LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Azacitidine is 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.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2).. 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals, ONUREG can cause fetal harm when administered to pregnant woman. There are no available data on ONUREG use in pregnant women to evaluate for 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 mg/m2 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 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 DataNo reproductive or developmental toxicity studies have been conducted with oral azacitidine.Early embryotoxicity studies in mice revealed 44% frequency of intrauterine embryonal death (increased resorption) after single intraperitoneal injection of mg/m2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on mg/m2 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 to 12 mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis).In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days to (postimplantation) at dose of mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis), although treatment in the preimplantation period (on gestation Days to 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after single intraperitoneal dose of to 12 mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis) given on gestation Days 9, 10, 11, or 12. In this study, azacitidine caused fetal death when administered at to 12 mg/m2 on gestation Days 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 SummaryThere 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 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 TestingPregnancy testing is recommended for females of reproductive potential before starting ONUREG.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose.. InfertilityBased 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 x ULN).No dose adjustment of ONUREG is recommended for patients with mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin to 1.5 ULN and any AST) [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions (5.2)] 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 Celgene Corporation at 1-888-423-5436 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 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 LeukemiaThe 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 through 14 of each 28-day cycle. Among patients who received ONUREG, 71% were exposed for 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: 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 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 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 summarizes the adverse reactions in QUAZAR.Table 2: Adverse Reactions (>= 5%) in Patients with AML Who Received ONUREG with Difference Between Arms of 2% Compared to Placebo in QUAZARAdverse ReactionONUREG (N=236)Placebo (N=233)All Grades (%)Grade or (%)All Grades (%)Grade or (%)Gastrointestinal disordersNausea65324< 1Vomiting603100Diarrhea505211Constipation391240Abdominal painGrouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain. 22213< 1General disorders and administration site conditionsFatigue astheniaGrouped term includes fatigue and asthenia. 444251InfectionsPneumoniaBroad 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. 279175Musculoskeletal and connective tissue disordersArthralgia14110< 1Pain in extremity11< 150Metabolism and nutrition disordersDecreased appetite13161Blood and lymphatic disordersFebrile neutropenia121188Nervous system disordersDizziness11090Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 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 summarizes select Grades or hematological laboratory abnormalities in QUAZAR.Table 3: Selected Hematological Laboratory Abnormalities That Worsened from Baseline in Patients Who Received ONUREG in QUAZARONUREGPlaceboLaboratory AbnormalityBaseline Grade 0-2 NPost-Baseline Grade or n (%)Baseline Grade 0-2 NPost-Baseline Grade or n (%)Neutropenia223109 (49)21750 (23)Thrombocytopenia22246 (21)21222 (10)Anemia22910 (4)2237 (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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactionInterstitial lung diseaseTumor lysis syndromeSweets syndrome (acute febrile neutrophilic dermatosis)Necrotizing fasciitis (including fatal cases)Differentiation syndrome. Hypersensitivity reaction. Interstitial lung disease. Tumor lysis syndrome. Sweets syndrome (acute febrile neutrophilic dermatosis). Necrotizing fasciitis (including fatal cases). Differentiation syndrome.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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/m2, approximately 4% of the recommended human daily dose of oral azacitidine on mg/m2 basis) administered intraperitoneal 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 mg/kg (6 mg/m2, approximately 3% of the recommended human daily dose of oral azacitidine on mg/m2 basis) once week for 50 weeks. tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 8% to 32% of the recommended human daily dose of oral azacitidine on mg/m2 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/m2 (at doses less than the recommended human daily dose on mg/m2 basis) daily for 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 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (at doses less than the recommended human daily dose on mg/m2 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 related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on Day of gestation.