Azacitidine

Dosage and Administration (

Warnings and Precautions (

Azacitidine is a nucleoside metabolic inhibitor indicated for the treatment of:

• Adult patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). (
  1.1 Myelodysplastic Syndromes (MDS)

  Azacitidine for injectionis indicated for treatment of adult patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
  )

• Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine (

  2.1 Important Administration Information

  Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine

  [see Warnings and Precautions ]

  
  
  

  ,

  5.1 Risks of Substitution with Other Azacitidine Products

  Due to substantial differences in the pharmacokinetic parameters

  [see Clinical Pharmacology ]

  , the recommended dose and schedule for azacitidine for injection are different from those of oral azacitidine products. Treatment of patients using azacitidine for injection at the recommended dosage of oral azacitidine may result in a fatal adverse reaction. Treatment of patients using oral azacitidine at the doses recommended for azacitidine for injection may not be effective.
  
  
  
  Do not substitute azacitidine for injection for oral azacitidine

  [see Dosage and Administration ]

  .
  
  

  ).
• MDS: The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is azacitidine for injection 75 mg/m²daily for 7 days to be administered by subcutaneous injection or intravenous infusion. See full prescribing information for schedule for subsequent cycles. Premedicate for nausea and vomiting (
  2.2 First Treatment Cycle for Adults

  The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m²subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting.

  Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.
  ).
• Continue treatment as long as the patient continues to benefit (
  2.3 Subsequent Treatment Cycles for Adults

  Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m²if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.
  )
• Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate (
  2.5 Dosage Adjustment Based on Hematology Laboratory Values

  • For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x10⁹/L, ANC greater than or equal to 1.5 x10⁹/L, and platelets greater than or equal to 75 x10⁹/L, adjust the dose as follows, based on nadir counts for any given cycle:

  Nadir Counts		% Dose in the Next Course
  ANC (x109/L) Less than 0.5 0.5 –1.5 Greater than 1.5	Platelets (x109/L) Less than 25 25-50 Greater than 50	50% 67% 100%

  • For adult patients whose baseline counts are WBC less than 3 x10⁹/L, ANC less than 1.5 x10⁹/L, or platelets less than 75 x10⁹/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose.

  WBC or Platelet Nadir % decrease in counts from baseline	Bone Marrow
  	Biopsy Cellularity at Time of Nadir
  	(%)
  	30-60	15-30	Less than 15
  		% Dose in the Next Course
  50-75	100	50	33
  Greater than 75	75	50	33

  If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%.
  , 2.6,
  2.7 Use in Geriatric Patients

  Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dose carefully and monitor renal function [

  see Warnings and Precautions and Use in Specific Populations ( 8.5

  )].
  ).

• Lyophilized powder in 100 mg single-dose vials (
  3 DOSAGE FORMS AND STRENGTHS

  • Lyophilized powder in 100 mg single-dose vials .

  Azacitidine for injection is supplied as lyophilized powder in 100 mg single-dose vials.
  ).

• Lactation: Advise not to breastfeed (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of azacitidine in human milk, the effects of azacitidine on the breastfed infant, or the effects of azacitidine on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies

  [see Nonclinical Toxicology ]

  and the potential for serious adverse reactions in nursing infants from azacitidine, advise patients not to breastfeed during treatment with azacitidine for injection and for 1 week after the last dose.
  ).