CELGENE 2058
`APOTEX v. CELGENE
`IPR2023-00512
`
`PRODUCT MONOGRAPH
`
`INCLUDING PATIENT MEDICATION INFORMATION
`
`PrONUREG®
`
`azacitidine tablets
`
`Tablets, 200 mg, 300 mg azacitidine, Oral
`
`Antineoplastic / Pyrimidine Analogue
`
`Celgene Inc., a Bristol-Myers Squibb company
`2344 Alfred-Nobel Blvd.
`Suite 300
`Saint-Laurent, QC
`H4S 0A4
`
`Date of Initial Approval:
`JAN-04-2021
`
`© 2020 Celgene Corporation.
`ONUREG is a registered trademark of Celgene Corporation used under license by Celgene Inc.
`
`Submission Control No: 240668
`
`ONUREG® Product Monograph
`
`Page 1 of 32
`
`

`

`RECENT MAJOR LABEL CHANGES
`
`Not Applicable.
`
`TABLE OF CONTENTS
`
`2
`4
`
`5
`6
`7
`
`8
`
`9
`
`RECENT MAJOR LABEL CHANGES......................................................................................2
`TABLE OF CONTENTS ..............................................................................................................2
`PART I: HEALTH PROFESSIONAL INFORMATION............................................................4
`1
`INDICATIONS....................................................................................................................4
`1.1
`Pediatrics....................................................................................................................4
`1.2 Geriatrics....................................................................................................................4
`CONTRAINDICATIONS ..................................................................................................4
`DOSAGE AND ADMINISTRATION...............................................................................4
`4.1 Dosing Considerations...............................................................................................4
`4.2 Recommended Dose and Dosage Adjustment...........................................................5
`4.3 Administration ...........................................................................................................7
`4.5 Missed Dose...............................................................................................................7
`OVERDOSAGE.................................................................................................................7
`DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING................8
`WARNINGS AND PRECAUTIONS ...............................................................................8
`7.1
`Special Populations..................................................................................................10
`7.1.1
`Pregnant Women................................................................................................. 10
`7.1.2
`Breast-feeding ..................................................................................................... 11
`7.1.3
`Pediatrics ............................................................................................................. 11
`7.1.4 Geriatrics ............................................................................................................. 11
`ADVERSE REACTIONS................................................................................................11
`8.1 Adverse Reaction Overview ....................................................................................11
`8.2 Clinical Trial Adverse Reactions.............................................................................11
`8.3
`Less Common Clinical Trial Adverse Reactions.....................................................14
`8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
`Quantitative Data ...............................................................................................................14
`8.5
`Post-Market Adverse Drug Reactions .....................................................................14
`DRUG INTERACTIONS.................................................................................................15
`9.2 Overview..................................................................................................................15
`9.3 Drug-Drug Interactions............................................................................................15
`9.4 Drug-Food Interactions............................................................................................16
`9.5 Drug-Herb Interactions ............................................................................................16
`9.6 Drug-Laboratory Test Interactions ..........................................................................16
`9.7 Drug-Lifestyle Interactions......................................................................................16
`ACTION AND CLINICAL PHARMACOLOGY...........................................................16
`
`10
`
`ONUREG® Product Monograph
`
`Page 2 of 32
`
`

`

`11
`12
`13
`14
`
`10.1 Mechanism of Action...........................................................................................16
`10.2
`Pharmacodynamics...............................................................................................16
`10.3
`Pharmacokinetics .................................................................................................17
`STORAGE, STABILITY AND DISPOSAL..................................................................18
`SPECIAL HANDLING INSTRUCTIONS.....................................................................18
`PHARMACEUTICAL INFORMATION ........................................................................19
`CLINICAL TRIALS .........................................................................................................19
`14.1
`Trial Design and Study Demographics ................................................................19
`14.2
`Study Results........................................................................................................22
`NON-CLINICAL TOXICOLOGY...................................................................................24
`16
`PATIENT MEDICATION INFORMATION...............................................................................27
`
`ONUREG® Product Monograph
`
`Page 3 of 32
`
`

