英文药名: Dacogen(Decitabine Injection) 中文药名: 达珂(地西他滨注射剂) 生产厂家: Johnson Inc./Eisai Inc. 药品简介 地西他滨注射液-达珂-DACOGEN（Decitabine for Injection） 骨髓增生异常综合征（MDS）是1组骨髓造血异常的疾病。尽管在每10万人中仅有5人会发病，但MDS在近年来受到了广泛的关注。部分原因是由于FDA批准了几种治疗MDS的原创新药，包括2004年的阿扎胞甘（azacitidine，Vidaza，Pharmion）和2005年的lenalidomide（Revlimid，Celgene）。 而在06年5月，FDA又批准了第三种MDS治疗药物—地西他滨注射剂（decitabine ，Dacogen，MGI公司）。 MDS是1个广泛的概念，包括多种类型，各种类型之间都有显著的不同。 而地西他滨是批准用于以下几种MDS的治疗： 曾接受过和未接受过治疗的MDS；所有法、美、英型（FAB）的原发性和继发性MDS，包括难治性贫血、环形铁粒幼细胞性难治性贫血、难治性贫血伴原始细胞增多、难治性贫血伴原始细胞增多转变型以及慢性粒-单核细胞性贫血；以及中度1级危险、中度2级危险和高危险的MDS。 “地西他滨是1种低甲基化阿扎胞甘，”血液病和肿瘤临床药理专家Sachin Shah说，“地西他滨磷酸化并与DNA结合后，可抑制DNA的甲基转移酶，从而起到抗肿瘤作用。”由此可促进DNA的低甲基化，使得细胞发生分化或凋亡。 “Decitabine在肿瘤细胞中诱导的低甲基化可能能够修复正常基因的功能，”Shah补充说。 初始治疗阶段，需给予地西他滨15 mg／m2，静脉滴注3~4 h，持续3天。 据生产商介绍；患者需接受至少4个疗程的治疗，每6周1个疗程。若要对治疗产生完全或部分应答，可能需要更长的疗程，如果对患者持续有效，则可持续进行治疗。 需要根据血液实验室检查的结果调整剂量。 MGI 公司说，血象恢复是指中性粒细胞达到1×109／L、血小板计数50×109／L。如果地西他滨治疗结束后的6周内血象仍未恢复，则下1疗程要延迟或减量。 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 ≥ 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  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: 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)   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) *N=14, **N=11, ***N=35 Cumulative AUC per cycle 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*  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 *Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674. 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  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 **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. 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, 50mg 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. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ACAF6E50-7CD3-4431-98EF-D1C07E3ED8C2 补充说明: MGI制药和SuperGen公司宣布，美国FDA批准了Dacogen（decitabine，地西他滨）注射液的上市申请，获批用于治疗骨髓异常综合征（MDS），包括所有法、美、英型（ＦＡＢ型）的已接受治疗和未接受治疗的，新发病的和继发性的MDS患者，以及按IPSS系统分为高危险、中度2级危险、中度1级危险的MDS患者。 　　 