`
` 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).
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`
`Important Administration Information
`2.1
`
`
`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
`
`
`
`
`
`
`
`
`11
`
`12
`
`
`
`Females and Males of Reproductive Potential
`8.3
`
`
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`CLINICAL STUDIES
`14
`
`
`REFERENCES
`15
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
`
`
`
`Reference ID: 4664690
`
`
` 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:
`
`
`
`
`
`
`
`• 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
`
`
`
` Severity
`
`
`
`
`
` Recommended Dosage Modification
`
`
`
`Adverse
`
` Reaction
`
`
`
` Myelosuppression
`
` [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
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
` Severity
`
`
` Grade 3 or 4 Nausea or
`
`
` Vomiting
`
`
`
`
`
`
`
` Grade 3 or 4 Diarrhea
`
`
`
`
`
`Adverse
`
` Reaction
`
`
` Gastrointestinal
`
` Toxicity [see
`
` Adverse Reactions
`
` (6.1)]
`
`
`
`
` Other Adverse
` Reactions [see
`
`Adverse Reactions
`
`
`(6.1)]
`
`
`
`
` Grade 3 or 4
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4664690
`
`
`
`
`
` Recommended Dosage Modification
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
` 4
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` 3
`
` 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)].
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
` 5
`
` 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)].
`Myelosuppression
`5.2
`
`
`
`
`
`
`
` 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)]
`
`
`
` Clinical Trials Experience
`
`
` 6.1
`
`
`
` 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
`
`
`
`
`Reference ID: 4664690
`
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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=233)
`(N=236)
`
`
`
`
`
`
`
`
` Grade 3 or 4
` Grade 3 or 4
`
` All Grades
`(%)
`(%)
`(%)
`
`
`
`
`
`
`
` 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
`
`
` 24
`
` 10
`
` 21
`
` 24
`
` 13
`
`
`
` 25
`
`
` < 1
`
` 0
`
` 1
`
` 0
`
` < 1
`
`
`
` 1
`
`
`
`
`
`
`
`Reference ID: 4664690
`
`
` 7
`
`
`
`
`
`
`
`
` 13
`
`
`
` 12
`
`
`
`
`
`
`
` 9
`
`
` 1
`
` < 1
`
`
`
` 1
`
`
`
` 11
`
`
`
` 17
`
`
` 10
`
` 5
`
`
`
` 6
`
`
`
` 8
`
`
`
` 5
`
`
` < 1
`
` 0
`
`
`
` 1
`
`
`
` 8
`
`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
` 11
`
`
`
`
` Dizziness
`
` 9
` 0
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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:
`
`
`
`
`
`
`
`
`Reference ID: 4664690
`
`
` 11
`
`
`
`
`
`
`
`
`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.
`
` 12
` CLINICAL PHARMACOLOGY
` 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.
`
`
`
`
`
`
`
`
`Reference ID: 4664690
`
`
`12
`
`
`
`
`
`
`
`
` Pharmacodynamics
` 12.2
`
`
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 4664690
`
`14
`
`
`
`
`
`
`
`
`
`
`
`The mutagenic and clastogenic pot