`

`PART I: HEALTH PROFESSIONAL INFORMATION
`
`1
`
`INDICATIONS
`
`ONUREG® (azacitidine tablets) is a nucleoside metabolic inhibitor indicated for:
`
` maintenance therapy in adult patients with acute myeloid leukemia (AML) who achieved
`complete remission (CR) or complete remission with incomplete blood count recovery (CRi)
`following induction therapy with or without consolidation treatment, and who are not eligible
`for hematopoietic stem cell transplantation (HSCT).
`
`Limitations of Use:
`
` ONUREG® is not interchangeable with, and should not be substituted with or for, azacitidine
`for injection. See DOSAGE AND ADMINISTRATION, Administration and WARNINGS
`AND PRECAUTIONS, General.
` 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. See WARNINGS AND PRECAUTIONS,
`General.
`
`1.1 Pediatrics
`
`Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health
`Canada has not authorized an indication for pediatric use.
`
`1.2 Geriatrics
`
`Geriatrics (≥ 65 years of age): No dosage adjustment is required for ONUREG® based on age,
`see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics.
`
`2 CONTRAINDICATIONS
`
`ONUREG® is contraindicated in patients who are hypersensitive to this drug or to any ingredient
`in the formulation, including any non-medicinal ingredient, or component of the container. For a
`complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
`
`ONUREG® is contraindicated in patients with advanced malignant hepatic tumors.
`
`4 DOSAGE AND ADMINISTRATION
`
`4.1 Dosing Considerations
`
` Health Canada has not authorized an indication for pediatric use, see INDICATIONS.
` No specific dose adjustments are recommended for elderly patients (≥ 65 years of age), see
`INDICATIONS.
` 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.
`
`ONUREG® Product Monograph
`
`Page 4 of 32
`
`

`

` ONUREG® can be administered to patients with renal impairment without initial dose
`adjustment, see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage
`Adjustment and CLINICAL PHARMACOLOGY, Pharmacokinetics.
`
`4.2 Recommended Dose and Dosage Adjustment
`
`Recommended Starting Dosage:
`
`The recommended starting dose of ONUREG® is 300 mg orally once daily on Day 1 through
`Day 14 of repeated 28-day treatment cycles.
`
`If the absolute neutrophil count (ANC) is less than 500/mcL on Day 1 of a cycle, do not
`administer ONUREG®. Delay the start of the cycle until the ANC is 500/mcL or more.
`
`ONUREG® maintenance therapy should be initiated after achievement of a CR/CRi following
`completion of induction and consolidation therapy or following induction if consolidation therapy
`is not planned.
`
`Dose Modifications During Treatment:
`
`Dose Adjustment for Renal Impairment: No dose adjustment is required for patients with mild to
`moderate renal impairment.
`
`ONUREG® can be administered to patients with severe renal impairment without initial dose
`adjustment. 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 WARNINGS AND PRECAUTIONS,
`Monitoring and Laboratory Tests.
`
`Dose Adjustment for 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).
`
`Dose Adjustment for Adverse Reactions: Dose modification guidelines for hematologic and non-
`hematologic adverse reactions are recommended based on clinical and laboratory findings if
`toxicities are judged related to ONUREG® (see Table 1).
`
`Dose Adjustment for Hematological and Nonhematological Adverse
`
`Table 1:
`Reactions
`Adverse Reaction
`Grade 4 Neutropenia
`
`Recommended Action
`
`First Occurrence
`
`ONUREG® Product Monograph
`
`Page 5 of 32
`
`

