ONUREG

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥ 10%) are nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb Company at 1-800-721-5072 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. Acute Myeloid Leukemia The safety of ONUREG was evaluated in QUAZAR [see Clinical Studies (14) ] . Patients received ONUREG 300 mg (N=236) or placebo (N=233) orally once daily on Days 1 through 14 of each 28-day cycle. Among patients who received ONUREG, 71% were exposed for 6 months or longer, and 49% were exposed for greater than one year. The median duration of exposure to ONUREG was 11.6 months (range: 0.5 to 74.3 months) and the median number of cycles was 12 (range: 1 to 82 cycles). Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥ 2% of patients who received ONUREG were pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG. Permanent discontinuation of ONUREG due to an adverse reaction occurred in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ONUREG in > 1% of patients included nausea (2.1%), diarrhea (1.7%), and vomiting (1.3%). Interruptions of ONUREG due to an adverse reaction occurred in 35% of patients. Adverse reactions which required an interruption of ONUREG in > 5% of patients included neutropenia (20%), thrombocytopenia (8%), and nausea (6%). Dose reductions of ONUREG due to an adverse reaction occurred in 14% of patients. Adverse reactions which required a dose reduction in > 1% of patients included neutropenia (6%), diarrhea (3.4%), thrombocytopenia (1.7%), and nausea (1.7%). The most common (≥ 10%) adverse reactions were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity. Table 2 summarizes the adverse reactions in QUAZAR. Table 2: Adverse Reactions (≥ 5%) in Patients with AML Who Received ONUREG with a Difference Between Arms of > 2% Compared to Placebo in QUAZAR Adverse Reaction ONUREG (N=236) Placebo (N=233) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) a Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain. b Grouped term includes fatigue and asthenia. c Broad scope term includes influenza, pneumonia, respiratory tract infection, respiratory tract infection viral, bronchopulmonary aspergillosis, lung infection, Staphylococcal infection, atypical pneumonia, lower respiratory tract infection, lung abscess, Pneumocystis jirovecii pneumonia, pneumonia bacterial, pneumonia fungal, Pseudomonas infection, hemoptysis, productive cough, pleural effusion, atelectasis, pleuritic pain, rales, Enterobacter test positive, and Hemophilus test positive. Gastrointestinal disorders Nausea 65 3 24 < 1 Vomiting 60 3 10 0 Diarrhea 50 5 21 1 Constipation 39 1 24 0 Abdominal pain a 22 2 13 < 1 General disorders and administration site conditions Fatigue / asthenia b 44 4 25 1 Infections Pneumonia c 27 9 17 5 Musculoskeletal and connective tissue disorders Arthralgia 14 1 10 < 1 Pain in extremity 11 < 1 5 0 Metabolism and nutrition disorders Decreased appetite 13 1 6 1 Blood and lymphatic disorders Febrile neutropenia 12 11 8 8 Nervous system disorders Dizziness 11 0 9 0 Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 2 were weight decreased (4%) in patients who received ONUREG. Neutropenia, thrombocytopenia, and anemia of any grade occurred in 74%, 65%, and 25% of patients who received ONUREG. Table 3 summarizes select Grades 3 or 4 hematological laboratory abnormalities in QUAZAR. Table 3: Selected Hematological Laboratory Abnormalities That Worsened from Baseline in Patients Who Received ONUREG in QUAZAR ONUREG Placebo Laboratory Abnormality Baseline Grade 0-2 N Post-Baseline Grade 3 or 4 n (%) Baseline Grade 0-2 N Post-Baseline Grade 3 or 4 n (%) Neutropenia 223 109 (49) 217 50 (23) Thrombocytopenia 222 46 (21) 212 22 (10) Anemia 229 10 (4) 223 7 (3) 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of intravenous or subcutaneous azacitidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity reaction • Interstitial lung disease • Tumor lysis syndrome • Sweet's syndrome (acute febrile neutrophilic dermatosis) • Necrotizing fasciitis (including fatal cases) • Differentiation syndrome

4 CONTRAINDICATIONS ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components [see Adverse Reactions (6.2) , Description (11) ] . History of severe hypersensitivity to azacitidine or its components ( 4 ).