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Azacitidine is 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 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 times the recommended dosage). Following single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) Cmax 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.. AbsorptionThe mean oral bioavailability is approximately 11% relative to subcutaneous administration. The median time to peak plasma concentration of azacitidine is hour.. Effect of FoodA high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect AUC0-INF and decreased Cmax by 21%.. DistributionThe mean (CV%) apparent volume of distribution (Vz/F) of azacitidine is 881 (67%). The in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma ratio is approximately 0.3.. EliminationThe mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance (CL/F) is 1240 L/hour (64%).. MetabolismAzacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.. ExcretionFollowing the administration of ONUREG 300 mg orally once daily, 2% of the dose was recovered unchanged in the urine.. Specific PopulationsAge (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 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 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 AUC0-INF by 19% and had no effect on Cmax.. 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of ONUREG was evaluated in QUAZAR (NCT01757535), multicenter, randomized, double-blind, placebo-controlled study. Eligible patients were ages 55 years or older, had AML, and were within 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 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 QUAZARParameterONUREG (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/physiciangls/PDF/aml.pdf. Accessed 01 Mar 2011.Age (years) Median (Min, Max)68.0 (55, 86)68.0 (55, 82)Age Category, (%) 65 years66 (28)68 (29) 65 years to 75 years144 (61)142 (61) >= 75 years28 (12)24 (10)Sex, (%) Male118 (50)127 (54) Female120 (50)107 (46)Race, (%) White216 (91)197 (84) Black or African American2 (1)6 (3) Asian6 (3)20 (9) Other12 (5)11 (5) Not Collected or Reported2 (1)0 (0)ECOG Performance Status, (%) 0116 (49)111 (47) 1101 (42)106 (45) 221 (9)15 (6) 30 (0)2 (1)Cytogenetic Risk Status at Diagnosis, (%) Intermediate Risk Intermediate risk was defined as normal cytogenetics +8, t(9;11), or Other undefined. 203 (85)203 (87) Poor Risk Poor risk was defined as Complex (>= abnormalities): -5; 5q-; -7; 7q-; 11q23 non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22). 35 (15)31 (13)Initial AML Classification, (%) AML with recurrent genetic abnormalities39 (16)46 (20) AML with myelodysplasia-related changes49 (21)42 (18) Therapy related myeloid neoplasms2 (1)0 (0) AML not otherwise specified148 (62)145 (62) Missing0 (0)1 (< 1)Type of AML, (%) Primary (de novo)213 (89)216 (92) Secondary25 (11)18 (8)Induction Response CR187 (79)197 (84) CRi51 (21)37 (16)Consolidation following induction therapy None52 (22)42 (18) cycle110 (46)102 (44) cycles70 (29)77 (33) cycles6 (3)13 (6)Disease status at study baseline CR185 (78)181 (77) CRi44 (18)38 (16) Not in CR or CRi9 (4)13 (6) Not Reported02 (1)The efficacy of ONUREG was established on the basis of overall survival (OS). The trial demonstrated statistically significant improvement in OS for patients randomized to ONUREG compared to placebo. subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi. The efficacy results are summarized in Table and Figure 1.Table 5: Efficacy Results (ITT Population) in QUAZARONUREG (N=238)Placebo (N=234)Overall SurvivalOS Events, (%)158 (66)171 (73)Median OS (95% CI) Months24.7 (18.7, 30.5)14.8 (11.7, 17.6)Hazard Ratio (95% CI) The hazard ratio is from 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 log-rank test stratified by the same factors. 0.69 (0.55, 0.86)p value 0.0009Figure 1: Kaplan-Meier Curve for Overall Survival (ITT Population) in QUAZAR. Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LeukemiaThe 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 through 14 of each 28-day cycle. Among patients who received ONUREG, 71% were exposed for 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: 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 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 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 summarizes the adverse reactions in QUAZAR.Table 2: Adverse Reactions (>= 5%) in Patients with AML Who Received ONUREG with Difference Between Arms of 2% Compared to Placebo in QUAZARAdverse ReactionONUREG (N=236)Placebo (N=233)All Grades (%)Grade or (%)All Grades (%)Grade or (%)Gastrointestinal disordersNausea65324< 1Vomiting603100Diarrhea505211Constipation391240Abdominal painGrouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain. 22213< 1General disorders and administration site conditionsFatigue astheniaGrouped term includes fatigue and asthenia. 444251InfectionsPneumoniaBroad 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. 279175Musculoskeletal and connective tissue disordersArthralgia14110< 1Pain in extremity11< 150Metabolism and nutrition disordersDecreased appetite13161Blood and lymphatic disordersFebrile neutropenia121188Nervous system disordersDizziness11090Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 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 summarizes select Grades or hematological laboratory abnormalities in QUAZAR.Table 3: Selected Hematological Laboratory Abnormalities That Worsened from Baseline in Patients Who Received ONUREG in QUAZARONUREGPlaceboLaboratory AbnormalityBaseline Grade 0-2 NPost-Baseline Grade or n (%)Baseline Grade 0-2 NPost-Baseline Grade or n (%)Neutropenia223109 (49)21750 (23)Thrombocytopenia22246 (21)21222 (10)Anemia22910 (4)2237 (3).

