AZACITIDINE: Package Insert and Label Information

AZACITIDINE- azacitidine injection, powder, lyophilized, for solution
CELLTRION USA, INC.

1 INDICATIONS AND USAGE

1.1 Myelodysplastic Syndromes (MDS)

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).

2 DOSAGE AND ADMINISTRATION

2.1 First Treatment Cycle

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.

2.2 Subsequent Treatment Cycles

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.

2.3 Dosage Adjustment Based on Hematology Laboratory Values

  • 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 ( x 109 /L) Platelets ( x1 09 /L )
Less than 0.5 Less than 25 50%
0.5 –1.5 25-50 67%
Greater than 1.5 Greater than 50 100%
  • 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

counts from baseline 

Bone Marrow Biopsy Cellularity at Time of Nadir (%)
30-60 15-30 Less than 15
50-75 Greater than 75 % Dose in the Next Course
100 50 33
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%.

2.4 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 (5.3)].

2.5 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 (5.3) and Use in Specific Populations (8.5)].

2.6 Preparation of Azacitidine for injection

Azacitidine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

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.

2.7 Instructions for Subcutaneous 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.

Subcutaneous 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).

2.8 Instructions for Intravenous Administration

Reconstitute the appropriate number of Azacitidine for injection vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Withdraw the required amount of Azacitidine for injection solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection.

Intravenous Solution Incompatibility

Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine for injection and should therefore be avoided.

Intravenous Administration

Azacitidine solution is administered intravenously. Administer the total dose over a period of 10 — 40 minutes. The administration must be completed within 1 hour of reconstitution of the Azacitidine for injection vial.

Solution Stability: Azacitidine for injection reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

4.1 Advanced Malignant Hepatic Tumors

Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2)].

4.2 Hypersensitivity to Azacitidine or Mannitol

Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

5 WARNINGS AND PRECAUTIONS

5.1 Anemia, Neutropenia and Thrombocytopenia

Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. 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 (2.3)].

5.2 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.

5.3 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 nonMDS 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 (2.4)].

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 (2.4, 2.5)]. Patients with MDS and renal impairment were excluded from the clinical studies.

5.4 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.

5.5 Embryo-Fetal Risk

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 [see Use in Specific Populations (8.1)].

Advise females with reproductive potential to avoid pregnancy during treatment with Azacitidine [see Use in Specific Populations (8.3)]. Men should be advised to not father a child while receiving treatment with Azacitidine.

6 ADVERSE REACTIONS

The following adverse reactions are described in other labeling sections:

Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route):

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

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