Azacitidine

Azacitidine for injection 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 injection is 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).

  
  
  

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that 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 (

  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)]

  ,

  5.1 Risks of Substitution with Other Azacitidine Products

  Due to substantial differences in the pharmacokinetic parameters

  [see Clinical Pharmacology (12.3)]

  , the recommended dose and schedule for azacitidine are different from those of oral azacitidine products. Treatment of patients using azacitidine 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 may not be effective.

  
  
  

  Do not substitute azacitidine for injection for oral azacitidine

  [see Dosage and Administration (2.1)]

  .

  ).
• MDS: The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is azacitidine for injection 75 mg/m² daily 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 patients for hematologic response and renal toxicities

  [see Warnings and Precautions (5.4)],

  and delay or reduce dosage if necessary

  [see Dosage and Administration (2.6)]

  .
  
  
  
  

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.
  ).
• Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate (
  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 patients for hematologic response and renal toxicities

  [see Warnings and Precautions (5.4)],

  and delay or reduce dosage if necessary

  [see Dosage and Administration (2.6)]

  .
  
  
  
  

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.
  ,
  2.6 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity

  If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course

  [see Warnings and Precautions (5.4)].
  ,
  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 (5.4)

  and

  Use in Specific Populations (8.5)

  ].
  ).

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 (13.1)]

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

• Risks of Substitution with Other Azacitidine Products
  :  Do not substitute azacitidine for 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)]
  ,
  5.1 Risks of Substitution with Other Azacitidine Products

  Due to substantial differences in the pharmacokinetic parameters

  [see Clinical Pharmacology (12.3)]

  , the recommended dose and schedule for azacitidine are different from those of oral azacitidine products. Treatment of patients using azacitidine 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 may not be effective.

  
  
  

  Do not substitute azacitidine for injection for oral azacitidine

  [see Dosage and Administration (2.1)]

  .
  ).
• Anemia, Neutropenia and Thrombocytopenia
  : Monitor complete blood counts (CBC) frequently  (
  5.2 Anemia, Neutropenia and Thrombocytopenia

  Azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with MDS. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle.

  In adult patients with MDS, after administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response

  [see

  Dosage and Administration (2.5)].

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.
  ).
• Hepatotoxicity
  : Patients with severe preexisting hepatic impairment are at higher risk for toxicity (
  5.3 Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment

  Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors

  [see Contraindications (4.1)].

  Monitor liver chemistries prior to initiation of therapy and with each cycle.

  Safety and effectiveness of azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.
  ).
• Renal Toxicity
  : Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (
  5.4 Renal Toxicity

  Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose

  [see Dosage and Administration (2.6)].

  
  
  

  Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity

  [see Dosage and Administration (2.6, 2.7)]

  . Patients with MDS and renal impairment were excluded from the clinical studies.

  
  
  

  Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.
  ).
• Tumor Lysis Syndrome
  : Azacitidine may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate  (
  5.5 Tumor Lysis Syndrome

  Azacitidine may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.
  ).
• Embryo-Fetal  Toxicity
  : Azacitidine can cause fetal harm. Advise female patients and male patients with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception (
  5.6 Embryo-Fetal Toxicity

  Based on the mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies.

  
  
  

  Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose

  [see

  Use in Specific Populations (8.1, 8.3)]

  .
  ).