CONTRAINDICATIONS SECTION.

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).

DESCRIPTION SECTION.

11 DESCRIPTION. Azacitidine is nucleoside metabolic inhibitor with molecular formula of C8H12N4O5 and molecular weight of 244 g/mol. The chemical name is: 4-amino-1--D-ribofuranosyl-s-triazin-2(1H)-one and the chemical structural is:Azacitidine is white to off-white solid. Azacitidine was found to be soluble in aqueous media across 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.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

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 through 14 of each 28-day cycle (2.2).Administer an antiemetic before each dose for at least the first cycles (2.2).. 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 through 14 of each 28-day cycle (2.2).. Administer an antiemetic before each dose for at least the first cycles (2.2).. 2.1Important 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)]. 2.2Recommended Dosage. The recommended dosage of ONUREG is 300 mg orally once daily with or without food on Days 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 cycles. Antiemetic prophylaxis may be omitted after cycles if there has been no nausea and vomiting.If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day of 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 dose about the same time each day.If 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 doses on the same day.If dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day.ONUREG is hazardous drug. Follow applicable special handling and disposal procedures.1 Swallow tablets whole. Do not cut, crush, or chew the tablets.. Take dose about the same time each day.. If 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 doses on the same day.. If dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day.. 2.3Monitoring and Dosage Modifications for Adverse Reactions. Monitor complete blood count every other week for the first cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 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 ReactionsAdverse ReactionSeverityRecommended Dosage ModificationMyelosuppression [see Warnings and Precautions (5.2)] Neutrophils less than 0.5 Gi/L on Cycle Day 1Interrupt treatment. Resume at the same dose once neutrophils return to 0.5 Gi/L or higher.Neutrophils less than Gi/L with fever at anytimeFirst OccurrenceInterrupt treatment. Resume at the same dose once neutrophils return to Gi/L or higher.Occurrence in Consecutive CyclesInterrupt treatment. After neutrophils return to Gi/L or higher, resume at reduced dose of 200 mg.If patient continues to experience febrile neutropenia after dose reduction, reduce the treatment duration by days.If febrile neutropenia reoccurs after dose and schedule reduction, discontinue ONUREG. Platelets less than 50 Gi/L with bleedingFirst OccurrenceInterrupt dose. Resume at the same dose once platelets return to 50 Gi/L or higher.Occurrence in Consecutive CyclesInterrupt dose. After platelets return to 50 Gi/L or higher, resume at reduced dose of 200 mg.If patient continues to experience thrombocytopenia with bleeding after dose reduction, reduce the treatment duration by days.If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue ONUREG. Gastrointestinal Toxicity [see Adverse Reactions (6.1)] Grade or Nausea or VomitingInterrupt dose. Resume at the same dose once toxicity has resolved to Grade or lower.If toxicity reoccurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.Grade or DiarrheaInterrupt dose. Resume at the same dose once toxicity has resolved to Grade or lower.If toxicity reoccurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade or 4Interrupt dose and provide medical support. Resume at the same dose once toxicity has resolved to Grade or lower.If toxicity re-occurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.. Interrupt treatment. Resume at the same dose once neutrophils return to 0.5 Gi/L or higher.. Interrupt treatment. Resume at the same dose once neutrophils return to Gi/L or higher.. Interrupt treatment. After neutrophils return to Gi/L or higher, resume at reduced dose of 200 mg.. If patient continues to experience febrile neutropenia after dose reduction, reduce the treatment duration by days.. If febrile neutropenia reoccurs after dose and schedule reduction, discontinue ONUREG.. Interrupt dose. Resume at the same dose once platelets return to 50 Gi/L or higher.. Interrupt dose. After platelets return to 50 Gi/L or higher, resume at reduced dose of 200 mg.. If patient continues to experience thrombocytopenia with bleeding after dose reduction, reduce the treatment duration by days.. If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue ONUREG.. Interrupt dose. Resume at the same dose once toxicity has resolved to Grade or lower.. If toxicity reoccurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.. If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.. If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.. Interrupt dose. Resume at the same dose once toxicity has resolved to Grade or lower.. If toxicity reoccurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.. If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.. If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.. Interrupt dose and provide medical support. Resume at the same dose once toxicity has resolved to Grade or lower.. If toxicity re-occurs, interrupt dose until resolved to Grade or lower. Resume at reduced dose of 200 mg.. If patient continues to experience the toxicity after dose reduction, reduce the treatment duration by days.. If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.