11 DESCRIPTION Azacitidine is a nucleoside metabolic inhibitor with a molecular formula of C 8 H 12 N 4 O 5 and a molecular weight of 244 g/mol. The chemical name is: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one and the chemical structural is: Azacitidine is a white to off-white solid. Azacitidine was found to be soluble in aqueous media across a pH range from 1.0 to 7.0. ONUREG (azacitidine) is supplied as film-coated tablets containing 200 mg or 300 mg of azacitidine for oral use. Each core tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose. The 200 and 300 mg tablet coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. In addition, the 200 mg tablet coating contains iron oxide red and the 300 mg tablet coating contains black iron oxide, iron oxide red, and iron oxide yellow. onureg-chem-structure

2 DOSAGE AND ADMINISTRATION • Do not substitute ONUREG for intravenous or subcutaneous azacitidine. The indications and dosing regimen for ONUREG differ from that of intravenous or subcutaneous azacitidine ( 2.1 , 5.1 ). • Administer ONUREG 300 mg orally once daily on Days 1 through 14 of each 28-day cycle ( 2.2 ). • Administer an antiemetic before each dose for at least the first 2 cycles ( 2.2 ). 2.1 Important Administration Information Do not substitute ONUREG for intravenous or subcutaneous azacitidine. The indications and dosing regimen for ONUREG differ from that of intravenous or subcutaneous azacitidine [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage The recommended dosage of ONUREG is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue ONUREG until disease progression or unacceptable toxicity. Administer an antiemetic 30 minutes prior to each dose of ONUREG for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting. If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer ONUREG. Delay the start of the cycle until the ANC is 0.5 Gi/L or more. Instruct patients on the following: • Swallow tablets whole. Do not cut, crush, or chew the tablets. • Take a dose about the same time each day. • If a dose of ONUREG is missed, or not taken at the usual time, take the dose as soon as possible on the same day, and resume the normal schedule the following day. Do not take 2 doses on the same day. • If a dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day. ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures. 1 2.3 Monitoring and Dosage Modifications for Adverse Reactions Monitor complete blood count every other week for the first 2 cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression. The recommended dosage modifications for adverse reactions are provided in Table 1. Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Recommended Dosage Modification Myelosuppression [see Warnings and Precautions (5.2) ] Neutrophils less than 0.5 Gi/L on Cycle Day 1 • Interrupt treatment. Resume at the same dose once neutrophils return to 0.5 Gi/L or higher. Neutrophils less than 1 Gi/L with fever at anytime First Occurrence • Interrupt treatment. Resume at the same dose once neutrophils return to 1 Gi/L or higher. Occurrence in 2 Consecutive Cycles • Interrupt treatment. After neutrophils return to 1 Gi/L or higher, resume at reduced dose of 200 mg. • If a patient continues to experience febrile neutropenia after dose reduction, reduce the treatment duration by 7 days. • If febrile neutropenia reoccurs after dose and schedule reduction, discontinue ONUREG. Platelets less than 50 Gi/L with bleeding First Occurrence • Interrupt dose. Resume at the same dose once platelets return to 50 Gi/L or higher. Occurrence in 2 Consecutive Cycles • Interrupt dose. After platelets return to 50 Gi/L or higher, resume at reduced dose of 200 mg. • If a patient continues to experience thrombocytopenia with bleeding after dose reduction, reduce the treatment duration by 7 days. • If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue ONUREG. Gastrointestinal Toxicity [see Adverse Reactions (6.1) ] Grade 3 or 4 Nausea or Vomiting • Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower. • If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG. Grade 3 or 4 Diarrhea • Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower. • If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 or 4 • Interrupt dose and provide medical support. Resume at the same dose once toxicity has resolved to Grade 1 or lower. • If toxicity re-occurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days. • If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.

