Dacogen

DACOGEN- decitabine injection, powder, lyophilized, for solution
Eisai Inc.

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 ≥ 1,000/μL and platelets ≥ 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/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 − 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 ≥ 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 (2˚C — 8˚C) infusion fluids and stored at 2˚C — 8˚C (36˚F — 46˚F) 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
DacogenN = 83 (%) Supportive CareN = 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*
DacogenN = 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.
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