MGI制药计划于今年第二季度上市该产品。Dacogen是一类低甲基化试剂，具有独特的治疗机制。2004年3月，SuperGen公司完成了Dacogen治疗MDS患者的Ⅲ期临床试验，向FDA报批。 　　 MGI制药与SuperGen公司达成协议，拥有该产品在全世界的独占开发、生产和经销权。两公司目前正计划将该药运用到更多的血液肿瘤疾病中。 [摘要] 地西他滨是DNA甲基转移酶抑制剂，具有治疗骨髓增生异常综合征的临床作用。地西他滨被磷酸化后，直接作用于DNA，抑制DNA甲基转移酶，从而使DNA低甲基化，细胞分化死亡。 恶性肿瘤是对人类威胁最大的疾病之一，对其治疗的研究也最为广泛深入。科学家们正从不同的生物学途径进行攻关。最近，科学家们又发现表遗传(epigenetics)原因，特别是现DNA甲基化异常在肿瘤的发生和转化中起着重要作用。 骨髓增生异常综合征(Myelodysplastic syndrome，MDS)是一组以血细胞的质、量异常和高风险成为急性白血病为特征的异质性的造血干细胞疾病。 美国每年新诊断MDS患者7000～12000例。虽然，MDS可发生在任何年龄段，但60岁以上发病率最高。 临床表现多变，很多病人死于骨髓衰竭并发症。典型症状是乏力、感染、易碰伤、出血和发热。临床的处理取决于病人的年龄、MDS的亚型、国际预后积分系统(IPSS)积分以及病人的情况(Ps)。标准的支持疗法似无助于疾病的改观和生命的延长，唯一能治愈MDS的措施是异基因造血干细胞移植(ALLOHSCT)，但对于大多数诊断MDS的老年患者不适用，而小剂量化疗对中高危患者则疗效低、复发率高。 由于MDS细胞的基因组DNA存在异常甲基化，许多重要功能基因的启动子CpG岛由于高度甲基化，转录水平被抑制导致功能失活。 如果肿瘤抑制基因启动子区和与维持基因组稳定性有关的基因出现新的甲基化，这些基因将沉默，使细胞可能获得生长优势而异常增生，成为促进肿瘤形成的主要因素。现认为，可采用DNA甲基化转移酶抑制剂治疗。 地西他滨是一种去甲基化药物，具有独特的甲基化转移酶抑制剂的治疗机制。2004年3月，SuperGen公司完成了地西他滨治疗MDS患者的一期临床试验。MGI制药和SuperGen公司宣布地西他滨是一类低甲基化试剂。 2006年，美国FDA批准了地西他滨(decitabine)注射液的上市申请，商品名为Dacogen，获批用于治疗骨髓异常综合征(MDS)。MGI制药与SuperGen公司达成协议，拥有该产品在全世界的独占开发、生产和经销权。两公司目前正计划将该药运用到更多的血液肿瘤疾病中，包括所有法、美、英型(FAB型)的已接受治疗和未接受治疗的，新发病的和继发性的MDS患者，以及按IPSS系统分为高危险、中度2级危险、中度1级危险的MDS患者。本文对其作用机制及临床应用等作一综述。 药物的结构与性质： 地西他滨(decitabine)：5-氮杂-2′-脱氧胞苷酸，一种天然2′-脱氧胞苷酸的腺苷类似物，通过抑制DNA甲基转移酶，减少DNA的甲基化，从而抑制肿瘤细胞增殖以及防止耐药的发生。 地西他滨的分子式为C8H12N4O4，分子量为228.21。 化学名称：4-氨基-1-(2-脱氧-β-D-赤式-顺-呋喃核糖)-1，3，5-三嗪-2(氢)-1。化合物编号(CAS)：2353-33-5地西他滨微溶于乙醇/水（50/50）、甲醇/水（50/50）、甲醇，略溶于水，溶于二甲基亚砜（DMSO）。 地西他滨注射液单次剂量20mL，其中包括50mg地西他滨，68mg磷酸二氢钾，11.6mg氢氧化钠。 药理学研究 因为去甲基化药物可活化肿瘤细胞抑癌基因，增强分化基因等调控基因的表达，所以可达到治疗MDS的目的。地西他滨被磷酸化后，发挥其抗肿瘤作用。它直接作用于DNA，抑制DNA甲基转移酶，从而使DNA低甲基化，细胞分化死亡。 地西他滨在体外抑制DNA甲基化，却不影响DNA的合成。 它可导致肿瘤细胞去甲基化，可以恢复基因的正常功能，这对于控制细胞的分化和增殖是非常重要的。但非增殖性细胞对地西他滨不敏感。 以MDS-RAEB细胞株SKM-1为研究对象，了解地西他滨促进SKM-1株分化和诱导凋亡作用以及可能机制。 