1 INDICATIONS AND USAGE ONUREG is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. ONUREG is a nucleoside metabolic inhibitor indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy ( 1 ).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azacitidine is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of azacitidine into the DNA of cancer cells in vitro, including acute myeloid leukemia cells, inhibited DNA methyltransferases, reduced DNA methylation and altered gene expression, including re-expression of genes regulating tumor suppression and cell differentiation. Incorporation of azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA methyltransferases, reduced RNA methylation, decreased RNA stability and decreased protein synthesis. Antileukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in AML cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo. 12.2 Pharmacodynamics Greater reduction in global DNA methylation was observed with higher azacitidine plasma exposure in patients with AML administered ONUREG for 14 days of a 28-day cycle. 12.3 Pharmacokinetics The systemic exposure of azacitidine is approximately dose proportional over the dose range of 120 mg to 600 mg once daily of ONUREG (0.4 to 2 times the recommended dosage). Following a single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) C max of azacitidine was 145 ng/mL (64%) and the mean AUC of azacitidine was 242 ng h/mL (65%). No accumulation was observed following ONUREG 300 mg once daily. Absorption The mean oral bioavailability is approximately 11% relative to subcutaneous administration. The median time to peak plasma concentration of azacitidine is 1 hour. Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect AUC 0-INF and decreased C max by 21%. Distribution The mean (CV%) apparent volume of distribution (V z /F) of azacitidine is 881 L (67%). The in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma ratio is approximately 0.3. Elimination The mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance (CL/F) is 1240 L/hour (64%). Metabolism Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Excretion Following the administration of ONUREG 300 mg orally once daily, < 2% of the dose was recovered unchanged in the urine. Specific Populations Age (46 years to 93 years), sex, body weight (39.3 kg to 129 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST), and mild to moderate renal impairment (CLcr 30 to 89 mL/min) have no clinically meaningful effect on the pharmacokinetics of oral azacitidine. The effects of race/ethnicity, moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST), and severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of oral azacitidine is unknown. Severe renal impairment increased azacitidine exposure by approximately 70% after a single or 41% after multiple subcutaneous daily administration. Drug Interaction Studies Effect of Gastric Acid Reducing Agents on Azacitidine: Coadministration of omeprazole (a proton pump inhibitor) with ONUREG increased azacitidine AUC 0-INF by 19% and had no effect on C max . In Vitro Studies Cytochrome P450 (CYP) Enzymes: Azacitidine does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically relevant concentrations. Azacitidine is not an inducer of CYP1A2, CYP2C19, or CYP3A. Transporter Systems: Azacitidine is not a substrate of P-glycoprotein (P-gp). Azacitidine does not inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.

12.1 Mechanism of Action Azacitidine is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of azacitidine into the DNA of cancer cells in vitro, including acute myeloid leukemia cells, inhibited DNA methyltransferases, reduced DNA methylation and altered gene expression, including re-expression of genes regulating tumor suppression and cell differentiation. Incorporation of azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA methyltransferases, reduced RNA methylation, decreased RNA stability and decreased protein synthesis. Antileukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in AML cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo.

12.2 Pharmacodynamics Greater reduction in global DNA methylation was observed with higher azacitidine plasma exposure in patients with AML administered ONUREG for 14 days of a 28-day cycle.

12.3 Pharmacokinetics The systemic exposure of azacitidine is approximately dose proportional over the dose range of 120 mg to 600 mg once daily of ONUREG (0.4 to 2 times the recommended dosage). Following a single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) C max of azacitidine was 145 ng/mL (64%) and the mean AUC of azacitidine was 242 ng h/mL (65%). No accumulation was observed following ONUREG 300 mg once daily. Absorption The mean oral bioavailability is approximately 11% relative to subcutaneous administration. The median time to peak plasma concentration of azacitidine is 1 hour. Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect AUC 0-INF and decreased C max by 21%. Distribution The mean (CV%) apparent volume of distribution (V z /F) of azacitidine is 881 L (67%). The in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma ratio is approximately 0.3. Elimination The mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance (CL/F) is 1240 L/hour (64%). Metabolism Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Excretion Following the administration of ONUREG 300 mg orally once daily, < 2% of the dose was recovered unchanged in the urine. Specific Populations Age (46 years to 93 years), sex, body weight (39.3 kg to 129 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST), and mild to moderate renal impairment (CLcr 30 to 89 mL/min) have no clinically meaningful effect on the pharmacokinetics of oral azacitidine. The effects of race/ethnicity, moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST), and severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of oral azacitidine is unknown. Severe renal impairment increased azacitidine exposure by approximately 70% after a single or 41% after multiple subcutaneous daily administration. Drug Interaction Studies Effect of Gastric Acid Reducing Agents on Azacitidine: Coadministration of omeprazole (a proton pump inhibitor) with ONUREG increased azacitidine AUC 0-INF by 19% and had no effect on C max . In Vitro Studies Cytochrome P450 (CYP) Enzymes: Azacitidine does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically relevant concentrations. Azacitidine is not an inducer of CYP1A2, CYP2C19, or CYP3A. Transporter Systems: Azacitidine is not a substrate of P-glycoprotein (P-gp). Azacitidine does not inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.

