Decitabine, a synthetic nucleoside analog of 2'-deoxycytidine, is an antineoplastic agent.1, 3, 4, 5
Decitabine is used for the treatment of myelodysplastic syndrome (MDS)1, 3, 4 and is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.2 The drug is indicated for use in patients with previously treated or untreated, de novo or secondary MDS of the following subtypes/groups: all French-American-British (FAB) subtypes (i.e., refractory anemia [RA], RA with ringed sideroblasts [ RARS], RA with excess blasts [ RAEB], RAEB in transformation to leukemia [ RAEB-T], chronic myelomonocytic leukemia [CMML]) and International Prognostic Scoring System (IPSS) risk groups with scores of 0.5 or higher (i.e., intermediate-1, intermediate-2, and high-risk groups).1, 3, 4
The current indication for decitabine is based on results of one randomized, open-label, phase 3 study and 2 open-label, single-arm, phase 2 studies.1, 3, 4 The phase 3 study included 170 adults with MDS who met FAB classification criteria and had an IPSS score of 0.5 or higher;1, 3, 4 patients with acute myelogenous leukemia (AML) were not intended to be included, although AML was diagnosed at baseline in 12 patients.1, 4 In this study, patients were randomized to receive either decitabine (15 mg/m2 IV over 3 hours, repeated every 8 hours for 3 consecutive days [total dosage per treatment cycle: 135 mg/m2]) plus supportive care (i.e., blood and blood product transfusions, prophylactic anti-infectives, hematopoietic growth factors) or supportive care alone.1, 4 The treatment cycle was repeated every 6 weeks, depending on the patient's clinical response and toxicity; patients received a median of 3 cycles (range: 0-9 cycles) of therapy.1, 4 Primary end points included overall response rate (complete plus partial responses) and time to AML or death.1, 4 Responses were classified using the MDS International Working Group (IWG) criteria.1, 4 A complete response to therapy (lasting at least 8 weeks) generally was defined as less than 5% myeloblasts and the absence of dysplastic changes in the bone marrow and improvements in peripheral blood cell counts (i.e., hemoglobin concentration exceeding 11 g/dL [without transfusions or exogenous erythropoietin], absolute neutrophil count [ANC] of at least 1500/mm3 [without hematopoietic growth factors], platelet count of at least 100,000/mm3 [without thrombopoietic agents]) in the absence of peripheral blast cells and dysplasia.1, 4 Partial response to therapy (lasting at least 8 weeks) generally was defined as at least a 50% decrease in blast cells in the bone marrow and responses in the peripheral blood similar to those of a complete response or improvement to a less advanced FAB subtype.3, 4 Patients were required to be independent of red blood cell and platelet transfusions during the time of response.1, 4 The overall response rate was 17% (9% complete and 8% partial responses) in patients receiving decitabine plus supportive care compared with 0% in those receiving supportive care alone.1, 4 The median duration of response was 288 days (range: 116-388 days).1 Median time to response was 93 days (range: 55-272 days), or after 2 treatment cycles; almost all patients who responded to decitabine therapy demonstrated a response by the fourth cycle.1 Approximately 13% of patients receiving decitabine plus supportive care met criteria for hematologic improvement (defined as a response less than partial response lasting at least 8 weeks), compared with 7% of those receiving supportive care alone.1, 4 Treatment with decitabine in combination with supportive care was associated with improved quality of life (as evidenced by improvements in parameters such as global health status, fatigue, and dyspnea)4 but did not substantially delay the median time to AML or death compared with supportive care alone.1, 4
In the 2 open-label, single-arm, phase 2 studies, a total of 164 patients with any of the 5 FAB subtypes of MDS received decitabine at a dosage of 15 mg/m2 IV over 4 hours, repeated every 8 hours for 3 consecutive days; the treatment cycle was repeated every 6 weeks.1 Overall response rates (complete plus partial responses) in these 2 studies were 24 and 26%.1
Premedication with antiemetics may be considered.1
Reconstitution and Administration
Decitabine is administered by continuous IV infusion over 3 hours.1
Decitabine powder for injection must be reconstituted and diluted prior to administration.1, 3 Decitabine sterile powder for injection is reconstituted by adding 10 mL of sterile water for injection to a vial labeled as containing 50 mg of decitabine to provide a solution containing 5 mg/mL.1, 3 Immediately after reconstitution, the appropriate dose should be withdrawn from the vial and diluted in an appropriate volume (e.g., 50-250 mL) of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to yield a final concentration of 0.1-1 mg/mL.1, 3 When infusion solutions of decitabine are prepared using IV infusion fluids that have not been prechilled, administration of the drug must be initiated within 15 minutes of reconstitution in order to ensure appropriate drug potency.1, 3 Therefore, unless IV infusion of decitabine can be initiated within 15 minutes of reconstitution, reconstituted solutions of the drug must be diluted in cold (2-8°C) IV infusion fluids; decitabine solutions prepared using cold, compatible infusion fluids may be stored at 2-8°C for up to 7 hours prior to administration.1, 3
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed when reconstituting or administering decitabine.1
The recommended dosage of decitabine for the treatment of myelodysplastic syndrome (MDS) in adults is 15 mg/m2 (administered by IV infusion over 3 hours) every 8 hours for 3 consecutive days (total dose per treatment cycle: 135 mg/m2); the treatment cycle should be repeated every 6 weeks.1, 3 The manufacturer recommends that patients receive at least 4 treatment cycles, although additional treatment cycles may be needed to achieve complete or partial response.1, 3 Decitabine should be continued as long as the patient is deriving benefit from therapy.1, 3 In the phase 3 study, the median duration of response to decitabine was 288 days.1
Alternative dosages of decitabine are being investigated in patients with MDS, and the optimum dosage remains to be established.3, 6, 7
Patients receiving decitabine therapy should be monitored for hematologic and nonhematologic toxicities; treatment should be delayed or dosage reduced accordingly.1 (` Dosage Modification for Hematologic Toxicity and also see Dosage Modification for Nonhematologic Toxicity under Dosage and Administration: Dosage.)
