ONUREG 200mg tablets medication leaflet

Onureg 200 mg film-coated tablets

Onureg 300 mg film-coated tablets

Onureg 200 mg film-coated tablets

Each film-coated tablet contains 200 mg azacitidine.

Each film-coated tablet contains 3.61 mg of lactose (as lactose monohydrate).

Onureg 300 mg film-coated tablets

Each film-coated tablet contains 300 mg azacitidine.

Each film-coated tablet contains 5.42 mg of lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Onureg 200 mg film-coated tablets

Pink, oval, film-coated tablet, 17.0x7.6 mm, debossed with “200” on one side and “ONU” on the otherside.

Onureg 300 mg film-coated tablets

Brown, oval, film-coated tablet, 19.0x9.0 mm, debossed with “300” on one side and “ONU” on theother side.

Onureg is indicated as maintenance therapy in adult patients with acute myeloid leukaemia (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 candidatesfor, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT).

Onureg treatment should be initiated and monitored under the supervision of a physician experiencedin the use of chemotherapeutic medicinal products.

Patients are to be treated with an anti-emetic 30 minutes prior to each dose of Onureg for the first2 treatment cycles. Anti-emetic prophylaxis may be omitted after 2 cycles, if there has been no nauseaand vomiting (see section 4.4).

The recommended dose is 300 mg azacitidine orally once daily. Each repeated cycle consists of atreatment period of 14 days followed by a treatment free period of 14 days (28-day treatment cycle).

Onureg treatment should be continued until no more than 15% blasts are observed in peripheral bloodor bone marrow or until unacceptable toxicity (see dose schedule modification guidance for diseaserelapse).

Onureg should not be used interchangeably with injectable azacitidine due to differences in theexposure, dose and schedule of treatment. Healthcare professionals are recommended to verify thename of the medicinal product, dose and administration route.

Complete blood counts should be performed prior to initiation of therapy. Complete blood countmonitoring is also recommended every other week for the first 2 cycles (56 days), every other weekfor the next 2 cycles after dose adjustment, and monthly thereafter, prior to the start of subsequentcycles of treatment (see section 4.4).

Dose schedule modification for AML disease relapse

In the case of disease relapse, with 5% to 15% blasts in peripheral blood or bone marrow, inconjunction with a clinical assessment, an extension of the dosing schedule from 14 to 21 days ofrepeated 28-day cycles should be considered. Dosing should not exceed 21 days during any 28-dayperiod. Onureg should be discontinued if more than 15% blasts are observed in either the peripheralblood or bone marrow or at the physician’s discretion.

Dose adjustment for adverse reactions

Dose modification guidelines for haematologic and non-haematologic adverse reactions arerecommended based on clinical and laboratory findings (see Table 1).

Table 1: Dose adjustments for haematologic and non-haematologic adverse reactions

Criteria* Recommended action

Grade 4 neutropenia or First occurrence

Grade 3 neutropenia with * Interrupt Onureg. Resume the treatment cycle at the samefever dose once neutrophils return to Grade 2 or lower.

* Use supportive care such as granulocyte colony stimulatingfactor (GCSF), as clinically indicated (see section 4.4).

Occurrence in 2 consecutive cycles

* Interrupt Onureg. Resume the treatment cycle at a reduceddose of 200 mg after neutrophils return to Grade 2 or lower.

* If a patient continues to experience the toxicity after dosereduction, reduce the treatment duration by 7 days.

* If the toxicity continues or re-occurs after dose and schedulereduction, discontinue Onureg.

* Use supportive care such as GCSF, as clinically indicated (seesection 4.4).

Grade 4 thrombocytopenia First occurrenceor Grade 3 * Interrupt Onureg. Resume the treatment cycle at the samethrombocytopenia with dose once platelets return to Grade 2 or lower.bleeding Occurrence in 2 consecutive cycles

* Interrupt Onureg. Resume the treatment cycle at a reduceddose of 200 mg after platelets return to Grade 2 or lower.

* If a patient continues to experience the toxicity after dosereduction, reduce the treatment duration by 7 days.

* If the toxicity continues or re-occurs after dose and schedulereduction, discontinue Onureg.

Criteria* Recommended action

Grade 3 or higher nausea, * Interrupt Onureg. Resume the treatment cycle at the samev omiting or diarrhoea dose once toxicity has resolved to Grade 1 or lower.

* Use supportive care such as anti-emetic therapy and treatdiarrhoea at the onset of symptoms (see section 4.4).

* If event re-occurs, interrupt dose until resolved to Grade 1 orlower and reduce the dose to 200 mg.