20221026

11

3 DOSAGE FORMS AND STRENGTHS Tablets: • 200 mg, pink, oval, film-coated tablet with debossed "200" on one side and "ONU" on the other side. • 300 mg, brown, oval, film-coated tablet with debossed "300" on one side and "ONU" on the other side. Tablets: 200 mg and 300 mg ( 3 ).

ONUREG azacitidine AZACITIDINE AZACITIDINE MANNITOL MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE ONU;200 ONUREG azacitidine AZACITIDINE AZACITIDINE MANNITOL MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE ONU;300

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m 2 , approximately 4% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) administered intraperitoneal 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with intraperitoneal azacitidine at 2 mg/kg (6 mg/m 2 , approximately 3% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m 2 (approximately 8% to 32% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in an in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine by intraperitoneal injection to male mice at 9.9 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) resulted in decreased weight of the testes and epididymides, decreased sperm counts accompanied by decreased pregnancy rates, and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m 2 resulted in an increase in abnormal embryos in mated females when examined on Day 2 of gestation.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m 2 , approximately 4% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) administered intraperitoneal 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with intraperitoneal azacitidine at 2 mg/kg (6 mg/m 2 , approximately 3% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m 2 (approximately 8% to 32% of the recommended human daily dose of oral azacitidine on a mg/m 2 basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in an in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine by intraperitoneal injection to male mice at 9.9 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) resulted in decreased weight of the testes and epididymides, decreased sperm counts accompanied by decreased pregnancy rates, and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m 2 resulted in an increase in abnormal embryos in mated females when examined on Day 2 of gestation.

NDA214120

ONUREG

azacitidine

59572-740

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 200 mg Bottle Label NDC 59572-730-14 ONUREG™ (azacitidine) tablets 200 mg Swallow tablets whole. Do not cut, crush, or chew the tablets. Rx only 14 Tablets CAUTION: Hazardous Agent onureg-200-bottle-label

Marketed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA ONUREG ® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company. ONUPI.004

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Advise patients of the risk of myelosuppression with ONUREG and of the need to monitor complete blood counts before and during treatment [see Warnings and Precautions (5.2) ] . Gastrointestinal Toxicity Advise patients of the risk of gastrointestinal toxicity with ONUREG and of the potential need to use anti-emetic or anti-diarrheal medications during treatment [see Adverse Reactions (6.1) ]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose [see Use in Specific Populations (8.3) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose [see Use in Specific Populations (8.3) ] . Lactation Advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose [see Use in Specific Populations (8.2) ] . Administration Advise patients to take ONUREG with or without food at about the same time each day and how to make up a missed or vomited dose. Advise patients to swallow tablets whole. Advise patients not to cut, crush, or chew the tablets [see Dosage and Administration (2.2) ] . Storage Instructions Advise patients to keep ONUREG in the original container (bottles or blisters). If bottles are dispensed, advise patients to keep the container tightly closed with both desiccant canisters inside and to not eat the desiccant canisters [see How Supplied/Storage and Handling (16) ] .

