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`5.58"
`141.77mm
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`
`NDC 59572-730-07
`
`Rx only
`
`«& ONUREG
`(azacitidine) tablets
`[200m
`
`Each tablet contains 200 mg of azacitidine.
`
`OneBlister Card
`Containing 7 Tablets
`CAUTION: Hazardous Agent
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`0.758"
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`«& ONUREG
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`2.931"
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`237.33mm
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`NDC 59572-740-07
`
`Rx only
`
`«& ONUREG
`(azacitidine) tablets
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`[See USP Controlled Room Temperature].
`Storein the original aluminum-aluminumblisters.
`
`Keepoutof reach of children.
`
`Manufactured by:
`Celgene Corporation
`Summit, NJ 07901
`
`© 2019 - 2020 Celgene Corporation
`
`Celgene Corporation is a wholly owned subsidiary of
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`
`MADEIN SWITZERLAND
`
`Recommended Dosage: See Prescr bing Information.
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`

`—————————— CONTRAINDICATIONS ——————————
`History of severe hypersensitivity to azacitidine or its components (4).
`
`—————–––—— WARNINGS AND PRECAUTIONS —————––—
`• 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).
`
`
`—————————— ADVERSE REACTIONS ——————————
`The most common adverse reactions (≥ 10%) are nausea, vomiting, diarrhea,
`fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia,
`decreased appetite, febrile neutropenia, dizziness, and pain in extremity.
`
`To report SUSPECTED ADVERSE REACTIONS, contact Celgene
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`———————— USE IN SPECIFIC POPULATIONS ———————
`Lactation: Advise not to breastfeed (8.2).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`
`Revised: 5/2021
`
` 8.3 Females and Males of Reproductive Potential
`
` 8.4 Pediatric Use
`
` 8.5 Geriatric Use
`
` 8.6 Renal Impairment
`
` 8.7 Hepatic Impairment
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ONUREG safely and effectively. See full prescribing information for
`ONUREG.
`
`ONUREG (azacitidine) tablets, for oral use
`Initial U S. Approval: 2004
`
`————————— INDICATIONS AND USAGE —————————
`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).
`
`———————— DOSAGE AND ADMINISTRATION ———————
`• 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, 5.1).
`• Administer ONUREG 300 mg orally once daily on Days 1 through 14 of
`each 28-day cycle (2.2).
`• Administer an antiemetic before each dose for at least the first 2 cycles
`(2.2).
`
`
`——————— DOSAGE FORMS AND STRENGTHS ———————
`Tablets: 200 mg and 300 mg (3).
`
`
`
`
`
`
` 1
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Information
`2.2 Recommended Dosage
`2.3 Monitoring and Dosage Modifications for Adverse Reactions
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Risks of Substitution with Other Azacitidine Products
`5.2 Myelosuppression
`5.3
`Increased Early Mortality in Patients with Myelodysplastic
`Syndromes
`5.4 Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
` 6.2 Postmarketing Experience
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
`6
`
`8
`
`
`
`
`
`
`1
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`
`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.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`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)].
`
`2.2
`
`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:
`
`• 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
`
`
`
`2
`
`
`
`
`

`

`2.3
`
`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.
`
`Table 1: Recommended Dosage Modifications for Adverse Reactions
`
`Adverse
`Reaction
`Myelosuppression
`[see Warnings
`and Precautions
`(5.2)]
`
`Severity
`
`Recommended Dosage Modification
`
`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
`
`
`
`Platelets less than 50 Gi/L with
`bleeding
`
`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.
`
`•
`
`•
`
`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.
`
`•
`
`•
`
`
`
`3
`
`
`
`
`

`

`Adverse
`Reaction
`
`Gastrointestinal
`Toxicity [see
`Adverse Reactions
`(6.1)]
`
`Grade 3 or 4 Nausea or
`Vomiting
`
`Grade 3 or 4 Diarrhea
`
`Grade 3 or 4
`
`Other Adverse
`Reactions [see
`Adverse Reactions
`(6.1)]
`
`
`
`
`
`
`
`
`
`Severity
`
`Recommended Dosage Modification
`
`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.
`
`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.
`
`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.
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`4
`
`
`
`
`

`

`3
`
`DOSAGE FORMS AND STRENGTHS
`
`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.
`CONTRAINDICATIONS
`4
`ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its
`components [see Adverse Reactions (6.2), Description (11)].
`5
`WARNINGS AND PRECAUTIONS
`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%. 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
`
`
`
`
`

`

`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/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)].
`6
`ADVERSE REACTIONS
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`• Myelosuppression [see Warnings and Precautions (5.2)]
`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).
`
`
`
`6
`
`
`
`
`

`

`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, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia,
`dizziness, 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
`ONUREG
`(N=236)
`All Grades
`Grade 3 or 4
`(%)
`(%)
`
`Adverse Reaction
`
`Placebo
`(N=233)
`Grade 3 or 4
`(%)
`
`All Grades
`(%)
`
`65
`60
`50
`39
`22
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`Constipation
`Abdominal paina
`General disorders and administration site conditions
`Fatigue / astheniab
`44
`Infections
`Pneumoniac
`
`27
`
`
`
`7
`
`
`3
`3
`5
`1
`2
`
`4
`
`9
`
`24
`10
`21
`24
`13
`
`25
`
`17
`
`< 1
`0
`1
`0
`< 1
`
`1
`
`5
`
`
`
`

