AZACITIDINE- azacitidine injection, powder, lyophilized, for solution
Dr. Reddy?s Laboratories Inc.
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 days. Patients should be premedicated for nausea and vomiting.
Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
2.2 Subsequent Treatment Cycles
Cycles should be repeated every weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for minimum of to cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.
2.3 Dosage Adjustment Based on Hematology Laboratory Values
For patients with baseline (start oftreatment) WBC ?3 x109 /L,ANC ?1.5 x109 /L and platelets ?75 x109 /L, adjust the dose as follows, based on nadir counts for any given cycle:
DOSAGE FORMS AND STRENGTHS
Azacitidine for injection is supplied as lyophilized powder in 100 mg single-use vials.
4 CONTRAINDICATIONS
4.1 Advanced Malignant Hepatic Tumors
Azacitidine for injection is contraindicated in patients with advanced malignant hepatic tumors
4.2 Hypersensitivity to Azacitidine or Mannitol
Azacitidine for injection is contraindicated in patients with known hypersensitivity to azacitidine or mannitol.
5 WARNINGS AND PRECAUTIONS
5.1 Anemia, Neutropenia and Thrombocytopenia
Azacitidine for injection causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at 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
5.2 Azacitidine For Injection Toxicity 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
Safety and effectiveness of azacitidine for injection 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 non MDS conditions. In addition, renal tubular acidosis, defined as fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held
Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, these patients should be closely monitored for toxicity Patients with MDS and renal impairment were excluded from the clinical studies.
5.4 Use in Pregnancy
Azacitidine for injection may cause fetal harm when administered to pregnant woman. Azacitidine caused congenital malformations in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with azacitidine for injection. There are no adequate and well-controlled studies in pregnant women using azacitidine for injection. If this drug is used during pregnancy or if patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
5.5 Use in Males
Men should be advised to not father child while receiving treatment with azacitidine for injection. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females
6 ADVERSE REACTIONS
The following adverse reactions are described in other labeling sections:
? Anemia, neutropenia and thrombocytopenia
? Hepatic coma [see Warnings and
? Elevated serum creatinine, renal failure, and renal tubular acidosis
Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.
Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
Pregnancy
Pregnancy Category D
DESCRIPTION
Azacitidine for injection contains azacitidine, which is pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-?-D-ribofuranosyl-1,3,5-triazin-2(1H)-on
Mechanism of Action
Azacitidine for injection is pyrimidine nucleoside analog of cytidine. Azacitidine for injection is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Azacitidine for injection is supplied as lyophilized powder in 100 mg single-use vials packaged in cartons of vial (NDC 43598-305-62).
Storage
Store unreconstituted vials at 20? to 25?C (68? to 77?F); [See USP Controlled Room Temperature].
Handling and Disposal
Procedures for proper handling and disposal of anticancer drugs should be applied. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