14 CLINICAL STUDIES The efficacy of ONUREG was evaluated in QUAZAR (NCT01757535), a multicenter, randomized, double-blind, placebo-controlled study. Eligible patients were ages 55 years or older, had AML, and were within 4 months of achieving first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with intensive induction chemotherapy. Patients may have received consolidation (see Table 4 ). Patients were excluded if they were candidates for hematopoietic stem cell transplantation at the time of screening. A total of 472 patients who completed induction with or without consolidation therapy were randomized 1:1 to receive ONUREG 300 mg (n=238) or placebo (n=234) orally on Days 1 through 14 of each 28-day cycle. Randomization was stratified by age at time of induction therapy (55 to 64 vs. ≥ 65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), prior history of MDS/CMML (yes vs. no), and received consolidation therapy following induction therapy (yes vs. no). Baseline demographic and disease characteristics are shown in Table 4. Table 4: Baseline Demographics and Disease-Related Characteristics in QUAZAR Parameter ONUREG (N=238) Placebo (N=234) AML=Acute Myeloid Leukemia, MDS=Myelodysplastic Syndrome, CMML=Chronic Myelomonocytic Leukemia, ECOG=Eastern Cooperative Oncology Group, CR=Morphologic Complete Remission, CRi=Morphologic complete remission with incomplete blood count recovery. Source for Intermediate and Poor Risk: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia. National Comprehensive Cancer Network website. Available at http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf. Accessed 01 Mar 2011. 1 Intermediate risk was defined as normal cytogenetics +8, t(9;11), or Other undefined. 2 Poor risk was defined as Complex (≥ 3 abnormalities): -5; 5q-; -7; 7q-; 11q23 - non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22). Age (years) Median (Min, Max) 68.0 (55, 86) 68.0 (55, 82) Age Category, n (%) < 65 years 66 (28) 68 (29) 65 years to < 75 years 144 (61) 142 (61) ≥ 75 years 28 (12) 24 (10) Sex, n (%) Male 118 (50) 127 (54) Female 120 (50) 107 (46) Race, n (%) White 216 (91) 197 (84) Black or African American 2 (1) 6 (3) Asian 6 (3) 20 (9) Other 12 (5) 11 (5) Not Collected or Reported 2 (1) 0 (0) ECOG Performance Status, n (%) 0 116 (49) 111 (47) 1 101 (42) 106 (45) 2 21 (9) 15 (6) 3 0 (0) 2 (1) Cytogenetic Risk Status at Diagnosis, n (%) Intermediate Risk 1 203 (85) 203 (87) Poor Risk 2 35 (15) 31 (13) Initial AML Classification, n (%) AML with recurrent genetic abnormalities 39 (16) 46 (20) AML with myelodysplasia-related changes 49 (21) 42 (18) Therapy related myeloid neoplasms 2 (1) 0 (0) AML not otherwise specified 148 (62) 145 (62) Missing 0 (0) 1 (< 1) Type of AML, n (%) Primary (de novo) 213 (89) 216 (92) Secondary 25 (11) 18 (8) Induction Response CR 187 (79) 197 (84) CRi 51 (21) 37 (16) Consolidation following induction therapy None 52 (22) 42 (18) 1 cycle 110 (46) 102 (44) 2 cycles 70 (29) 77 (33) 3 cycles 6 (3) 13 (6) Disease status at study baseline CR 185 (78) 181 (77) CRi 44 (18) 38 (16) Not in CR or CRi 9 (4) 13 (6) Not Reported 0 2 (1) The efficacy of ONUREG was established on the basis of overall survival (OS). The trial demonstrated a statistically significant improvement in OS for patients randomized to ONUREG compared to placebo. A subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi. The efficacy results are summarized in Table 5 and Figure 1. Table 5: Efficacy Results (ITT Population) in QUAZAR ONUREG (N=238) Placebo (N=234) 1 The hazard ratio is from a Cox proportional hazards model stratified by age (55 to 64 vs. ≥65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), and received consolidation therapy (yes vs. no). The p-value is two-sided from a log-rank test stratified by the same factors. Overall Survival OS Events, n (%) 158 (66) 171 (73) Median OS (95% CI) Months 24.7 (18.7, 30.5) 14.8 (11.7, 17.6) Hazard Ratio (95% CI) 1 0.69 (0.55, 0.86) p value 1 0.0009 Figure 1: Kaplan-Meier Curve for Overall Survival (ITT Population) in QUAZAR onureg-os-quazar

15 REFERENCES 1. "OSHA Hazardous Drugs." OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.html

8.5 Geriatric Use Of the 238 patients in QUAZAR who received ONUREG, 72% were 65 years of age or older, while 12% were 75 years of age or older. No overall differences in safety or effectiveness of ONUREG were observed between these patients and younger patients.

