CELGENE 2062
`APOTEX v. CELGENE
`IPR2023-00512
`
`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 ———————
`intravenous or subcutaneous
`• Do not substitute ONUREG for
`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).
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`2
`
`INDICATIONS AND USAGE
`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
`
`—————————— 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: 9/2020
`
`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.
`
`1
`
`Reference ID: 4664690
`
`

`

`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:
`
`• Do not split, crush, or chew ONUREG 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
`
`Reference ID: 4664690
`
`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.
`
`•
`
`•
`
`Reference ID: 4664690
`
`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)]
`
`Reference ID: 4664690
`
`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.
`
`Reference ID: 4664690
`
`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
`
`6
`
`Reference ID: 4664690
`
`

`

`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, 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
`Placebo
`(N=236)
`(N=233)
`All Grades
`Grade 3 or 4
`Grade 3 or 4
`(%)
`(%)
`(%)
`
`All Grades
`(%)
`
`Adverse Reaction
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`Constipation
`Abdominal paina
`General disorders and administration site conditions
`Fatigue / astheniab
`44
`
`65
`60
`50
`39
`22
`
`3
`3
`5
`1
`2
`
`4
`
`7
`
`24
`10
`21
`24
`13
`
`25
`
`< 1
`0
`1
`0
`< 1
`
`1
`
`Reference ID: 4664690
`
`

`

`9
`
`1
`< 1
`
`1
`
`11
`
`17
`
`10
`5
`
`6
`
`8
`
`13
`
`12
`
`Infections
`27
`Pneumoniac
`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.
`
`5
`
`< 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
`Baseline
`Post-Baseline
`Grade 0-2
`Grade 3 or 4
`N
`n (%)
`223
`109 (49)
`222
`46 (21)
`229
`10 (4)
`
`Placebo
`Baseline
`Post-Baseline
`Grade 0-2
`Grade 3 or 4
`N
`n (%)
`217
`50 (23)
`212
`22 (10)
`223
`7 (3)
`
`Reference ID: 4664690
`
`8
`
`

`

`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.
`
`• 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
`
`Reference ID: 4664690
`
`9
`
`

`

`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).
`
`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.
`
`Reference ID: 4664690
`
`10
`
`

`

`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.
`
`8.5
`
`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.
`
`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
`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)].
`
`8.7
`
`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)].
`
`11
`
`DESCRIPTION
`
`Azacitidine is a nucleoside metabolic inhibitor with a molecular formula of C8H12N4O5 and 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:
`
`11
`
`Reference ID: 4664690
`
`

`

`NH2
`
`N
`
`N
`
`HO
`
`N
`
`O
`
`O
`
`OH OH
`
`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
`
`Reference ID: 4664690
`
`

`

`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.
`
`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.
`
`Reference ID: 4664690
`
`13
`
`

`

`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 multiple subcutaneous daily administration.
`
`Drug Interaction Studies
`
`Effect of Gastric Acid Reducing Agents on Azacitidine:
`
`Coadministration of omeprazole (a proton pump inhibitor) with ONUREG increased azacitidine
`AUC0-INF by 19% and had no effect on Cmax.
`
`In Vitro Studies
`
`Cytochrome P450 (CYP) Enzymes: Azacitidine does not inhibit CYP1A2, CYP2B6, CYP2C8,
`CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically relevant concentrations.
`Azacitidine is not an inducer of CYP1A2, CYP2C19, or CYP3A.
`
`Transporter Systems: Azacitidine is not a substrate of P-glycoprotein (P-gp). Azacitidine does
`not inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporters (OAT)
`OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3,
`or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.
`13
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced
`tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 4%
`of the recommended human daily dose of oral azacitidine on a mg/m2 basis) administered
`intraperitoneal 3 times per week for 52 weeks. An increased incidence of tumors in the
`lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with
`intraperitoneal azacitidine at 2 mg/kg (6 mg/m2, approximately 3% of the recommended human
`daily dose of oral azacitidine on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity
`study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 8% to 32% of the
`recommended human daily dose of oral azacitidine on a mg/m2 basis) revealed an increased
`incidence of testicular tumors compared with controls.
`
`14
`
`Reference ID: 4664690
`
`

