Azacitidine

1 INDICATIONS AND USAGE 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 ) 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.

12.1 Mechanism of Action Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine 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.

2 DOSAGE AND ADMINISTRATION 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 , 5.1 ). MDS: The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for injection 75 mg/m 2 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 ). Continue treatment as long as the patient continues to benefit ( 2.3 ). Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate ( 2.3 , 2.6 , 2.7 ). 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) ] 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/m 2 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. 2.3 Subsequent Treatment Cycles for Adults Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m 2 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 (5.4) ], 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. 2.5 Dosage Adjustment Based on Hematology Laboratory Values For adult patients with baseline (start of treatment) WBC greater than or equal to 3x10 9 /L, ANC greater than or equal to 1.5x10 9 /L, and platelets greater than or equal to 75x10 9 /L, adjust the dose as follows, based on nadir counts for any given cycle: Nadir Counts % Dose in the Next Course ANC (x10 9 /L) Platelets (x10 9 /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 adult patients whose baseline counts are WBC less than 3 x 10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x 10 9 /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 than15 % 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%. 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

6 ADVERSE REACTIONS Most common adverse reactions (>30%) in adult patients with MDS by subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Shilpa Medicare Limited 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are described in other labeling sections: Anemia, Neutropenia and Thrombocytopenia [ see Warnings and Precautions (5.2) ] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [ see Warnings and Precautions (5.3) ] Renal Toxicity [ see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [ see Warnings and Precautions (5.5) ] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MDS The data described below reflect exposure to Azacitidine in 443 patients with MDS from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) [see Clinical Studies (14.1) ]. In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m 2 . In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily Azacitidine doses of 75 mg/m 2 . Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS: 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) in Adult Patients with MDS: Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia. Table 3 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Azacitidine-treated group than for the observation group: patients received Azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months. Table 3: Most Frequently Observed Adverse Reactions (≥ 5% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term a All Azacitidine b (N=220) Observation c (N=92) Blood and lymphatic system disorders Anemia

5 WARNINGS AND PRECAUTIONS Risks of Substitution with Other Azacitidine Products : Do not substitute Azacitidine for oral azacitidine ( 2.1 , 5.1 ). Anemia, Neutropenia and Thrombocytopenia : Monitor complete blood counts (CBC) frequently ( 5.2 ). Hepatotoxicity : Patients with severe preexisting hepatic impairment are at higher risk for toxicity ( 5.3 ). Renal Toxicity : Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys ( 5.4 ). 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 ). 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 ). 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 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 may not be effective. Do not substitute Azacitidine for Injection for oral azacitidine [see Dosage and Administration (2.1) ]. 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. 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. 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 Admin

4 CONTRAINDICATIONS Advanced Malignant Hepatic Tumors ( 4.1 ). Hypersensitivity to Azacitidine or Mannitol ( 4.2 ). 4.1 Advanced Malignant Hepatic Tumors Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [ see Warnings and Precautions (5.3) ]. 4.2 Hypersensitivity to Azacitidine or Mannitol Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

10 OVERDOSAGE One case of overdose with Azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m 2 , almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine overdosage.