8.4 Pediatric Use The safety and effectiveness of ONUREG in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, ONUREG can cause fetal harm when administered to a pregnant woman. There are no available data on ONUREG use in pregnant women to evaluate for a drug-associated risk. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses less than the recommended human daily dose of oral azacitidine on a mg/m 2 basis (see Data ) . Advise pregnant women of the potential risk to the fetus. The estimated background of major birth defects and miscarriage for 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 No reproductive or developmental toxicity studies have been conducted with oral azacitidine. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of 6 mg/m 2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on a mg/m 2 basis) 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 approximately 3 to 12 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days 4 to 8 (postimplantation) at a dose of 6 mg/m 2 (at doses less than 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 intraperitoneal dose of 3 to 12 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) given on gestation Days 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 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, ONUREG can cause fetal harm when administered to a pregnant woman. There are no available data on ONUREG use in pregnant women to evaluate for a drug-associated risk. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses less than the recommended human daily dose of oral azacitidine on a mg/m 2 basis (see Data ) . Advise pregnant women of the potential risk to the fetus. The estimated background of major birth defects and miscarriage for 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 No reproductive or developmental toxicity studies have been conducted with oral azacitidine. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of 6 mg/m 2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on a mg/m 2 basis) 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 approximately 3 to 12 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days 4 to 8 (postimplantation) at a dose of 6 mg/m 2 (at doses less than 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 intraperitoneal dose of 3 to 12 mg/m 2 (at doses less than the recommended human daily dose on a mg/m 2 basis) given on gestation Days 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 are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential ONUREG can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential before starting ONUREG. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose. Infertility Based on animal data, ONUREG may impair male or female fertility [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of ONUREG in pediatric patients have not been established. 8.5 Geriatric Use Of the 238 patients in QUAZAR who received ONUREG, 72% were 65 years of age or older, while 12% were 75 years of age or older. No overall differences in safety or effectiveness of ONUREG were observed between these patients and younger patients. 8.6 Renal Impairment Monitor patients with severe renal impairment (creatinine clearance [CLcr] 15 to 29 mL/min calculated by Cockcroft-Gault formula) more frequently for adverse reactions and modify the ONUREG dosage for adverse reactions [see Dosage and Administration (2.3) ] . No dose adjustment of ONUREG is recommended for patients with mild to severe renal impairment (CLcr 15 to 89 mL/min) [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment ONUREG has not been studied in patients with pre-existing severe hepatic impairment (total bilirubin > 3 × ULN). A recommended dosage of ONUREG has not been established for patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN). No dose adjustment of ONUREG is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ONUREG tablets are available as: • 200 mg: pink, oval, film-coated tablets with debossed "200" on one side and "ONU" on the other side. • 300 mg: brown, oval, film-coated tablets with debossed "300" on one side and "ONU" on the other side. Table 6 lists the package configurations and strengths. Table 6: ONUREG Package Configurations and NDC Numbers Package Configuration Tablet Strength NDC Number Bottles of 14 with two desiccant cannisters 200 mg 59572-730-14 Bottles of 14 with two desiccant cannisters 300 mg 59572-740-14 One blister card containing 7 tablets 200 mg 59572-730-07 One blister card containing 7 tablets 300 mg 59572-740-07 Storage • Store bottles at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed. Store and dispense in the original bottle (with two desiccant canisters). • Store blisters at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original aluminum-aluminum blisters. Handling and Disposal ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures. 1 If powder comes in contact with skin, immediately and thoroughly wash with soap and water. If powder comes in contact with mucous membranes, immediately flush the area with water.

Storage • Store bottles at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed. Store and dispense in the original bottle (with two desiccant canisters). • Store blisters at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original aluminum-aluminum blisters.