Onureg Drug Information

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.

• 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

Pregnancy Risk Summary Based on its mechanism of action 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).

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

is contraindicated in patients with known severe hypersensitivity to azacitidine or its components . History of severe hypersensitivity to azacitidine or its components.