Azacitidine

RECENT MAJOR CHANGES Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 ) 8/2016 Warnings and Precautions ( 5.2 , 5.3 , 5.4 , 5.5 ) 8/2016

1 INDICATIONS & USAGE Azacitidine for injection (Azacitidine), 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 (Azacitidine), 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 Bristol-Myers Squibb’s Vidaza (azacitidine for injection). However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that information.

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 ). 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 ). 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 ( 2.4 , 2.5 , 2.6 ). 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 as described below. 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. 2.4 Dosage Adjustment Based on Hematology Laboratory Values For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x10 9 /L, ANC greater than or equal to 1.5 x10 9 /L, and platelets greater than or equal to 75 x10 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) Less than 0.5 0.5 to 1.5 Greater than 1.5 Platelets (x10 9 /L) Less than 25 25 to 50 Greater than 50 50% 67% 100% For adult patients whose baseline counts are WBC less than 3 x10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x10 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 to 60 15 to 30 Less than 15 50 to 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%. 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 …

3 DOSAGE FORMS AND STRENGTHS Azacitidine for Injection is a sterile, white to off-white lyophilized cake or powder containing 100 mg azacitidine and is supplied in a clear glass vial for single-dose use. Lyophilized cake or powder in 100 mg single-dose vials. ( 3 )

4 CONTRAINDICATIONS Advanced Malignant Hepatic Tumors ( 4.1 ) . Hypersensitivity to Azacitidine or Mannitol (4 .2 ) . 4.1 Advanced Malignant Hepatic Tumors Azacitidine for injection is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions ( 5.3 )]. 4.2 Hypersensitivity to Azacitidine or Mannitol Azacitidine for injection is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

6 ADVERSE REACTIONS The following adverse reactions are described in other labeling sections: o Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.2)] o Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.3)] o Renal Toxicity [see Warnings and Precautions (5.4)] o Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] 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 Reliance Life Sciences PVT. LTD. at 1-800-889-2333 / rls.drugsafety@relbio.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 2 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 2: 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) Bloo …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ). 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 . 8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3 to 12 mg/m 2 (approximately 4% to 16% the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 to 8 (postimplantation) at a dose of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 basis), although treatment in the preimplantation period (on gestation days 1 to 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m 2 (approximately 8% the recommended human daily dose on a mg/m 2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3 to 12 mg/m 2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities). 8.2 Lactation Risk Summary There is no information on the presence of azacitidine or its metabolites in human milk, the effects on a breast-fed child, or the effects 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 a breastfeed child, advise women not to breastfeed during treatment with Azacitidine for Injection and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Azacitidine for Injection. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months after the last dose [ see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months after the last dose [ see Nonclinical T …

12.1 Mechanism of Action Azacitidine for Injection is a 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 .

11 DESCRIPTION Azacitidine is a nucleoside metabolic inhibitor. The molecular formula is C 8 H 12 N 4 O 5 . The molecular weight is 244. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows: Azacitidine is a white to almost white powder. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO). Azacitidine for Injection is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Each vial of Azacitidine for Injection contains 100 mg of azacitidine, 170 mg sucrose, monosodium phosphate monohydrate and disodium hydrogen phosphate, dihydrate as a sterile lyophilized powder. 9dca4f01-figure-01

10 OVERDOSAGE One case of overdose with Azacitidine for Injection 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 for Injection overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Azacitidine for Injection is a white to off-white lyophilized powder or lyophilized cake and is supplied as follows: NDC Azacitidine for Injection (100 mg per vial) Package Factor 71288- 153 -95 100 mg of Azacitidine and 100 mg Mannitol in a 30mL Single-Dose Vial 1 vial per carton Storage Store unreconstituted vials at 20o to 25oC (68o to 77oF); excursions permitted between 15o to 30oC (59o to 86oF). [See USP Controlled Room Temperature.] Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Handling and Disposal Azacitidine for Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1