Decitabine
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Decitabine Prescribing Information
Decitabine for injection is indicated for treatment of adult 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.
- Three Day Regimen:Administer decitabine for injection 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 Recommended DosagePre-Medications and Baseline Testing
• Consider pre-medicating for nausea with antiemetics.
• Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.Decitabine for Injection Regimen OptionsThree Day RegimenAdminister decitabine for injection at a dose of 15 mg/m2by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. . A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity[ see Dosage and Administration (2.2)].
Five Day Regimen
Administer decitabine for injection at a dose of 20 mg/m2by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity[see Dosage and Administration (2.2)].Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.Patients with Renal or Severe Hepatic Impairment
Treatment with decitabine for injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with decitabine for injection. - Five Day Regimen:Administer decitabine for injection at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks.)
2.1 Recommended DosagePre-Medications and Baseline Testing
• Consider pre-medicating for nausea with antiemetics.
• Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.Decitabine for Injection Regimen OptionsThree Day RegimenAdminister decitabine for injection at a dose of 15 mg/m2by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. . A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity[ see Dosage and Administration (2.2)].
Five Day Regimen
Administer decitabine for injection at a dose of 20 mg/m2by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity[see Dosage and Administration (2.2)].Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.Patients with Renal or Severe Hepatic Impairment
Treatment with decitabine for injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with decitabine for injection.
For Injection: 50 mg of decitabine as a sterile, white to almost white lyophilized powder in a single-dose vial for reconstitution.
Lactation:
Advise not to breastfeed. (Risk Summary
There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from decitabine in a breastfed child, advise women not to breastfeed while receiving decitabine and for at least 2 weeks after the last dose.
None.
- Neutropenia and Thrombocytopenia:Perform complete blood counts and platelet counts. ()
5.1 MyelosuppressionFatal and serious myelosuppression occurs in decitabine-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of decitabine dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade 3 or 4 occurring in 87% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed
[ see Dosage and Administration (2.2)].Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS. - Embryo-Fetal Toxicity:Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception (,
5.2 Embryo-Fetal ToxicityBased on findings from human data, animal studies and its mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman
[ see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving decitabine and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose[ see Use in Specific Populations (8.1, 8.3)].,8.1 PregnancyRisk Summary
Based on findings from human data, animal studies, and the mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman[ see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].Limited published data on decitabine use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on a mg/m2basis(see Data). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.DataHuman Data
A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated.Animal Data
In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring.
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/m2and decreased fetal weight was observed at both dose levels. The 3 mg/m2dose 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/m2was 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.
The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2IP 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). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.)8.3 Females and Males of Reproductive PotentialPregnancy Testing
Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine.ContraceptionFemales
Decitabine can cause fetal harm when administered to pregnant women[ see Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception while receiving decitabine and for 6 months following the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose
[ see Nonclinical Toxicology (13.1)].Infertility
Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine. The reversibility of the effect on fertility is unknown[ see Nonclinical Toxicology (13.1)].
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