`

`Adverse Reaction
`(Absolute Neutrophil Count
`(ANC): < 500/mcL)
`or
`Grade 3 Neutropenia with
`Fever
`(ANC: 500 – 1000/mcL)
`
`Grade 4 Thrombocytopenia
`(Platelets: < 25,000/mcL)
`or
`Grade 3 Thrombocytopenia
`with Active Bleeding
`(Platelets: 25,000 – 50,000/mcL)
`
`Grade 3 or Higher
`Nausea, Vomiting or Diarrhea
`
`
`
`
`
`
`
`Recommended Action
`Interrupt dose. Resume at the same dose once
`neutrophils return to Grade 2 or lower.
` The use of supportive care such as granulocyte colony
`stimulating factor (GCSF), as clinically indicated, may
`be considered.
`Occurrence in 2 Consecutive Cycles
`Interrupt dose. After neutrophils return to Grade 2 or
`
`lower, reduce dose to 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®.
` The use of supportive care such as GCSF, as clinically
`indicated, may be considered.
`First Occurrence
`Interrupt dose. Resume at the same dose once
`
`platelets return to Grade 2 or lower.
`Occurrence in 2 Consecutive Cycles
`Interrupt dose. After platelets return to Grade 2 or
`
`lower, reduce dose to 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 event reoccurs, interrupt dose until resolved to
`Grade 1 or lower. Reduce the dose to 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®.
`
`
`
`
`
`
`
`
`
`
`
`
`
`ONUREG® Product Monograph
`
`Page 6 of 32
`
`

`

`Adverse Reaction
`Other Grade 3 or Higher
`Nonhematologic Events
`
`Recommended Action
`Interrupt dose and provide medical support. Resume
`at the same dose once toxicity has resolved to
`Grade 1 or lower.
`If event reoccurs, interrupt dose until resolved to
`Grade 1 or lower. Reduce the dose to 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®.
`
`
`
`
`
`
`
`
`
`Continuation and Discontinuation Recommendations:
`
`ONUREG®, given Day 1 through Day 14 of repeated 28-day treatment cycles, is intended for
`continuous use. ONUREG® treatment should be continued until more than 15% blasts are
`observed in peripheral blood or bone marrow or until unacceptable toxicity occurs. Discontinue
`ONUREG® if more than 15% blasts are observed in either the peripheral blood or bone marrow
`or at the physician’s discretion.
`
`4.3 Administration
`
`ONUREG® can be taken with or without food. Do not split, crush, or chew ONUREG® tablets.
`Administer a dose at about the same time each day. Consider providing prophylactic anti-emetic
`therapy during ONUREG® treatment.
`ONUREG® is not interchangeable with, and should not be substituted with or for, azacitidine for
`injection. Due to differences in exposure, the dose and schedule recommendations for
`ONUREG® are different from those for injectable azacitidine. Verify drug name, dose, and
`administration route. See INDICATIONS, Limitation of Use.
`
`4.5 Missed Dose
`
`If a dose of ONUREG® is missed, or not taken at the usual time, administer the dose as soon as
`possible on the same day, and return to the normal time of dose administration 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, but return to the normal time of dose administration the following day.
`
`5 OVERDOSAGE
`
`In the event of overdose, monitor the patient with appropriate blood counts and provide
`supportive treatment, as necessary. There is no known specific antidote for ONUREG®
`overdose.
`
`For management of a suspected drug overdose, contact your regional poison control centre.
`
`ONUREG® Product Monograph
`
`Page 7 of 32
`
`

