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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.

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Warnings and Precautions

Risks of substitution with other azacitidine products1

Due to substantial differences in the pharmacokinetic parameters, 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

Myelosuppression1

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%

A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia, respectively

<1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia

Monitor complete blood counts and modify the dosage as recommended

Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs

Increased early mortality in patients with myelodysplastic syndromes1

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

107 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

Embryo-fetal toxicity1

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/m2 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

Adverse Reactions

ONUREG® safety was assessed in the QUAZAR® AML-001 trial1

The majority of adverse reactions (ARs) were mild to moderate (Grade 1 or 2) with ONUREG®1

ARs (≥5%) in patients with AML who received ONUREG® with a difference between arms of >2%
compared with placebo in QUAZAR® AML-0011

Chart detailing rates of adverse reactions for ONUREG® and placebo patients in the QUAZAR® AML-001 trial. Chart detailing rates of adverse reactions for ONUREG® and placebo patients in the QUAZAR® AML-001 trial.

aGrouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and GI pain.

bGrouped term includes fatigue and asthenia.

cBroad 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 Haemophilus test positive.

Assessment of selected hematological abnormalities1

Selected hematological laboratory abnormalities that worsened from baseline in patients who received ONUREG® in QUAZAR® AML-0011

Chart detailing number of ONUREG® and placebo patients who experienced hematological abnormalities during the QUAZAR® AML-001 trial. Chart detailing number of ONUREG® and placebo patients who experienced hematological abnormalities during the QUAZAR® AML-001 trial.

Treatment duration1,2

The median of 12 cycles and mean of 19 cycles of ONUREG® treatment. The median of 12 cycles and mean of 19 cycles of ONUREG® treatment.

*1 cycle=28 days (median).

For ONUREG®-treated patients, GI ARs were highest during the first 2 cycles of treatment and then subsequently decreased3

Select treatment-emergent adverse events (TEAEs) of GI disorders by cycle of onset (cycles 1-24)3

Graph depicting frequency of gastro-intestinal adverse reactions among ONUREG® and placebo patients in the QUAZAR® AML-001 trial. Graph depicting frequency of gastro-intestinal adverse reactions among ONUREG® and placebo patients in the QUAZAR® AML-001 trial.

TEAEs include adverse events that started between first dose date and the date 28 days after the last dose date of study treatment.

Percentage is based on the number of subjects who are exposed to investigational product at the beginning of each cycle category for the treatment group. A subject with multiple occurrences of a TEAE is counted only once in each cycle category.

Discontinuations & Dose Modifications

Discontinuations and dose modifications in the QUAZAR® AML-001 trial with ONUREG®1

Graphic showing rate of discontinuations and dose modifications in the QUAZAR® AML 001 trial with ONUREG®. Graphic showing rate of discontinuations and dose modifications in the QUAZAR® AML 001 trial with ONUREG®.
Dosing and Administration

INDICATION

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.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ONUREG® is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.

WARNINGS AND PRECAUTIONS

Risks of Substitution with Other Azacitidine Products

Due to substantial differences in the pharmacokinetic parameters, 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 with ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG® for intravenous or subcutaneous azacitidine.

Myelosuppression

New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.

Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS)

In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG® or placebo. 107 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 the ONUREG® arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG® for MDS have not been established. Treatment of MDS with ONUREG® is not recommended outside of controlled trials.

Embryo-Fetal Toxicity

ONUREG® can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. 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.

ADVERSE REACTIONS

Serious adverse reactions occurred in 15% of patients who received ONUREG®. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG®.

Most common (≥10%) adverse reactions with ONUREG® vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).

LACTATION

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.

Please see full Prescribing Information for ONUREG®.

References:
  1. ONUREG® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.
  2. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
  3. Büchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27(1):61-69.
  4. Röllig C, Kramer M, Gabrecht M, et al. Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients. Ann Oncol. 2018;29(4):973-978.
  5. Brinda B, Khan I, Parkin B, Konig H. The rocky road to personalized medicine in acute myeloid leukaemia. J Cell Mol Med. 2018;22(3):1411-1427.
  6. SEER Cancer Statistics Review 1975-2017. National Cancer Institute website. https://seer.cancer.gov/csr/1975_2017/. Accessed August 28, 2020.
  7. Wei AH, Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383(26):2526-2537.
  8. ONUREG® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.
  9. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020;4(15):3528-3549.
  10. Medeiros BC, Satram S. Real world treatment patterns and comparative effectiveness among elderly patients with acute myeloid leukemia in the United States. Ann Hematol Oncol. 2020;7(1):1283.
  11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed June 14, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  12. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. New Engl J Med. 2015;373:1136-1152.
  13. Hamadani M, Craig M, Awan FT, Devine SM. How we approach patient evaluation for hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45:1259-1268.
  14. Klepin HD, Estey E, Kadia T. More versus less therapy for older adults with acute myeloid leukemia: new perspectives on an old debate. Am Soc Clin Oncol Educ Book. 2019;39:421-432.
  15. Lipof JJ, Loh KP, O’Dwyer K, Liesveld JL. Allogeneic hematopoietic cell transplantation for older adults with acute myeloid leukemia. Cancers (Basel). 2018;10(6):179.
  16. U.S. Food and Drug Administration approves Onureg® (azacitidine tablets), a new oral therapy, as continued treatment for adults in first remission with acute myeloid leukemia [press release]. Bristol Myers Squibb website. https://news.bms.com/news/corporate-financial/2020/U.S.-Food-and-Drug-Administration-Approves-Onureg-azacitidine-tablets-a-New-Oral-Therapy-as-Continued-Treatment-for-Adults-in-First-Remission-with-Acute-Myeloid-Leukemia/default.aspx. Published September 1, 2020. Accessed July 21, 2021.
  17. U.S. Food and Drug Administration approves Onureg® (azacitidine tablets), a new oral therapy, as continued treatment for adults in first remission with acute myeloid leukemia [press release]. Bristol Myers Squibb website. https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-onureg-azacitidine-ta. Published September 1, 2020. Accessed September 1, 2020.
  18. Wei AH, Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383(Suppl):1-25.
  19. Döhner H, Wei AH, Roboz GJ, et al. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacytidine. Blood. 2022;140(15):1674-1685.
  20. Wei AH, Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383(26):2526-2537.
  21. Data on file, Celgene Corporation. Summit, New Jersey.
  22. Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 in patients with acute myeloid leukemia (AML) in first remission [oral presentation at ASH 2019]. Blood. 2019;134(Suppl 2):LBA-3.
  23. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
  24. Ravandi F, Roboz GJ, Wei AH, et al. Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial. J Hematol Oncol. 2021;14(1):133.