`

`1
`< 1
`
`1
`
`11
`
`10
`5
`
`6
`
`8
`
`13
`
`12
`
`Musculoskeletal and connective tissue disorders
`Arthralgia
`14
`Pain in extremity
`11
`Metabolism and nutrition disorders
`Decreased appetite
`Blood and lymphatic disorders
`Febrile neutropenia
`Nervous system disorders
`0
`9
`0
`11
`Dizziness
`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 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.
`
`< 1
`0
`
`1
`
`8
`
`Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 2 were weight
`decreased (4%) in patients who received ONUREG.
`
`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
`
`
`
`Laboratory Abnormality
`
`Neutropenia
`
`Thrombocytopenia
`
`Anemia
`
`ONUREG
`Post-Baseline
`Grade 3 or 4
`n (%)
`
`Baseline
`Grade 0-2
`N
`
`Placebo
`Post-Baseline
`Grade 3 or 4
`n (%)
`
`Baseline
`Grade 0-2
`N
`
`223
`
`222
`
`229
`
`109 (49)
`
`46 (21)
`
`10 (4)
`
`217
`
`212
`
`223
`
`50 (23)
`
`22 (10)
`
`7 (3)
`
`Postmarketing Experience
`6.2
`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.
`
`
`
`8
`
`
`
`
`

`

`• Hypersensitivity reaction
`
`•
`
`Interstitial lung disease
`
`• Tumor lysis syndrome
`
`• Sweet’s syndrome (acute febrile neutrophilic dermatosis)
`
`• Necrotizing fasciitis (including fatal cases)
`
`• Differentiation syndrome
`
`8
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`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
`
`
`
`9
`
`
`
`
`

`

`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).
`
`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.
`
`
`
`10
`
`
`
`
`

`

`8.5
`
`Geriatric Use
`
`Of the 238 patients in QUAZAR whoreceived 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
`ONUREGwereobserved between these patients and youngerpatients.
`
`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
`ONUREGdosage for adverse reactions /see Dosage and Administration(2.3)].
`
`Nodose adjustment of ONUREGis recommendedfor patients with mild to severe renal
`impairment (CLer 15 to 89 mL/min) /see Clinical Pharmacology (12.3)).
`
`8.7
`
`Hepatic Impairment
`
`ONUREGhasnotbeenstudied in patients with pre-existing severe hepatic impairment(total
`bilirubin > 3 « ULN).
`
`A recommended dosage of ONUREGhasnotbeenestablished for patients with moderate
`hepatic impairment(total bilirubin > 1.5 to 3 x ULN).
`
`No dose adjustment of ONUREGis recommendedfor patients with mild hepatic impairment
`(total bilirubin < ULN and AST > ULN,ortotal bilirubin 1 to 1.5 x ULN and any AST) /see
`Clinical Pharmacology (12.3)].
`
`11
`
`DESCRIPTION
`
`Azacitidine is a nucleoside metabolic inhibitor with a molecular formula of CsHi2N4Os and a
`molecular weight of 244 g/mol. The chemical nameis: 4-amino-1-B-D-ribofuranosyl]-s-triazin-
`2(1H)-one and the chemical structuralis:
`
`11
`
`

`

`
`
`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.
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`
`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.
`12.2
`Pharmacodynamics
`
`Greater reduction in global DNA methylation was observed with higher azacitidine plasma
`exposure in patients with AML administered ONUREG for 14 days of a 28-day cycle.
`12.3
`Pharmacokinetics
`
`The systemic exposure of azacitidine is approximately dose proportional over the dose range of
`120 mg to 600 mg once daily of ONUREG (0.4 to 2 times the recommended dosage). Following
`a single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) Cmax of
`azacitidine was 145 ng/mL (64%) and the mean AUC of azacitidine was 242 ng h/mL (65%). No
`accumulation was observed following ONUREG 300 mg once daily.
`
`
`
`12
`
`
`
`
`

`

`Absorption
`
`The mean oral bioavailability is approximately 11% relative to subcutaneous administration. The
`median time to peak plasma concentration of azacitidine is 1 hour.
`
`Effect of Food
`
`A high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect
`AUC0-INF and decreased Cmax by 21%.
`
`Distribution
`
`The mean (CV%) apparent volume of distribution (Vz/F) of azacitidine is 881 L (67%). The
`in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma
`ratio is approximately 0.3.
`
`Elimination
`
`The mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance
`(CL/F) is 1240 L/hour (64%).
`
`Metabolism
`
`Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.
`
`Excretion
`
`Following the administration of ONUREG 300 mg orally once daily, < 2% of the dose was
`recovered unchanged in the urine.
`
`Specific Populations
`
`Age (46 years to 93 years), sex, body weight (39.3 kg to 129 kg), mild hepatic impairment (total
`bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST), and mild to
`moderate renal impairment (CLcr 30 to 89 mL/min) have no clinically meaningful effect on the
`pharmacokinetics of oral azacitidine. The effects of race/ethnicity, moderate to severe hepatic
`impairment (total bilirubin > 1.5 × ULN and any AST), and severe renal impairment (CLcr 15 to
`29 mL/min) on the pharmacokinetics of oral azacitidine is unknown.
`
`Severe renal impairment increased azacitidine exposure by approximately 70% after a single or
`41% after mu