`

`6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
`
`Dosage Forms, Strengths, Composition and Packaging.
`Dosage Form /
`Strength/
`Composition
`Tablet 200 mg
`azacitidine
`
`Table 2:
`
`Route of
`Administration
`
`Oral
`
`Oral
`
`Non-medicinal Ingredients
`
`croscarmellose sodium, hypromellose, iron oxide
`red, lactose monohydrate, polyethylene
`glycol/macrogol, magnesium stearate, mannitol,
`silicified microcrystalline cellulose, titanium dioxide,
`triacetin
`black iron oxide, croscarmellose sodium,
`hypromellose, iron oxide red, iron oxide yellow,
`lactose monohydrate, polyethylene glycol/macrogol,
`magnesium stearate, mannitol, silicified
`microcrystalline cellulose, titanium dioxide, triacetin
`
`Tablet 300 mg
`azacitidine
`
`ONUREG® tablets are available in 7 count blister packages.
`
`7 WARNINGS AND PRECAUTIONS
`
`General
`
`Due to substantial differences in the pharmacokinetic parameters (see ACTION AND CLINICAL
`PHARMACOLOGY, Pharmacokinetics), 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, Administration and INDICATIONS, Limitation of Uses).
`
`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.
`Therefore, 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. (See INDICATIONS,
`Limitation of Uses)
`
`Carcinogenesis and Mutagenesis
`
`In vitro studies demonstrated that azacitidine is mutagenic and clastogenic in bacterial and
`mammalian cell systems. Azacitidine induced neoplastic lesions and tumours in multiple tissues
`
`ONUREG® Product Monograph
`
`Page 8 of 32
`
`

`

`in rats and mice administered with azacitidine intraperitoneally (see NON-CLINICAL
`TOXICOLOGY).
`
`Cardiovascular
`
`Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or
`pulmonary disease were excluded from the pivotal clinical study and therefore the safety and
`efficacy of ONUREG® in these patients have not been established.
`
`No thorough clinical QT/QTc study or in vitro studies (hERG, canine Purkinje fiber assay) were
`performed to rule out the effect of ONUREG® on QT prolongation. An in vivo safety
`pharmacology study in dogs receiving azacitidine reported increased QTc interval, but
`interpretation of this study is limited by confounding effects associated with toxicity (see NON-
`CLINICAL TOXICOLOGY).
`
`Driving and Operating Machinery
`
`No studies on the effects on the ability to drive or use machinery have been performed. Patients
`should be advised that they may experience undesirable effects such as fatigue, asthenia, and
`gastrointestinal reactions such as nausea, vomiting, diarrhea and constipation, during treatment
`with ONUREG®. Therefore, caution should be exercised when driving or operating a vehicle or
`potentially dangerous machinery.
`
`Gastrointestinal
`
`Gastrointestinal toxicities were the most frequent adverse reactions in the ONUREG® treatment
`group. Nausea (64.8%), vomiting (59.7%), and diarrhea (50.4%) were reported in patients
`treated with ONUREG®. Grade 3 or 4 diarrhea, vomiting, or nausea occurred in 5.1%, 3.0%,
`and 2.5%, respectively in patients treated with ONUREG®. The first occurrence of Grade 3 or 4
`diarrhea, vomiting, or nausea occurred within the first 2 cycles in 1.3%, 3.0%, and 1.7%,
`respectively in patients treated with ONUREG®.
`Consider providing prophylactic anti-emetic therapy during ONUREG® treatment. Treat diarrhea
`with antidiarrheal medications promptly at the onset of symptoms.
`
`Hematologic
`
`New or worsening Grade 3 or higher neutropenia (41.1%), thrombocytopenia (22.5%), or febrile
`neutropenia (11.4%) were commonly reported (10% or more) adverse reactions in patients
`treated with ONUREG®. The first occurrence of Grade 3 or 4 neutropenia, thrombocytopenia, or
`febrile neutropenia occurred within the first 2 cycles in 19.9%, 10.6%, and 1.7%, respectively in
`patients treated with ONUREG®.
`
`Monitor complete blood counts and modify the dosage as recommended (see WARNINGS AND
`PRECAUTIONS, Monitoring and Laboratory Tests). Consider the use of supportive care such
`as granulocyte colony stimulating factor (GCSF) as clinically indicated.
`
`ONUREG® Product Monograph
`
`Page 9 of 32
`
`