研究表明，3.2mmol/L地西他滨可使异常甲基化的Pl5INK4B恢复正常的去甲基化，表达增强，从而抑制SKM-l细胞增殖，促进分化，可能是其治疗MDS的主要机制。 Bahar等最近报道，应用地西他滨可重新激活肿瘤细胞中DNA损伤诱导生长抑制基因(GADD45beta)的表达。Alleman等报道，地西他滨可使移植肾肿瘤细胞老鼠身上的肿瘤明显变小。 Miotto等则报道，地西他滨可使CDH4肿瘤抑制基因在肠癌和胃癌细胞中重新表达。KAWAKAMI等研究则表明，地西他滨可使膀胱癌DNA修复基因（hMSH3)恢复表达，从而影响膀胱癌的生长。 Romaih.KI等在免疫缺陷大鼠的肾下被膜进行U2OS异种嫁接，进而研究地西他滨在体内对肿瘤生长和分化的影响。通过免疫组织化学方法，采用5-甲基胞苷抗体能检测到异种嫁接大鼠细胞核的甲基化水平降低了。地西他滨能显著地减小肿瘤异种嫁接的尺寸（P <0.05）。 临床药理和药物代谢动力学 SuperGen公司对17O例确诊的成年MDS患者进行了标记开放性多中心随机对照临床研究。试验组89例患者随机接受地西他滨治疗加支持性医护治疗，对照组81例患者随机仅接受支持医疗。 试验组患者每8小时接受本品治疗，剂量为15mg/m2静脉滴注3小时，连续用药3天。每6周使用地西他滨治疗1次。 支持疗法包括输血或血液制品、预防性使用抗菌药物及生长因子。治疗288天后，本品治疗组平均总有效率为17%，支持疗法组为0(P<0.001)。本品组完全应答率为9%，部分应答率为8%。病理学确诊的MDS患者，以地西他滨至少治疗2个疗程，总有效率为21%。此外，本品组13%的患者血液学得到改善，支持疗法组改善率仅为7%。 Wijermans等用地西他滨治疗具有高危MDS的老年病人，每6周1个疗程，每疗程持续3天，剂量为15mg/m2，每疗程总剂量在120～150mg/m2之间。结果在121例中，49%对治疗有良好反应，其中20%完全好转，10%部分好转，19%血液学指标有改善。 Issa等采用地西他滨15mg/m2/天，静脉滴注>1h，每周5天，连续两周治疗50例（其中，AMI/MDS 44例，CML 5例，ALL 1例），有效率为65%。而Kantarjian等认为地西他滨最佳剂量为20mg/m2/天，静脉滴注>1h连续5天，且定期重复治疗，疗效更好。由于MDS的表现异质性，对IPSS系统中度-2和高危病人至少应接受4个疗程，部分可达6个疗程或更多，为了最大限度地增加低甲基化药物的疗效，应尽可能长期治疗。 目前，暂时无注射地西他滨15 mg/m2的药物代谢动力学有效数据。实体瘤患者注射地西他滨20～30mg/m2/天，治疗72小时后，其药代动力学数据呈二相性分布特征。总体清除率为（124±19）L/m2/时,终相消除半衰期为（0.51±0.31）小时。地西他滨的血浆蛋白结合率可忽略不计(<1%)。人体中的地西他滨准确代谢和消除途径机理尚未研究明确。在肝、粒细胞、肠的上皮组织中，地西他滨通过胞二磷胆碱的脱氨作用而消除，但这仅仅是一种可能的途径。 临床使用说明 剂量和用法： 第一治疗周期的推荐剂量为静脉注射地西他滨15mg/m23小时，间隔8小时重复一次，连续三天。患者须提前服用止吐剂。此疗程每六周重复一次。患者最少应经过四个疗程，直到病情得到控制与好转。第一和第二治疗周期中，骨髓抑制和中性粒细胞减少症较常见。较严重的中性粒细胞减少症发生率为87%，血小板减少症为85%，热性的中性粒细胞减少症为23%，白细胞减少为22%。骨髓抑制是减少剂量或中断治疗的主要原因。在整个治疗的过程中须密切关注血小板数量，随时调整剂量或暂停治疗。 不良反应 常见副反应：中性白细胞减少(症)、血小板减少(症)、贫血、疲劳、发热、咳嗽、恶心、便秘、腹泻、高血糖、热性的中性白细胞减少(症)。 地西他滨慎用于下列情况的患者：肾病、肝机能障碍、血清肌酸肝>20mg/dl、转氨酶高于正常人两倍、血清胆红素>1.5mg/dl。孕妇及哺乳期妇女禁用。 展望 地西他滨是DNA甲基转移酶抑制剂，治疗骨髓增生异常综合征患者有积极的临床作用。临床研究表明，增加剂量和给药多样化会增加反应率。进一步的研究工作需要阐明在治疗非白血性白血病方面适当的剂量和治疗循环的数量和间期，建立这些制剂长期的安全性监测。在未来，能够增加基因的复活作用和靶基因的表达的联合治疗法，可能会达到最优化的效果.