Onureg
(Azacitidine)Dosage & Administration
Onureg Prescribing Information
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.
• 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 Important Administration InformationDo 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)].).5.1 Risks of Substitution with Other Azacitidine ProductsDue 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)].• Administer ONUREG 300 mg orally once daily on Days 1 through 14 of each 28-day cycle ().2.2 Recommended DosageThe recommended dosage of ONUREG is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue ONUREG until disease progression or unacceptable toxicity.
Administer an antiemetic 30 minutes prior to each dose of ONUREG for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting.
If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer ONUREG. Delay the start of the cycle until the ANC is 0.5 Gi/L or more.
Instruct patients on the following:
• Swallow tablets whole. Do not cut, crush, or chew the tablets.• Take a dose about the same time each day.• If a dose of ONUREG is missed, or not taken at the usual time, take the dose as soon as possible on the same day, and resume the normal schedule the following day. Do not take 2 doses on the same day.• If a dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day.
ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures.1
• Administer an antiemetic before each dose for at least the first 2 cycles ().2.2 Recommended DosageThe recommended dosage of ONUREG is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue ONUREG until disease progression or unacceptable toxicity.
Administer an antiemetic 30 minutes prior to each dose of ONUREG for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting.
If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer ONUREG. Delay the start of the cycle until the ANC is 0.5 Gi/L or more.
Instruct patients on the following:
• Swallow tablets whole. Do not cut, crush, or chew the tablets.• Take a dose about the same time each day.• If a dose of ONUREG is missed, or not taken at the usual time, take the dose as soon as possible on the same day, and resume the normal schedule the following day. Do not take 2 doses on the same day.• If a dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day.
ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures.1
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.
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.
ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components
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
Azacitidine is a nucleoside metabolic inhibitor with a molecular formula of C8H12N4O5and a molecular weight of 244 g/mol. The chemical name is: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one and the chemical structural is:
Azacitidine is a white to off-white solid. Azacitidine was found to be soluble in aqueous media across a pH range from 1.0 to 7.0.
ONUREG (azacitidine) is supplied as film-coated tablets containing 200 mg or 300 mg of azacitidine for oral use. Each core tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose. The 200 and 300 mg tablet coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. In addition, the 200 mg tablet coating contains iron oxide red and the 300 mg tablet coating contains black iron oxide, iron oxide red, and iron oxide yellow.
• Risks of Substitution with Other Azacitidine Products: Do not substitute ONUREG for intravenous or subcutaneous azacitidine (,2.1 Important Administration InformationDo 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)].).5.1 Risks of Substitution with Other Azacitidine ProductsDue 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)].• 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 Monitoring and Dosage Modifications for Adverse ReactionsMonitor complete blood count every other week for the first 2 cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression.
The recommended dosage modifications for adverse reactions are provided in Table 1.
Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse ReactionSeverityRecommended Dosage ModificationMyelosuppression
[see Warnings and Precautions (5.2)]Neutrophils less than 0.5 Gi/L on Cycle Day 1
• Interrupt treatment. Resume at the same dose once neutrophils return to 0.5 Gi/L or higher.
Neutrophils less than 1 Gi/L with fever at anytime
First Occurrence
• Interrupt treatment. Resume at the same dose once neutrophils return to 1 Gi/L or higher.
Occurrence in 2 Consecutive Cycles
• Interrupt treatment. After neutrophils return to 1 Gi/L or higher, resume at reduced dose of 200 mg.• If a patient continues to experience febrile neutropenia after dose reduction, reduce the treatment duration by 7 days.• If febrile neutropenia reoccurs after dose and schedule reduction, discontinue ONUREG.
Platelets less than 50 Gi/L with bleeding
First Occurrence
• Interrupt dose. Resume at the same dose once platelets return to 50 Gi/L or higher.
Occurrence in 2 Consecutive Cycles
• Interrupt dose. After platelets return to 50 Gi/L or higher, resume at reduced dose of 200 mg.• If a patient continues to experience thrombocytopenia with bleeding after dose reduction, reduce the treatment duration by 7 days.• If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue ONUREG.
Gastrointestinal Toxicity
[see Adverse Reactions (6.1)]Grade 3 or 4 Nausea or Vomiting
• Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower.• If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.• If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.• If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.
Grade 3 or 4 Diarrhea
• Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower.• If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.• If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.• If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.
Other Adverse Reactions
[see Adverse Reactions (6.1)]Grade 3 or 4
• Interrupt dose and provide medical support. Resume at the same dose once toxicity has resolved to Grade 1 or lower.• If toxicity re-occurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.• If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.• If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.
).5.2 MyelosuppressionNew 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. 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.• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and use of effective contraception (,5.4 Embryo-Fetal ToxicityBased 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/m2basis 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)].,8.1 PregnancyRisk SummaryBased 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/m2basis(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.
DataAnimal DataNo 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/m2azacitidine (at doses less than the recommended human daily dose of oral azacitidine on a mg/m2basis) 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/m2(at doses less than the recommended human daily dose on a mg/m2basis).
In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days 4 to 8 (postimplantation) at a dose of 6 mg/m2(at doses less than the recommended human daily dose on a mg/m2basis), 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/m2(at doses less than the recommended human daily dose on a mg/m2basis) given on gestation Days 9, 10, 11, or 12. In this study, azacitidine caused fetal death when administered at 3 to 12 mg/m2on 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).
).8.3 Females and Males of Reproductive PotentialONUREG 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.
ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 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 3 months after the last dose.
InfertilityBased on animal data, ONUREG may impair male or female fertility
[see Nonclinical Toxicology (13.1)].