DOSAGE FORMS & STRENGTHS SECTION.

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.. 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).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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 TestingPregnancy testing is recommended for females of reproductive potential before starting ONUREG.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose.. InfertilityBased on animal data, ONUREG may impair male or female fertility [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

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.

HEPATIC IMPAIRMENT SUBSECTION.

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 x ULN).No dose adjustment of ONUREG is recommended for patients with mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin to 1.5 ULN and any AST) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedONUREG 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 lists the package configurations and strengths.Table 6: ONUREG Package Configurations and NDC NumbersPackage ConfigurationTablet StrengthNDC NumberBottles of 14 with two desiccant cannisters200 mg59572-730-14Bottles of 14 with two desiccant cannisters300 mg59572-740-14One blister card containing tablets200 mg59572-730-07One blister card containing tablets300 mg59572-740-07. 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.. StorageStore bottles at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Keep bottle tightly closed.Store and dispense in the original bottle (with two desiccant canisters).Store blisters at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Store in the original aluminum-aluminum blisters.. Store bottles at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Keep bottle tightly closed.Store and dispense in the original bottle (with two desiccant canisters).. Store blisters at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].Store in the original aluminum-aluminum blisters.. Handling and DisposalONUREG is 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.

INDICATIONS & USAGE SECTION.

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 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. MyelosuppressionAdvise 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 ToxicityAdvise 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 ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 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 months after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with ONUREG and for 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 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 InstructionsAdvise 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)].

NONCLINICAL TOXICOLOGY SECTION.

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/m2, approximately 4% of the recommended human daily dose of oral azacitidine on mg/m2 basis) administered intraperitoneal 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 mg/kg (6 mg/m2, approximately 3% of the recommended human daily dose of oral azacitidine on mg/m2 basis) once week for 50 weeks. tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 8% to 32% of the recommended human daily dose of oral azacitidine on mg/m2 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/m2 (at doses less than the recommended human daily dose on mg/m2 basis) daily for 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 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (at doses less than the recommended human daily dose on mg/m2 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 related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on Day of gestation.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 200 mg Bottle Label. NDC 59572-730-14ONUREG(TM) (azacitidine) tablets200 mgSwallow tablets whole. Do not cut, crush, or chew the tablets.Rx only 14 TabletsCAUTION: Hazardous Agent. PRINCIPAL DISPLAY PANEL 200 mg Bottle Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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 28-day cycle.

PHARMACOKINETICS SECTION.

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 times the recommended dosage). Following single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) Cmax 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.. AbsorptionThe mean oral bioavailability is approximately 11% relative to subcutaneous administration. The median time to peak plasma concentration of azacitidine is hour.. Effect of FoodA high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect AUC0-INF and decreased Cmax by 21%.. DistributionThe mean (CV%) apparent volume of distribution (Vz/F) of azacitidine is 881 (67%). The in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma ratio is approximately 0.3.. EliminationThe mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance (CL/F) is 1240 L/hour (64%).. MetabolismAzacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.. ExcretionFollowing the administration of ONUREG 300 mg orally once daily, 2% of the dose was recovered unchanged in the urine.. Specific PopulationsAge (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 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 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 AUC0-INF by 19% and had no effect on Cmax.. 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 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.