* If a patient continues to experience the toxicity after dosereduction, reduce the treatment duration by 7 days.

* If the toxicity continues or re-occurs after dose and schedulereduction, discontinue Onureg.

Other Grade 3 or higher * Interrupt Onureg and provide medical support according tonon-haematological events local recommendations. Resume the treatment cycle at thesame dose once toxicity has resolved to Grade 1 or lower.

* If the toxicity re-occurs, interrupt Onureg until resolved to

Grade 1 or lower and reduce dose to 200 mg.

* If a patient continues to experience the toxicity after dosereduction, reduce the treatment duration by 7 days.

* If the toxicity continues or re-occurs after dose and schedulereduction, discontinue Onureg.

* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Toxicity grades are inaccordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.3 (NCI-

CTCAE v4.3).

Missed or delayed doses

If a dose of Onureg is missed, or not taken at the usual time, the dose should be taken as soon aspossible on the same day. Then, the next scheduled dose should be taken at the normal time thefollowing day. Two doses should not be taken on the same day.

If a dose is vomited, another dose must not be taken on the same day. Instead return to the normal timeof dose administration the following day.

No dose adjustments are recommended for patients over 65 years of age (see section 5.2).

Onureg can be administered to patients with mild, moderate or severe renal impairment without initialdose adjustment (see section 5.2).

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (BIL)≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or BIL 1 to 1.5 × ULNand any AST) (see section 5.2).

Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN)should be monitored more frequently for adverse reactions and appropriate dose adjustment should bemade (see Table 1).

The safety and efficacy of Onureg in children and adolescents below 18 years have not beenestablished. No data are available.

Onureg is for oral use.

Onureg can be taken with or without food. The tablets should be swallowed whole with a glass ofwater at about the same time each day. They should not be split, crushed, dissolved or chewed (seesection 6.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

Treatment with Onureg can be associated with neutropenia, thrombocytopenia and febrile neutropenia(see section 4.8 for frequencies). Interruption, reduction or discontinuation of Onureg may benecessary to manage haematological toxicities. Patients should be advised to promptly report febrileepisodes. Patients with low platelet counts should be advised to report early signs or symptoms ofbleeding. Supportive care such as antibiotics and/or antipyretics for management of infection/feverand GCSF for neutropenia should be provided based on individual patient characteristics, treatmentresponse and according to the current clinical guidelines (see section 4.2 Table 1).

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg(see section 4.8). Patients should be administered prophylactic anti-emetic therapy for the first 2 cyclesof Onureg treatment (see section 4.2). Diarrhoea should be treated promptly at the onset of symptoms.

Interruption, reduction or discontinuation of Onureg may be necessary to manage gastrointestinaltoxicities (see section 4.2).

Women of childbearing potential have to use effective contraception during and up to 6 months aftertreatment. Men have to use effective contraception during and up to 3 months after treatment (seesection 4.6).

Onureg tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially'sodium-free'.

No formal clinical drug-drug interaction studies with azacitidine have been conducted.

In case of concomitant administration with other antineoplastic agents, caution and monitoring isrecommended as an antagonistic, additive, or synergistic pharmacodynamic effect cannot be excluded.

These effects may be dependent on the dose, sequence and schedule of administration.

Onureg exposure was minimally affected when co-administered with a proton pump inhibitor(omeprazole). Therefore, dose modification is not required when Onureg is co-administered withproton pump inhibitors or other pH modifiers.

An in vitro study of azacitidine with human liver fractions indicated that azacitidine was notmetabolised by cytochrome P450 isoforms (CYPs). Therefore, interactions with CYP inducers orinhibitors are considered unlikely (see section 5.2).

Clinically relevant inhibitory or inductive effects of azacitidine on the metabolism of cytochrome

P450 substrates are unlikely (see section 5.2). No clinically relevant drug-drug interactions areexpected when Onureg is co-administered with substrates of P-glycoprotein (P-gp), breast cancerresistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic aniontransporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT)

OCT2.

Azacitidine is not a substrate of P-gp, therefore it is not expected to interact with P-gp inducers orinhibitors.

Women of childbearing potential have to use effective contraception during and up to 6 months aftertreatment. Men should be advised not to father a child while receiving treatment and have to useeffective contraception during and up to 3 months after treatment (see sections 4.4 and 5.3).

There are no adequate data from the use of Onureg in pregnant women. Studies in mice and rats haveshown reproductive and developmental toxicity (see section 5.3). The potential risk for humans isunknown. Based on results from animal studies and its mechanism of action, Onureg is notrecommended during pregnancy (especially during the first trimester, unless clearly necessary) and inwomen of childbearing potential not using contraception. The advantages of treatment should beweighed against the possible risk for the foetus in every individual case. If a patient or partnerbecomes pregnant while taking Onureg, the patient should be informed of the potential risk to thefoetus.