`

`Hepatic/Biliary/Pancreatic
`
`Patients with extensive tumor burden due to metastatic disease have been rarely reported to
`experience progressive hepatic coma and death during injectable treatment with azacitidine,
`especially in such patients with baseline serum albumin < 30 g/L. ONUREG® is contraindicated
`in patients with advanced malignant hepatic tumors (see CONTRAINDICATIONS).
`
`Monitoring and Laboratory Tests
`Complete blood count monitoring is recommended every other week for the first 2 cycles
`(56 days), every other week for the next 2 cycles after dose adjustment, and monthly thereafter,
`prior to start of next cycle.
`
`Monitor patients with severe renal impairment (CLcr 15 to 29 mL/min) more frequently for
`adverse reactions and modify the ONUREG® dosage for adverse reactions, see DOSING AND
`ADMINISTRATION, Recommended Dose and Dosage Adjustment. No dose adjustment of
`ONUREG® is required for patients with mild to severe renal impairment (CLcr 15 to 89 mL/min),
`see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics.
`
`Sexual Health
`
`Fertility
`
`There are no human data on the effect of azacitidine on fertility. In animals, adverse effects of
`azacitidine on male and female fertility have been documented. See NON-CLINICAL
`TOXICOLOGY
`
`Reproduction
`
`Pregnancy testing is recommended for females of reproductive potential before starting
`ONUREG®.
`
`If either a female of reproductive potential wishes to have a child or a male wishes to conceive a
`child, they should seek advice for reproductive counseling and cryo-conservation of either ovum
`or sperm prior to starting ONUREG®.
`
`7.1 Special Populations
`
`7.1.1 Pregnant Women
`
`Azacitidine may cause fetal harm when administered to a pregnant woman based on its
`mechanism of action and findings in animals. There are no available data on ONUREG® use in
`pregnant women. Azacitidine was teratogenic in animals and caused embryo-fetal lethality in
`animals at doses less than the recommended human daily dose of oral azacitidine, see NON-
`CLINICAL TOXICOLOGY.
`
`Females of childbearing potential should be advised to avoid pregnancy during treatment with
`azacitidine. If this drug is used during pregnancy or if a patient becomes pregnant while taking
`this drug, the patient should be apprised of the potential hazard to the fetus. Advise females of
`reproductive potential to use effective contraception during treatment with ONUREG® and for at
`least 6 months after the last dose.
`
`ONUREG® Product Monograph
`
`Page 10 of 32
`
`

`

`7.1.1.1 Males with Female Sexual Partners of Reproductive Potential
`
`Males with female sexual partners of reproductive potential should not conceive a child and
`should use effective contraception during treatment with ONUREG®, and for at least 6 months
`after the last dose.
`
`7.1.2 Breast-feeding
`
`It is not known whether azacitidine or its metabolites are excreted in human milk or the effects
`on the nursing child or milk production. Due to the potential serious adverse reactions in the
`nursing child, breast-feeding must be discontinued during ONUREG® therapy and for one week
`after the last dose.
`
`7.1.3 Pediatrics
`
`Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health
`Canada has not authorized an indication for pediatric use.
`
`7.1.4 Geriatrics
`
`Geriatrics (≥ 65 years of age): No dosage adjustment is required for ONUREG® based on age,
`see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics.
`
`8 ADVERSE REACTIONS
`
`8.1 Adverse Reaction Overview
`
`This section describes the safety data from the QUAZAR (CC-486-AML-001) trial (see
`CLINICAL TRIALS).
`
`The most frequently reported adverse events (≥ 10%) were nausea, vomiting, diarrhea,
`neutropenia, fatigue/asthenia, anemia, constipation, thrombocytopenia, abdominal pain,
`respiratory tract infection, arthralgia, decreased appetite, febrile neutropenia, back pain,
`leukopenia, pain in extremity, dizziness and pneumonia. The most frequent serious adverse
`events to ONUREG® that occurred in ≥ 2% of patients were febrile neutropenia (6.8%),
`pneumonia (5.1%) and pyrexia (2.1%).
`
`Permanent discontinuation of ONUREG® due to an adverse event occurred in 6.8% of patients.
`The most common adverse events to ONUREG® requiring permanent discontinuation in 1% or
`more of patients included nausea (2.1%), diarrhea (1.7%), and vomiting (1.3%).
`
`Adverse events in the ONUREG® arm requiring dosage interruption in 2% or more of patients
`included neutropenia (19.9%), thrombocytopenia (8.5%), nausea (5.5%), diarrhea (4.2%),
`vomiting (3.8%), pneumonia (3.4%), leukopenia (2.5%), febrile neutropenia (2.1%), and alanine
`aminotransferase increased (2.1%). Adverse events to ONUREG® requiring dosage reduction in
`1% or more of patients included neutropenia (5.5%), diarrhea (3.4%), thrombocytopenia (1.7%),
`and nausea (1.7%).
`
`8.2 Clinical Trial Adverse Reactions
`
`Because clinical trials are conducted under very specific conditions, the adverse reaction rates
`
`ONUREG® Product Monograph
`
`Page 11 of 32
`
`

