Decitabine (Monograph)

Brand name: Dacogen
Drug class: Antineoplastic Agents
Chemical name: 4-Amino-1-(2-deoxy-β-d-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one
Molecular formula: C₈H₁₂N₄O₄
CAS number: 2353-33-5

Introduction

Antineoplastic agent; a synthetic nucleoside analog of 2′-deoxycytidine.

Uses for Decitabine

Myelodysplastic Syndrome

Treatment of myelodysplastic syndrome (MDS); designated an orphan drug by FDA for this use.

Used in patients with previously treated or untreated, de novo or secondary MDS of 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 (i.e., intermediate-1, intermediate-2, and high-risk groups).

Decitabine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

• Consider premedicating with an antiemetic to prevent nausea and vomiting.

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Reconstitution

Reconstitute vial containing 50 mg of decitabine with 10 mL of sterile water for injection to provide a solution containing 5 mg/mL.

Dilution

Immediately after reconstitution, dilute appropriate dose in an appropriate volume (e.g., 50–250 mL) of 0.9% sodium chloride, 5% dextrose, or lactated Ringer’s injection to yield a final concentration of 0.1–1 mg/mL.

Dilute reconstituted solutions in cold (2–8°C) compatible IV infusion fluids, unless administration can occur within 15 minutes of reconstitution. (See Storage under Stability.)

Rate of Administration

Administer by continuous IV infusion over 3 hours.

Dosage

Withhold therapy if S_cr ≥2 mg/dL, serum ALT or total bilirubin concentration ≥2 times the ULN, or if active or uncontrolled infection occurs; delay subsequent cycles until recovery occurs. (See Adequate Patient Evaluation and Monitoring under Cautions.)

Adults

Myelodysplastic Syndrome

IV

15 mg/m² every 8 hours for 3 consecutive days (total dose 135 mg/m² per treatment cycle) every 6 weeks.

A minimum of 4 treatment cycles is recommended; however, additional cycles may be needed to achieve a complete or partial response.

Continue treatment as long as the patient is deriving benefit.

Dosage Modification for Hematologic Toxicity

Dosage modification is based on time to hematologic recovery (i.e., ANC ≥1000/mm³, platelet count ≥50,000/mm³) from previous treatment cycle.

Hematologic recovery >6 to <8 weeks from previous treatment cycle: Delay next treatment cycle up to 2 weeks and temporarily reduce dosage 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).

Hematologic recovery >8 to <10 weeks from previous treatment cycle: Evaluate for disease progression (i.e., by bone marrow aspirates). If no disease progression, delay next treatment cycle up to 2 more weeks and reduce dosage to 11 mg/m² every 8 hours for 3 consecutive days (total dosage during treatment cycle: 99 mg/m²). Reduced dosage may be maintained or increased in subsequent treatment cycles as clinically indicated.

Special Populations

Hepatic Impairment

Routine dosage reduction not required.

Renal Impairment

Possible decreased elimination; dosage reduction may be necessary.

Cautions for Decitabine

Contraindications

• Known hypersensitivity to decitabine.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Women should avoid pregnancy during therapy; men should not father child during therapy and for 2 months after therapy. If used during pregnancy or if patient becomes pregnant during therapy, apprise of potential fetal hazard.

Major Toxicities

Hematologic Effects

Risk of dose-limiting and potentially fatal myelosuppression, manifested commonly as severe neutropenia, severe thrombocytopenia, and anemia. Myelosuppression may occur more frequently in the first and second treatment cycles and may not indicate progression of underlying MDS.

Delay or reduce dosage for subsequent cycles based on hematologic recovery. (See Dosage Modification for Hematologic Toxicity under Dosage and Administration.)

Consider the early use of hematopoietic growth factor and/or anti-infective therapy to prevent or treat complicating infections.

General Precautions

Adequate Patient Evaluation and Monitoring

Perform CBC and platelet counts prior to each treatment cycle and periodically thereafter.

Monitor liver function tests and S_cr prior to each treatment cycle. Do not administer to patients with serum ALT or total bilirubin concentrations ≥2 times the ULN or S_cr ≥2 mg/dL.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether decitabine is distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy in those ≥65 years of age similar to that in younger adults; however, increased sensitivity to the drug in some geriatric individuals cannot be ruled out.

Hepatic Impairment

Not studied in patients with hepatic impairment.

Use with caution and monitor carefully. Dosage adjustment not expected to be necessary.

Renal Impairment

Not studied in patients with renal impairment.

Use with caution and monitor carefully. Dosage reduction may be necessary.

Common Adverse Effects

Neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia.

Drug Interactions

No formal drug interaction studies to date; however, in vitro studies suggest that decitabine is not a substrate for CYP enzymes and is unlikely to inhibit or induce CYP enzymes.

Decitabine Pharmacokinetics

Distribution

Extent

Following IV administration, decitabine rapidly enters cells by a nucleoside-specific transport mechanism; distributed into body fluids and crosses the blood-brain barrier.

Plasma Protein Binding

<1%.

Elimination

Metabolism

Converted intracellularly to an active 5′-triphosphate metabolite. Also undergoes deamination by cytidine deaminase, principally in the liver, as well as granulocytes, intestinal epithelium, and whole blood.

Elimination Route

Exact elimination pathways unknown; however, decitabine and its metabolites appear to be ultimately eliminated renally.

Half-life

Biphasic; terminal half-life is approximately 0.51 hour.

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Dilute immediately after reconstitution. Solutions diluted in cold (2–8°C) infusion fluids may be stored at 2–8°C for up 7 hours. Solutions diluted in infusion fluids that are not cold must be used within 15 minutes of reconstitution.

Compatibility

Parenteral

Solution Compatibility

Actions

• Exert its antineoplastic effect by incorporating into DNA and inhibiting DNA methyltransferase, thereby causing hypomethylation of DNA. Does not appear to cause major suppression of DNA synthesis.

• 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.

• May exert a direct cytotoxic effect by forming covalent adducts with DNA methyltransferase in rapidly dividing cells. Nonproliferating cells are relatively insensitive to decitabine.

• Cell-cycle specific, acting principally in the S phase of the cell cycle; does not inhibit progression of cells from G1 into S phase.

Advice to Patients

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed. Advise women to avoid pregnancy during therapy and advise men not to father a child during and for 2 months following discontinuance of therapy. Necessity of advising pregnant women of the risk to the fetus.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver or kidney disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

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