POSTMARKETING EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hypersensitivity reactionInterstitial lung diseaseTumor lysis syndromeSweets syndrome (acute febrile neutrophilic dermatosis)Necrotizing fasciitis (including fatal cases)Differentiation syndrome. Hypersensitivity reaction. Interstitial lung disease. Tumor lysis syndrome. Sweets syndrome (acute febrile neutrophilic dermatosis). Necrotizing fasciitis (including fatal cases). Differentiation syndrome.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals, ONUREG can cause fetal harm when administered to pregnant woman. There are no available data on ONUREG use in pregnant women to evaluate for 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 mg/m2 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 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 DataNo reproductive or developmental toxicity studies have been conducted with oral azacitidine.Early embryotoxicity studies in mice revealed 44% frequency of intrauterine embryonal death (increased resorption) after single intraperitoneal injection of mg/m2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on mg/m2 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 to 12 mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis).In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days to (postimplantation) at dose of mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis), although treatment in the preimplantation period (on gestation Days to 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after single intraperitoneal dose of to 12 mg/m2 (at doses less than the recommended human daily dose on mg/m2 basis) given on gestation Days 9, 10, 11, or 12. In this study, azacitidine caused fetal death when administered at to 12 mg/m2 on gestation Days 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).

REFERENCES SECTION.

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

RENAL IMPAIRMENT SUBSECTION.