Dosage Modification for Hematologic Toxicity
If hematologic recovery (i.e., absolute neutrophil count [ANC] of at least 1000/mm3, platelet count of at least 50,000/mm3) from the previous treatment cycle requires more than 6 weeks but less than 8 weeks, the next treatment cycle should be delayed for up to 2 weeks, and dosage of decitabine should be temporarily reduced at the start of the next cycle to 11 mg/m2 every 8 hours for 3 consecutive days (total dosage during treatment cycle: 99 mg/m2).1 If hematologic recovery from the previous treatment cycle requires more than 8 weeks but less than 10 weeks, the patient should be evaluated for disease progression (i.e., by bone marrow aspirates).1 In the absence of progression, the next treatment cycle should be delayed for up to 2 more weeks, and dosage of decitabine in the next cycle should be reduced to 11 mg/m2 every 8 hours for 3 consecutive days (total dosage during treatment cycle: 99 mg/m2).1 This reduced dosage may be maintained or increased in subsequent treatment cycles as clinically indicated.1
Dosage Modification for Nonhematologic Toxicity
If serum creatinine concentration increases to 2 mg/dL or greater, serum ALT or total bilirubin concentration increases to 2 or more times the upper limit of normal, or active or uncontrolled infection occurs, decitabine therapy should not be restarted until the toxicity has been resolved.1
Dosage adjustment is not expected to be necessary in patients with hepatic impairment.3 However, dosage reduction may be necessary in patients with renal impairment.3 (See Hepatic Impairment and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
No dosage adjustments are necessary in geriatric patients except those necessary to minimize subsequent toxicity associated with therapy.1 (See Dosage Modification for Hematologic Toxicity and also see Dosage Modification for Nonhematologic Toxicity under Dosage and Administration: Dosage.)
Known hypersensitivity to decitabine or any ingredient in the formulation.1
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Pregnancy should be avoided during therapy.1 If used during pregnancy or if pregnancy occurs during therapy, apprise of potential fetal hazard.1
Male patients receiving the drug should be advised to not father a child during and for 2 months after discontinuance of decitabine therapy.1
Myelosuppression (commonly manifested as anemia, severe neutropenia, and severe thrombocytopenia) is the most common cause of decitabine dosage delay, reduction, or discontinuance.1 In the phase 3 study of decitabine in myelodysplastic syndrome (MDS), neutropenia, thrombocytopenia, or anemia occurred in 90, 89, or 82%, respectively, of patients receiving the drug; severe (grade 3 or 4) neutropenia or thrombocytopenia was reported in 87 or 85%, respectively, of those receiving the drug.1 Fatalities associated with the underlying disease and myelosuppression, possibly resulting from decitabine therapy, have been reported.1 Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycle, and may not necessarily indicate progression of underlying MDS.1
Complete blood cell and platelet counts should be performed prior to each treatment cycle and periodically thereafter as needed to monitor response and toxicity.1 After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be delayed or reduced based on hematologic recovery.1 (See Dosage Modification for Hematologic Toxicity under Dosage and Administration: Dosage.)
