AZACITIDINE — azacitidine injection, powder, lyophilized, for solution
Wockhardt USA LLC.
Azacitidine for injection is indicated for treatment of 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).
The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously 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.
Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m2 if 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 (5.3) ], and delay or reduce dosage if necessary as described below.
- For patients with baseline (start of treatment) WBC greater than or equal to 3.0 x109 /L, ANC greater than or equal to 1.5 x109 /L, and platelets greater than or equal to 75.0 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)||Platelets (x109 /L)|
|Less than 0.5||Less than 25.0||50%|
|Greater than 1.5||Greater than 50.0||100%|
- For patients whose baseline counts are WBC less than 3.0 x109 /L, ANC less than 1.5 x109 /L, or platelets less than 75.0 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||Bone Marrow Biopsy Cellularity at Time of Nadir (%)|
|counts from baseline||30-60||15-30||Less than 15|
|% Dose in the Next Course|
|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%.
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 (5.3) ].
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 (5.3) and Use in Specific Populations (8.5)].
The Azacitidine for injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly [see How Supplied/Storage and Handling (16) ]. Do not save any unused portions for later administration.
Reconstitute Azacitidine for injection aseptically with 4 mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.
Preparation for Immediate Subcutaneous Administration: For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product must be refrigerated immediately. When Azacitidine for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC — 8ºC, 36ºF — 46ºF) for up to 8 hours. When Azacitidine for injection is reconstituted using refrigerated (2ºC — 8ºC, 36ºF — 46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC — 8ºC, 36ºF — 46ºF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.
To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.
Azacitidine for injection suspension is administered subcutaneously. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
Suspension Stability: Azacitidine for injection reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC — 8ºC, 36ºF — 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).
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