`

`observed in the clinical trials may not reflect the rates observed in practice and should not be
`compared to the rates in the clinical trials of another drug. Adverse reaction information from
`clinical trials is useful for identifying drug-related adverse events and for approximating rates.
`
`Treatment emergent adverse events (TEAEs) observed in the QUAZAR (CC-486-AML-001) trial
`are listed in Table 3. Median treatment duration differed between the two groups: of 11.6
`months (range: 0.5 to 74.3 months) for the ONUREG® treated patients and 5.7 months (range:
`0.7 to 68.5 months) for the placebo arm.
`
`All Treatment Emergent Adverse Events Reported in ≥ 5% and Grade 3/4
`Table 3:
`Treatment Emergent Adverse Events Reported in ≥ 1% of ONUREG® Treated Patients (≥
`1% frequency versus placebo) from the CC-486-AML-001 trial (safety population)
`
`System Organ Class
`Preferred Term
`
`ONUREG®
`n = 236
`All Grade
`Grade 3-4
`N (%)
`N (%)
`
`Placebo
`n = 233
`All Grade
`Grade 3-4
`N (%)
`N (%)
`
`Gastrointestinal Disorders
`153 (65)
`Nausea
`141 (60)
`Vomiting
`119 (50)
`Diarrhea
`91 (39)
`Constipation
`51 (22)
`Abdominal pain*
`13 (6)
`Flatulence
`Blood and lymphatic system disorders
`Neutropenia
`105 (45)
`Thrombocytopenia
`79 (34)
`Anemia
`48 (20)
`Febrile neutropenia
`28 (12)
`Leukopenia
`25 (11)
`Infections and infestations
`Influenza
`Pneumonia†
`Urinary tract infection‡
`Bronchitis
`Rhinitis
`Cellulitis
`Lung Infection
`
`18 (8)
`24 (10)
`22 (9)
`13 (6)
`12 (5)
`9 (4)
`4 (2)
`
`6 (3)
`7 (3.0)
`12 (5)
`3 (1)
`4 (2)
`0 (0)
`
`97 (41)
`53 (23)
`33 (14)
`27 (11)
`18 (8)
`
`3 (1)
`2 (1)
`4 (2)
`0 (0)
`0 (0)
`4 (2)
`4 (2)
`
`55 (24)
`23 (10)
`50 (22)
`56 (24)
`30 (13)
`4 (2)
`
`61 (26)
`63 (27)
`42 (18)
`18 (8)
`19 (8)
`
`7 (3)
`13 (6)
`17 (7)
`9 (4)
`4 (2)
`3 (1)
`2 (1)
`
`1 (0.4)
`0 (0)
`3 (1)
`0 (0)
`1 (0.4)
`0 (0)
`
`55 (24)
`50 (22)
`30 (13)
`18 (8)
`14 (6)
`
`0 (0)
`1 (0.4)
`2 (1)
`0 (0)
`0 (0)
`1 (0.4)
`1 (0.4)
`
`ONUREG® Product Monograph
`
`Page 12 of 32
`
`