Elevated liver function test results, hyperbilirubinemia, and cholecystitis have been reported in clinical trials in patients receiving decitabine.1
Liver function tests should be obtained prior to initiation of decitabine.1 If serum ALT or total bilirubin concentration increases to 2 or more times the upper limit of normal, decitabine therapy should not be restarted until the toxicity has been resolved.1
Serum creatinine concentrations should be obtained prior to initiation of decitabine.1 If serum creatinine concentration increases to 2 mg/dL or greater, decitabine therapy should not be restarted until the toxicity has been resolved.1
Pneumonia, cellulitis, candidal infection (e.g., oral candidiasis), catheter-related infection, urinary tract infection, staphylococcal infection, sinusitis, and bacteremia each have been reported in 5% or more of patients receiving decitabine in the phase 3 study in MDS.1 Other infections reported in patients receiving decitabine include fungal infection, sepsis, respiratory tract infection (e.g., bronchopulmonary aspergillosis, pseudomonal lung infection), peridiverticular abscess, and Mycobacterium avium complex (MAC) infection.1
Clinicians should consider the need for early initiation of hematopoietic growth factor and/or anti-infective therapy to prevent or treat infections in patients with MDS.1, 3 If active or uncontrolled infection occurs, decitabine therapy should not be restarted until the infection has been resolved.1
Category D.1 (See Users Guide and also see Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
It is not known whether decitabine or its metabolites are distributed into milk.1 Because of the potential for serious adverse reactions to decitabine in nursing infants, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of decitabine have not been established in pediatric patients.1
Of the 83 patients receiving decitabine in the phase 3 study, 61 (73%) were 65 years of age or older and 21 (25%) were 75 years of age or older.1 No overall differences in efficacy or safety were observed between geriatric and younger patients, but the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1
Safety and efficacy not established in patients with hepatic impairment.1 In clinical studies, decitabine was not administered in patients with transaminase concentrations exceeding 2 times normal or in those with serum bilirubin concentrations exceeding 1.5 mg/dL.1, 3
Use with caution1 and monitor carefully.3 Dosage adjustment not expected to be necessary.3
Safety and efficacy not established in patients with renal impairment.1 In clinical studies, decitabine was not administered in patients with serum creatinine concentrations exceeding 2 mg/dL.1, 3
Decitabine and its metabolites are ultimately eliminated renally.3 Therefore, use with caution1 and monitor carefully;3 dosage reduction may be necessary.3
The most common adverse effects reported in clinical trials of decitabine are neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.1 Other adverse effects reported in 20% or more of patients receiving decitabine in the phase 3 study and occurring more frequently with decitabine than with supportive care alone include febrile neutropenia, leukopenia, headache, insomnia, vomiting, peripheral edema, hypoalbuminemia, hypomagnesemia, pallor, rigors, pneumonia, hypokalemia, ecchymosis, and arthralgia.1
No formal drug interaction studies have been performed to date.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interaction unlikely.3
Pharmacokinetic interaction with highly protein-bound drugs unlikely.1
Decitabine, a synthetic nucleoside analog of 2'-deoxycytidine, is an antineoplastic agent.1, 3, 4, 5 The antineoplastic activity of decitabine depends on intracellular conversion of the drug to its 5'-triphosphate metabolite.1, 5 Following conversion to decitabine triphosphate, the drug appears to exert its antineoplastic effect by incorporating into DNA and inhibiting DNA methyltransferase (the enzyme responsible for methylating newly synthesized DNA in mammalian cells), thereby causing hypomethylation of DNA.1, 3, 4, 5 The concentration of decitabine required for inhibition of DNA methylation in vitro does not appear to cause major suppression of DNA synthesis.1 Hypomethylation may restore normal function to genes silenced by aberrant DNA methylation (e.g., tumor suppressor genes) that are critical for cellular differentiation, proliferation, senescence, and apoptosis.1, 5 In rapidly dividing cells, decitabine that has been incorporated into DNA also may exert a direct cytotoxic effect by forming covalent adducts with DNA methyltransferase.1, 5 Nonproliferating cells are relatively insensitive to decitabine.1 Decitabine is cell-cycle specific, acting principally in the S phase of the cell cycle; the drug does not inhibit progression of cells from G1 into S phase.5
Following IV administration, decitabine rapidly enters cells by a nucleoside-specific transport mechanism; the drug distributes into body fluids and crosses the blood-brain barrier.5 The exact route of elimination and the metabolic fate of decitabine in humans are not known.1 One possible elimination pathway is deamination by cytidine deaminase, an enzyme found principally in the liver and to a lesser extent in granulocytes, intestinal epithelium, and whole blood.1, 3, 5 In vitro studies indicate that decitabine is not a substrate for, and is unlikely to inhibit or induce, cytochrome P-450 (CYP) isoenzymes.1 Less than 1% of decitabine is bound to plasma proteins.1 The terminal elimination half-life of decitabine is approximately 0.51 hour.1
Importance of women informing clinicians immediately if they are or plan to become pregnant.1 Necessity of advising women to avoid pregnancy during decitabine therapy and of advising men not to father a child during and for 2 months following discontinuance of therapy.1 Necessity of advising pregnant women of the risk to the fetus.1
Importance of women informing clinicians if they are breast-feeding.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., underlying hepatic or renal disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 50 mg |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions November 1, 2006. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. MGI Pharma, Inc. Dacogen® (decitabine for injection) prescribing information. Bloomington, MN; 2006 May.
2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website ([Web]). Accessed 2006 Jul 13.
3. MGI Pharma, Inc., Bloomington, MN: Personal communication.
4. Kantarjian H, Issa JP, Rosenfeld CS et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer . 2006; 106:1794-803. [PubMed 16532500]
5. Momparler RL. Pharmacology of 5-Aza-2'-deoxycytidine (decitabine). Semin Hematol . 2005; 42:S9-16. [PubMed 16015507]
6. Kantarjian HM, Issa JP. Decitabine dosing schedules. Semin Hematol . 2005; 42:S17-22.
7. Myelodysplastic syndromes. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2006 Aug 24.