`

`The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems
`Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains
`WP14 Pro, WP3103P, WP3104P, and CC103; in an in vitro forward gene mutation assay in
`mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in
`mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in
`bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the
`induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.
`
`Administration of azacitidine by intraperitoneal injection to male mice at 9.9 mg/m2 (at doses
`less than the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating
`with untreated female mice resulted in decreased fertility and loss of offspring during subsequent
`embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or
`16 weeks at doses of 15 to 30 mg/m2 (at doses less than the recommended human daily dose on a
`mg/m2 basis) resulted in decreased weight of the testes and epididymides, decreased sperm
`counts accompanied by decreased pregnancy rates, and increased loss of embryos in mated
`females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in
`abnormal embryos in mated females when examined on Day 2 of gestation.
`14
`CLINICAL STUDIES
`
`The efficacy of ONUREG was evaluated in QUAZAR (NCT01757535), a multicenter,
`randomized, double-blind, placebo-controlled study. Eligible patients were ages 55 years or
`older, had AML, and were within 4 months of achieving first complete remission (CR) or
`complete remission with incomplete blood count recovery (CRi) with intensive induction
`chemotherapy. Patients may have received consolidation (see Table 4). Patients were excluded
`if they were candidates for hematopoietic stem cell transplantation at the time of screening.
`
`A total of 472 patients who completed induction with or without consolidation therapy were
`randomized 1:1 to receive ONUREG 300 mg (n=238) or placebo (n=234) orally on Days 1
`through 14 of each 28-day cycle. Randomization was stratified by age at time of induction
`therapy (55 to 64 vs. ≥ 65 years), cytogenetic risk category at time of induction therapy
`(intermediate risk vs. poor risk), prior history of MDS/CMML (yes vs. no), and received
`consolidation therapy following induction therapy (yes vs. no). Baseline demographic and
`disease characteristics are shown in Table 4.
`
`Table 4: Baseline Demographics and Disease-Related Characteristics in QUAZAR
`ONUREG
`Placebo
`(N=238)
`(N=234)
`
`Parameter
`Age (years)
`
`Median (Min, Max)
`
`Age Category, n (%)
`
`68.0 (55, 86)
`
`68.0 (55, 82)
`
`Reference ID: 4664690
`
`15
`
`

`

`Parameter
`< 65 years
`
`65 years to < 75 years
`
`≥ 75 years
`
`Sex, n (%)
`
`Male
`
`Female
`
`Race, n (%)
`
`White
`
`Black or African American
`
`Asian
`
`Other
`
`Not Collected or Reported
`
`ECOG Performance Status, n (%)
`
`0
`
`1
`
`2
`
`3
`
`Cytogenetic Risk Status at Diagnosis, n (%)
`
`Intermediate Risk 1
`
`Poor Risk 2
`
`Initial AML Classification, n (%)
`
`AML with recurrent genetic abnormalities
`
`AML with myelodysplasia-related changes
`
`Therapy related myeloid neoplasms
`
`AML not otherwise specified
`
`Missing
`
`Type of AML, n (%)
`
`Primary (de novo)
`
`Secondary
`
`Reference ID: 4664690
`
`16
`
`ONUREG
`(N=238)
`66 (28)
`
`144 (61)
`
`28 (12)
`
`118 (50)
`
`120 (50)
`
`Placebo
`(N=234)
`68 (29)
`
`142 (61)
`
`24 (10)
`
`127 (54)
`
`107 (46)
`
`216 (91)
`
`197 (84)
`
`2 (1)
`
`6 (3)
`
`12 (5)
`
`2 (1)
`
`116 (49)
`
`101 (42)
`
`21 (9)
`
`0 (0)
`
`203 (85)
`
`35 (15)
`
`39 (16)
`
`49 (21)
`
`2 (1)
`
`148 (62)
`
`0 (0)
`
`213 (89)
`
`25 (11)
`
`6 (3)
`
`20 (9)
`
`11 (5)
`
`0 (0)
`
`111 (47)
`
`106 (45)
`
`15 (6)
`
`2 (1)
`
`203 (87)
`
`31 (13)
`
`46 (20)
`
`42 (18)
`
`0 (0)
`
`145 (62)
`
`1 (< 1)
`
`