It is unknown whether azacitidine or its metabolites are excreted in human milk. Due to the potentialserious adverse reactions in the breastfed child, breast-feeding is contraindicated during Onuregtherapy (see section 4.3).

There are no human data on the effect of azacitidine on fertility. In animals, adverse effects ofazacitidine on male fertility have been documented (see section 5.3). Patients who wish to conceive achild should be advised to seek reproductive counselling and cryo-conservation of either the ovum orsperm prior to starting Onureg treatment.

Onureg has minor influence on the ability to drive and use machines. Fatigue has been reported withthe use of Onureg. Therefore, caution is recommended when driving or operating machines.

The most common adverse reactions are nausea (64.8%), vomiting (59.7%), diarrhoea (50.4%),neutropenia (44.5%), fatigue/asthenia (44.1%)5, constipation (38.6%), thrombocytopenia (33.5%),abdominal pain (21.6%)4, respiratory tract infection (17%)2, arthralgia (13.6%), decreased appetite(12.7%), febrile neutropenia (11.9%), back pain (11.9%), leucopenia (10.6%), pain in extremity(10.6%) and pneumonia (10.2%)1.

Serious adverse reactions occurred in 16.1% of patients receiving Onureg. The most common seriousadverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)1.

Permanent discontinuation of Onureg due to an adverse reaction occurred in 6.8% of patients. Themost common adverse reactions requiring permanent discontinuation are nausea (2.1%), diarrhoea(1.7%), and vomiting (1.3%).

Dose interruptions due to an adverse reaction occurred in 36.4% of patients who received Onureg.

Adverse reactions requiring dose interruption include neutropenia (19.9%), thrombocytopenia (8.5%),nausea (5.5%), diarrhoea (4.2%), vomiting (3.8%), pneumonia (3.4%)1, leucopenia (2.5%), febrileneutropenia (2.1%), and abdominal pain (2.1%)4.

Dose reductions due to an adverse reaction period occurred in 14% of patients who received Onureg.

Adverse reactions requiring dose reduction included neutropenia (5.5%), diarrhoea (3.4%),thrombocytopenia (1.7%), and nausea (1.7%).

Table 2 presents the frequency category of ADRs reported in the pivotal Phase 3 study with Onureg. Atotal of 236 patients received Onureg. The median treatment duration was 11.6 months (range: 0.5 to74.3 months) for Onureg arm.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot beestimated from the available data). Within each frequency grouping, undesirable effects are presentedin order of decreasing seriousness. Adverse reactions are presented in the table below according to thehighest frequency observed.

Table 2: Adverse drug reactions (ADRs) in AML patients receiving Onureg maintenancetherapy

System organ class All gradesa frequency

Infections and infestations Very common

Pneumonia1, 6, respiratory tract infection2

Common

Influenza, urinary tract infection3, bronchitis, rhinitis

Blood and lymphatic system disorders Very common

Neutropenia, thrombocytopenia6, febrile neutropenia6,leucopenia

Metabolism and nutrition disorders Very common

Decreased appetite

Psychiatric disorders Common

Anxiety

Gastrointestinal disorders Very common

Nausea, vomiting, diarrhoea, constipation, abdominal pain4

Musculoskeletal and connective tissue Very commondisorders Arthralgia, back pain, pain in extremity

System organ class All gradesa frequency

General disorders and administration Very commonsite conditions Fatigue/asthenia5

Investigations Common

Weight decreaseda All AEs with at least 5.0% of patients in the Onureg arm and at least 2.0% higher frequency than the placeboarm.1 Grouped terms include pneumonia, bronchopulmonary aspergillosis, lung infection, Pneumocystis jiroveciipneumonia, atypical pneumonia, pneumonia bacterial, and pneumonia fungal.2 Grouped terms include upper respiratory tract infection, respiratory tract infection, and respiratory tractinfection viral.3 Grouped terms include urinary tract infection, urinary tract infection bacterial, Escherichia urinary tractinfection, and cystitis.4 Grouped terms include abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain.5 Grouped terms include fatigue and asthenia.6 Adverse reactions in which at least one was considered to be life threatening (if the outcome of the reactionwas death, it is included with death cases).