`

`System Organ Class
`Preferred Term
`
`ONUREG®
`n = 236
`All Grade
`Grade 3-4
`N (%)
`N (%)
`General disorders and administrative site conditions
`Fatigue / asthenia
`104 (44)
`Metabolism and nutrition disorders
`30 (13)
`Decreased appetite
`Musculoskeletal and connective tissue disorders
`Arthralgia
`
`9 (4)
`
`2 (1)
`
`32 (14)
`
`2 (1)
`
`28 (12)
`
`25 (11)
`
`25 (11)
`
`5 (2)
`
`3 (1)
`
`1 (0.4)
`
`0 (0.0)
`
`5 (2)
`
`Back pain
`
`Pain in extremity
`
`Nervous System Disorders
`
`Dizziness
`
`Syncope
`
`Psychiatric Disorders
`
`Anxiety
`
`Investigations
`
`Alanine aminotransferase
`increased
`Blood Uric Acid Increased
`
`Placebo
`n = 233
`All Grade
`Grade 3-4
`N (%)
`N (%)
`
`58 (25)
`
`15 (6)
`
`24 (10)
`
`23 (10)
`
`12 (5)
`
`21 (9)
`
`1 (0.4)
`
`3 (1)
`
`2 (1)
`
`1 (0.4)
`
`2 (1)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (0.4)
`
`4 (2)
`
`2 (1)
`
`4 (2)
`
`2 (1)
`
`2 (1)
`
`0 (0.0)
`
`16 (7)
`
`0 (0.0)
`
`8 (3)
`
`1 (0.4)
`
`5 (2)
`Injury, Poisoning and Procedural Complications
`
`12 (5)
`
`3 (1)
`
`5 (2)
`
`Fall
`
`Cardiac Disorders
`
`12 (5)
`
`1 (0.4)
`
`Atrial Fibrillation
`0 (0.0)
`4 (2)
`4 (2)
`4 (2)
`Treatment-emergent adverse events include adverse events that started between the first dose date and
`the date 28 days after the last dose date of study treatment.
`A subject is counted only once for multiple events within preferred term/system organ class.
`* Grouped terms included abdominal pain, abdominal pain upper, abdominal discomfort, and
`gastrointestinal pain.
`† Grouped terms included pneumonia, bronchopulmonary aspergillosis, lung infection, Pneumocystis
`jirovecii pneumonia, atypical pneumonia, pneumonia bacterial, and pneumonia fungal.
`‡ Grouped terms included urinary tract infection, urinary tract infection bacterial, Escherichia urinary tract
`infection, and cystitis.
`
`ONUREG® Product Monograph
`
`Page 13 of 32
`
`