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)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: May 2021 Patient Information ONUREG(R) (on-u-reg) (azacitidine) tablets, for oral useWhat is ONUREGONUREG is prescription medicine used for continued treatment of adults with acute myeloid leukemia (AML) who:had first complete remission (CR) following intensive induction chemotherapy with or without recovery of your blood cell counts, and who are not able to complete intensive curative therapy.It is not known if ONUREG is safe and effective in children under 18 years of age.Do not take ONUREG if you:are allergic to azacitidine or any of the ingredients in ONUREG. See the end of this leaflet for complete list of ingredients in ONUREG.Before taking ONUREG, tell your healthcare provider about all of your medical conditions, including if you:have kidney or liver problems.are pregnant or plan to become pregnant. ONUREG can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should perform pregnancy test before you start treatment with ONUREG.You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG.Tell your healthcare provider right away if you become pregnant during treatment with ONUREG. Males with female sexual partner who can become pregnant: You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG. are breastfeeding or plan to breastfeed. It is not known if ONUREG passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of ONUREG.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take ONUREGTake ONUREG exactly as your healthcare provider tells you to take it.Your healthcare provider will prescribe an anti-nausea medicine for you to take to help prevent nausea and vomiting during your treatment with ONUREG.Take the anti-nausea medicine 30 minutes before each dose of ONUREG.Your healthcare provider may decide to stop the anti-nausea medicine after your second cycle of ONUREG, if you do not have any nausea or vomiting. Take ONUREG by mouth time each day beginning on Day through Day 14 of each 28-day cycle.Take ONUREG with or without food at about the same time each day.Swallow ONUREG tablets whole. Do not cut, crush, or chew the tablets.If the powder from ONUREG tablets comes in contact with your skin, wash the area well right away with soap and water.If the powder from ONUREG tablets comes in contact with your eyes or mouth (mucous membranes), flush the area right away with water.If you miss dose of ONUREG, or if you do not take your dose at the usual time, take the dose as soon as possible that day. Take your next dose at the regular time the next day. Do not take doses on the same day to make up for missed dose.If you vomit after taking dose of ONUREG, do not take another dose on the same day. Take your next dose at the regular time the next day.What are the possible side effects of ONUREGONUREG can cause serious side effects, including:New or worsening low white blood cell counts (neutropenia). New or worsening low white blood cell counts are common but can also be severe during treatment with ONUREG. If your white blood cell counts become very low, you are at increased risk for infections. Your healthcare provider will check your white blood cell counts before and during treatment with ONUREG. Your healthcare provider may prescribe medicine to help increase your white blood cell count if needed. Tell your healthcare provider right away if you get any of the following symptoms:fever or chillsbody achesfeeling very tired or weakunusual headachesNew or worsening low platelet counts (thrombocytopenia). Low platelet counts are common but can also be severe during treatment with ONUREG. Your healthcare provider will check your platelet counts before and during treatment with ONUREG. Tell your healthcare provider right away if you have any unusual bruising or bleeding. Your healthcare provider may change your dose or tell you to stop taking ONUREG if you have low blood cell counts.ONUREG may cause fertility problems in males and females, which may affect your ability to have children. Talk with your healthcare provider if you have concerns about fertility.The most common side effects of ONUREG include:nausea and vomiting. See How should take ONUREGdiarrhea. You may need to be treated with anti-diarrheal medicines.tiredness or weaknessconstipationstomach area (abdominal) painpneumoniajoint paindecreased appetitepain in arms or legsdizzinessThese are not all of the possible side effects of ONUREG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ONUREGStore bottles or blisters of ONUREG tablets at room temperature between 68F to 77F (20C to 25C).Store ONUREG tablets in the original bottle or the original aluminum-aluminum blisters.Bottles of ONUREG contain drying agent (desiccant) canisters. Do not eat the desiccant canisters. Keep the ONUREG bottle tightly closed.Talk to your healthcare provider about how to safely throw away (dispose of) any unused or expired ONUREG.Keep ONUREG and all medicines out of the reach of childrenGeneral information about the safe and effective use of ONUREG.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ONUREG for condition for which it was not prescribed. Do not give ONUREG to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ONUREG that is written for health professionals.What are the ingredients in ONUREGActive ingredient: azacitidineInactive ingredients:Each core tablet contains: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose.The pink 200 mg tablet coating contains: hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin.The brown 300 mg tablet coating contains: black iron oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin.Manufactured by: Celgene Corporation, Wholly Owned Subsidiary of Bristol Myers Squibb, 86 Morris Avenue, Summit, NJ 07901 ONUREG(R) is registered trademark of Celgene Corporation. Patent: www.celgene.com/therapies (C) 2020 Celgene Corporation. All rights reserved. ONUPPI V3 5/2021 For more information, go to www.ONUREG.com or call 1-888-423-5436.. had first complete remission (CR) following intensive induction chemotherapy with or without recovery of your blood cell counts, and who are not able to complete intensive curative therapy.. are allergic to azacitidine or any of the ingredients in ONUREG. See the end of this leaflet for complete list of ingredients in ONUREG.. have kidney or liver problems.. are pregnant or plan to become pregnant. ONUREG can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should perform pregnancy test before you start treatment with ONUREG.You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG.Tell your healthcare provider right away if you become pregnant during treatment with ONUREG. Males with female sexual partner who can become pregnant: You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG. Your healthcare provider should perform pregnancy test before you start treatment with ONUREG.. You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG.. Tell your healthcare provider right away if you become pregnant during treatment with ONUREG.. You should use effective birth control (contraception) during treatment and for at least months after your last dose of ONUREG.. are breastfeeding or plan to breastfeed. It is not known if ONUREG passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of ONUREG.. Take ONUREG exactly as your healthcare provider tells you to take it.. Your healthcare provider will prescribe an anti-nausea medicine for you to take to help prevent nausea and vomiting during your treatment with ONUREG.Take the anti-nausea medicine 30 minutes before each dose of ONUREG.Your healthcare provider may decide to stop the anti-nausea medicine after your second cycle of ONUREG, if you do not have any nausea or vomiting. Take the anti-nausea medicine 30 minutes before each dose of ONUREG.. Your healthcare provider may decide to stop the anti-nausea medicine after your second cycle of ONUREG, if you do not have any nausea or vomiting.. Take ONUREG by mouth time each day beginning on Day through Day 14 of each 28-day cycle.. Take ONUREG with or without food at about the same time each day.. Swallow ONUREG tablets whole. Do not cut, crush, or chew the tablets.. If the powder from ONUREG tablets comes in contact with your skin, wash the area well right away with soap and water.. If the powder from ONUREG tablets comes in contact with your eyes or mouth (mucous membranes), flush the area right away with water.. If you miss dose of ONUREG, or if you do not take your dose at the usual time, take the dose as soon as possible that day. Take your next dose at the regular time the next day. Do not take doses on the same day to make up for missed dose.. If you vomit after taking dose of ONUREG, do not take another dose on the same day. Take your next dose at the regular time the next day.. New or worsening low white blood cell counts (neutropenia). New or worsening low white blood cell counts are common but can also be severe during treatment with ONUREG. If your white blood cell counts become very low, you are at increased risk for infections. Your healthcare provider will check your white blood cell counts before and during treatment with ONUREG. Your healthcare provider may prescribe medicine to help increase your white blood cell count if needed. Tell your healthcare provider right away if you get any of the following symptoms:. fever or chills. body aches. feeling very tired or weak. unusual headaches. New or worsening low platelet counts (thrombocytopenia). Low platelet counts are common but can also be severe during treatment with ONUREG. Your healthcare provider will check your platelet counts before and during treatment with ONUREG. Tell your healthcare provider right away if you have any unusual bruising or bleeding. Your healthcare provider may change your dose or tell you to stop taking ONUREG if you have low blood cell counts.. nausea and vomiting. See How should take ONUREG. diarrhea. You may need to be treated with anti-diarrheal medicines.. tiredness or weakness. constipation. stomach area (abdominal) pain. pneumonia. joint pain. decreased appetite. pain in arms or legs. dizziness. Store bottles or blisters of ONUREG tablets at room temperature between 68F to 77F (20C to 25C).. Store ONUREG tablets in the original bottle or the original aluminum-aluminum blisters.. Bottles of ONUREG contain drying agent (desiccant) canisters. Do not eat the desiccant canisters. Keep the ONUREG bottle tightly closed.. Talk to your healthcare provider about how to safely throw away (dispose of) any unused or expired ONUREG.

