Azacitidine

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 ).

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 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 ).

• 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 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. 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 a fetus and use of effective contraception ( 5.4 , 8.1 , 8.3 ).

5.1 Risks of Substitution with Other Azacitidine Products Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology (12.3) ] , the recommended dose and schedule for 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 a 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 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG, respectively. Febrile neutropenia occurred in 12% , and sepsis was reported in 6%, including 1 fatal case . A 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.

5.3 Increased 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 a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a 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.

5.4 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m 2 basis caused fetal death and anomalies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 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 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

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, upper respiratory tract infection, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, skin infection, and pain in extremity. 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, upper respiratory tract infection, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, skin infection, 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 acute sinusitis, adenoviral upper respiratory infection, chronic tonsillitis, influenza, nasopharyngitis, pharyngitis, rhinitis, sinusitis, sinusitis fungal, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection. d 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 Upper respiratory tract infection c 34 2 28 0 Pneumonia d 27 9 17 5 Skin infection e 11 3 8 1 Sepsis f 6 g 5 3 3 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 e Broad scope term includes cellulitis, erythema migrans, folliculitis, fungal skin infection, furuncle, herpes simplex, herpes zoster, nail bed infection, nail infection, onychomycosis, skin infection, staphylococcal skin infection. f Grouped term includes: Sepsis, bacterial sepsis, neutropenic sepsis, device related sepsis, Klebsiella sepsis, Septic shock, Staphylococcal sepsis, and urosepsis. g Includes 1 fatal adverse reaction. Clinically relevant adverse reactions in less than 5% of patients who received ONUREG included Investigations: Weight decreased 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

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). No dose adjustment of ONUREG is recommended for patients with mild or moderate hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 3 × ULN and any AST) [see Clinical Pharmacology (12.3) ] .

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.