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.
Important 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)].
Recommended Dosage
The 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:
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- Swallow tablets whole. Do not cut, crush, or chew the tablets.
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- Take a dose about the same time each day.
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- 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.
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- 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
Monitoring and Dosage Modifications for Adverse Reactions
Monitor 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.
| Adverse Reaction | Severity | Recommended Dosage Modification |
|---|---|---|
Myelosuppression [see Warnings and Precautions (5.2)] | Neutrophils less than 0.5 Gi/L on Cycle Day 1 |
|
Neutrophils less than 1 Gi/L with fever at anytime | First Occurrence
Occurrence in 2 Consecutive Cycles
| |
Platelets less than 50 Gi/L with bleeding | First Occurrence
Occurrence in 2 Consecutive Cycles
| |
Gastrointestinal Toxicity [see Adverse Reactions (6.1)] | Grade 3 or 4 Nausea or Vomiting |
|
Grade 3 or 4 Diarrhea |
| |
Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 or 4 |
|
Tablets:
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- 200 mg, pink, oval, film-coated tablet with debossed "200" on one side and "ONU" on the other side.
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- 300 mg, brown, oval, film-coated tablet with debossed "300" on one side and "ONU" on the other side.
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/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 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/m2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on a 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 3 to 12 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 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/m2 (at doses less than the recommended human daily dose on a mg/m2 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/m2 (at doses less than the recommended human daily dose on a mg/m2 basis) given on gestation Days 9, 10, 11, or 12. In this study, azacitidine caused fetal death when administered at 3 to 12 mg/m2 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).
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.
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)].
Pediatric Use
The safety and effectiveness of ONUREG in pediatric patients have not been established.
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.
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)].
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 3 × ULN).
No dose adjustment of ONUREG is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].
ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components [see Adverse Reactions (6.2), Description (11)].
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)].
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%. 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.
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.
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/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 [see Use in Specific Populations (8.1, 8.3)].