`

`Data cut-off date: 15 Jul 2019
`
`8.3 Less Common Clinical Trial Adverse Reactions
`
`Other adverse reactions that did not meet criteria for inclusion in Table 3 were respiratory tract
`infections (RTI; 18%) and weight decreased (4%) in patients treated with ONUREG®. RTI was a
`grouped term which included upper respiratory tract infection, respiratory tract infection, and
`respiratory tract infection viral.
`
`8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
`Quantitative Data
`
`Changes in selected laboratory abnormalities that have worsened from baseline in ≥20% of
`patients receiving ONUREG® with a difference versus placebo of >10% is listed in Table 4.
`Table 4:
`Selected Laboratory Abnormalities that Worsened from Baseline Reported
`in ≥20% of ONUREG® Treated Patients (> 10% frequency versus placebo) from the CC-
`486-AML-001 trial
`Laboratory Parameter1
`
`ONUREG®
`N = 236
`n (%)
`All Grades
`Grade ≥3
`All Grades
`176 (76)
`152 (64)
`203 (86)
`Decrease in neutrophils
`165 (71)
`127 (54)
`201 (85)
`Decrease in white blood cells
`67 (29)
`27 (11)
`103 (44)
`Decrease in red blood cells
`1Not all lab shifts were reported as Treatment Emergent Adverse Events (TEAEs)
`
`Placebo
`N = 233
`n (%)
`Grade ≥3
`111 (48)
`75 (32)
`14 (6)
`
`8.5 Post-Market Adverse Drug Reactions
`
`The following adverse reactions have been identified during post-approval use of intravenous or
`subcutaneous azacitidine.
`
`Blood and lymphatic system disorders:
` Hemorrhagic diathesis
`
`Cardiac disorders:
` Atrial fibrillation, cardiac failure congestive, cardiac failure, pericardial effusion
`
`Gastrointestinal disorders:
` Colitis, intestinal perforation, pancreatitis acute, subileus
`
`Hepatobiliary disorders:
` Hepatic failure, hepatitis, ascites, hyperbilirubinemia, jaundice
`
`Infections and infestations:
` Sepsis, septic shock, infection, bacterial sepsis, abscess intestinal, cellulitis,
`pseudomonal sepsis, lower respiratory tract infection, bronchopulmonary aspergillosis,
`Clostridium difficile colitis, lobar pneumonia, lung infection pseudomonal
`
`Injury, poisoning and procedural complications:
`
`ONUREG® Product Monograph
`
`Page 14 of 32
`
`

`

` Splenic rupture
`
`Investigations:
` Blood creatinine increased, blood bilirubin increased, AST increased, ALT increased
`
`Metabolism and nutrition disorders:
` Dehydration, hyperglycemia, hyponatremia, tumor lysis syndrome
`
`Nervous system disorders:
` Grand mal convulsion
`
`Renal and urinary disorders:
` Renal failure acute, renal failure
`
`Respiratory, thoracic, and mediastinal disorders:
`Interstitial lung disease, pulmonary embolism, acute respiratory distress syndrome
`
`
`Skin and subcutaneous tissue disorders:
`Leukocytoclastic vasculitis, pyoderma gangrenosum, Sweet’s syndrome (acute febrile
`neutrophilic dermatosis), necrotizing fasciitis
`
`9 DRUG INTERACTIONS
`
`9.2 Overview
`
`Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome
`P450 isoforms (CYPs). Therefore, interactions with CYP inhibitors and inducers are unlikely to
`have any impact on the metabolism of ONUREG®.
`
`ONUREG® is not a substrate of P-glycoprotein (P-gp).
`
`Multiple nucleoside transporters are involved in azacitidine transport, therefore azacitidine
`uptake is unlikely to be altered by single nucleotide polymorphisms in individual nucleoside
`transporters or nucleoside modulators.
`
`9.3 Drug-Drug Interactions
`
`Oral azacitidine exposure was minimally affected when co-administered with a proton pump
`inhibitor (omeprazole). Therefore, a dose modification is not required when ONUREG® is co-
`administered with proton pump inhibitors or other pH modifiers.
`
`No clinically relevant drug-drug interactions would be expected when ONUREG® is co-
`administered with CYP or transporter substrates. In vitro, azacitidine did not inhibit
`P-glycoprotein (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.
`
`In vitro studies indicated that at concentrations up to 100 µM (approximately 30-fold higher than
`clinically achievable concentrations), azacitidine did not induce cytochrome P450 isoenzymes
`(CYPs) 1A2, 2C19, or 3A4 or 3A5. Using in vitro studies at concentrations up to 100 µM,
`
`ONUREG® Product Monograph
`
`Page 15 of 32
`
`

`

`azacitidine did not inhibit P450 isoenzymes CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and
`2E1. Therefore, CYP induction or inhibition by azacitidine at clinically achievable plasma
`concentrations is unlikely.
`
`9.4 Drug-Food Interactio