SPL UNCLASSIFIED SECTION.

2.1Important 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risks of Substitution with Other Azacitidine Products: Do not substitute ONUREG for intravenous or subcutaneous azacitidine (2.1, 5.1).Myelosuppression: Monitor complete blood counts every other week for the first cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the cycles after any dose reduction. Withhold and then resume at same or reduced dose or discontinue ONUREG based on severity (2.3, 5.2).Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and use of effective contraception (5.4, 8.1, 8.3).. Risks of Substitution with Other Azacitidine Products: Do not substitute ONUREG for intravenous or subcutaneous azacitidine (2.1, 5.1).. Myelosuppression: Monitor complete blood counts every other week for the first cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the cycles after any dose reduction. Withhold and then resume at same or reduced dose or discontinue ONUREG based on severity (2.3, 5.2).. Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and use of effective contraception (5.4, 8.1, 8.3).. 5.1Risks 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 ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in fatal adverse reaction. Treatment of patients using ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective.Do not substitute ONUREG for intravenous or subcutaneous azacitidine [see Dosage and Administration (2.1)].. 5.2 Myelosuppression. New or worsening Grade or neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG, respectively. Febrile neutropenia occurred in 12%. dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia, respectively. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia.Monitor complete blood counts and modify the dosage as recommended [see Dosage and Administration (2.2, 2.3)]. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.. 5.3Increased Early Mortality in Patients with Myelodysplastic Syndromes. In AZA-MDS-003 (NCT01566695), 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to myelodysplastic syndromes were randomized to ONUREG or placebo. One-hundred and seven patients received median of cycles of ONUREG 300 mg daily for 21 days of 28-day cycle. Enrollment was discontinued early due to higher incidence of early fatal and/or serious adverse reactions in patients who received ONUREG compared with placebo. The most frequent fatal adverse reaction was sepsis. The safety and effectiveness of ONUREG for treatment of myelodysplastic syndromes have not been established. Treatment of patients with myelodysplastic syndromes with ONUREG is not recommended outside of controlled trials.. 5.4Embryo-Fetal Toxicity. Based on the mechanism of action and findings in animals, ONUREG can cause fetal harm when administered to pregnant woman. Azacitidine administered to pregnant rats via single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on mg/m2 basis caused fetal death and anomalies.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least months after the last dose [see Use in Specific Populations (8.1, 8.3)].