearrangements in larvae of fruit flies.

        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).  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

        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 Dacogen therapy plus supportive care (only 83 received Dacogen), 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 Dacogen 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 Dacogen
    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 Dacogen arm received Dacogen 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 Dacogen-treated patients and 0% in the SC group (p<0.001).  (SeeTable 6) The overall response rate was 21% (12/56) in Dacogen-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 Dacogen was 288 days (116-388) and median time to response (range) was 93 days (55-272).  All but one of the Dacogen-treated patients who responded did so by the fourth cycle.  Benefit was seen in an additional 13% of Dacogen-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients.  Dacogen treatment did not significantly delay the median time to AML or death versus supportive care.

    Table 6 Analysis of Response (ITT)
    Parameter Dacogen
    N=89
    Supportive Care
    N=81
      **p-value <0.001 from two-sided Fisher's Exact Test comparing Dacogen vs. Supportive Care.
      †In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance.
     Overall Response Rate (CR+PR)†  15 (17%)** 0 (0%)
          Complete Response (CR)   8 (9%) 0 (0%)
          Partial Response (PR)   7 (8%) 0 (0%)
     Duration of Response    
      Median time to (CR+PR) response - Days (range)   93 (55-272)   NA
      Median Duration of (CR+PR) response - Days (range)   288 (116-388)   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

        Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of Dacogen 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 Dacogen by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1-5 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 Characteristic

    Dacogen
    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)*

    Parameter

     Dacogen
    N=99

    Overall Response Rate (CR+PR)
         Complete Response (CR)
         Partial Response (PR)

    16 (16%)
    15 (15%)
    1 (1%)

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

     
    162 (50-267)
    443 (72-722+)

     + indicates censored observation
     * Cheson BD, Bennett JM, et al. Report of an International Working Group to
    Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

  • 15 REFERENCES

    1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
    2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
    3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193.
    4. Polovich M., White JM, Kelleher LO (eds). Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) 2005. Pittsburgh, PA: Oncology Nursing Society.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

        NDC 62856-600-01, 50 mg single-dose vial individually packaged in a carton.

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


  • 17 PATIENT COUNSELING INFORMATION

    Instructions for Patients

        Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Dacogen and for I month afterwards, and to use effective contraception during this time, [See Warnings and Precautions (5.3)].

        Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months afterwards. During these times, men with female partners of childbearing potential should use effective contraception [See Warnings and Precautions (5.4) and Nonclinical Toxicology (13.1)].

        Patients should be advised to monitor and report any symptoms of neutropenia, thrombocytopenia, or fever to their physician as soon as possible [See Warnings and Precautions (5.1)].

    Eisai Inc.
    Manufactured by Pharmachemie B.V. Haarlem, The Netherlands
    Manufactured for Eisai Inc., Woodcliff Lake, NJ 07677

    Dacogen® is a registered trademark of Astex Pharmaceuticals, Inc.,
    Dublin, CA, U.S.A. used under license.


  • PRINCIPAL DISPLAY PANEL

    NDC 62856-600-01

    DACOGEN®
    decitabine for injection
    50 mg per vial

    FOR INTRAVENOUS USE ONLY
    WARNING: Cytotoxic Agent
    Single use sterile vial

    Rx ONLY

    NDC 62856-600-01 DACOGEN® decitabine for injection 50 mg per vial FOR INTRAVENOUS USE ONLY WARNING: Cytotoxic Agent Single use sterile vial Rx ONLY

  • PRINCIPAL DISPLAY PANEL

    NDC 62856-600-01

    DACOGEN®
    decitabine for injection
    50 mg per vial

    FOR INTRAVENOUS USE ONLY
    WARNING: Cytotoxic Agent
    Single use sterile vial

    Rx ONLY

    NDC 62856-600-01 DACOGEN® decitabine for injection 50 mg per vial FOR INTRAVENOUS USE ONLY WARNING: Cytotoxic Agent Single use sterile vial Rx ONLY

  • INGREDIENTS AND APPEARANCE
    DACOGEN 
    decitabine injection, powder, lyophilized, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62856-600
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    DECITABINE (UNII: 776B62CQ27) (DECITABINE - UNII:776B62CQ27) DECITABINE 50 mg  in 20 mL
    Inactive Ingredients
    Ingredient Name Strength
    POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:62856-600-01 1 in 1 CARTON 05/03/1996 12/31/2018
    1 20 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA021790 05/03/1996 12/31/2018
    Labeler - Eisai Inc. (831600833)
    Establishment
    Name Address ID/FEI Business Operations
    Pharmachemie B.V. 402108922 MANUFACTURE(62856-600)