New or worsening Grade 3 or higher neutropenia (41.1%), thrombocytopenia (22.5%), or febrileneutropenia (11.4%) were commonly reported adverse reactions in patients treated with Onureg. Thefirst occurrence of Grade 3 or 4 neutropenia, thrombocytopenia, or febrile neutropenia occurred withinthe first 2 cycles in 19.9%, 10.6%, and 1.7%, respectively in patients treated with Onureg. Seesection 4.2 for monitoring and management guidance.

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg.

Nausea (64.8%), vomiting (59.7%), and diarrhoea (50.4%) were reported in patients treated with

Onureg. Grade 3 or higher diarrhoea occurred in 5.1% of patients and Grade 3 or higher vomiting andnausea occurred in 3.0% and 2.5%, respectively in patients treated with Onureg. The first occurrenceof Grade 3 or 4 nausea, vomiting, or diarrhoea occurred within the first 2 cycles in 1.7%, 3.0%, and1.3%, respectively, in patients treated with Onureg. See section 4.2 for monitoring and managementguidance.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, the patient should be monitored with appropriate blood counts and supportivetreatment should be provided, as necessary, according to local recommendations. There is no knownspecific antidote for an overdose with Onureg.

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code:

L01BC07

Azacitidine is a DNA methyltransferase inhibitor and epigenetic modifier. Azacitidine is incorporatedinto DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotidetriphosphates. Incorporation of azacitidine into the DNA of AML cells, modified epigenetic pathwaysthrough the inhibition of DNA methyltransferases, and reduction of DNA methylation. This led toalteration of gene expression, including re-expression of genes regulating tumour suppression,immune pathways, cell cycle, and cell differentiation. Incorporation of azacitidine into the RNA of

AML cells, inhibited RNA methyltransferase, reduced RNA methylation, decreased RNA stability,and decreased protein synthesis.

The efficacy and safety of Onureg was studied in a multi-centre, placebo-controlled, Phase 3 study

QUAZAR AML-001 (CC-486-AML-001) with a double-blind, randomised, parallel-group designwhich evaluated Onureg versus placebo as maintenance therapy in AML patients. Patients wereenrolled with de novo AML, AML secondary to prior diagnosis of myelodysplastic syndromes (MDS),or chronic myelomonocytic leukaemia (CMML); the patients were aged ≥ 55 years, and had achievedfirst complete remission (CR) or complete remission with incomplete blood count recovery (CRi)within 4 months (+/- 7 days) after intensive induction chemotherapy with or without consolidationtherapy. Patients were not eligible for HSCT at the time of randomisation, which included patientswho did not have a transplant donor, or who chose not to proceed to HSCT.

Patients in both treatment arms received best supportive care as deemed necessary by the investigator.

Best supportive care included, but was not limited to, treatment with red blood cell (RBC)transfusions, platelet transfusions, use of erythropoiesis stimulating agent, antibiotic, antiviral and/orantifungal therapy, GCSF, anti-emetic therapy, and nutritional support.

Patients who achieved a CR/CRi after completion of intensive induction therapy with or withoutconsolidation were administered Onureg 300 mg (N = 236) or placebo (N = 233) once daily on Days 1through 14 of each 28-day cycle. In the event of disease relapse (5% to 15% blasts in peripheral bloodor bone marrow), the dose schedule was extended to 21 days of repeated 28-day treatment cycles permedical discretion. Treatment continued until disease progression (more than 15% blasts wereobserved in peripheral blood or bone marrow) or until unacceptable toxicity.

A total of 472 patients were randomised 1:1 between Onureg and placebo treatment arms. Baselinedemographic and disease characteristics for the AML patient population were balanced betweentreatment arms as shown in Table 3. The median treatment duration was 11.6 months (range: 0.5 to74.3 months) for the Onureg arm versus 5.7 months (range: 0.7 to 68.5 months) for the placebo arm. Atotal of 51 patients (21%) receiving Onureg and 40 patients (17%) receiving placebo extended theirdose schedule to 300 mg daily for 21 days due to AML disease relapse.

Of the 469 patients in the Phase 3 study who received treatment, 61% (285/469) were 65 years of ageor older and 11% (51/469) were 75 years of age or older. No overall differences in safety or efficacyof Onureg were observed between these patients and younger patients.

Table 3: Baseline demographics and disease-related characteristics in study

CC-486-AML-001

Onureg Placebo

Parameter (N = 238) (N = 234)

Age (years)

Median (min, max) 68.0 (55, 86) 68.0 (55, 82)

Age category, n (%)< 65 years 66 (27.7) 68 (29.1)≥ 65 years to < 75 years 144 (60.5) 142 (60.7)≥ 75 years 28 (11.8) 24 (10.3)

Onureg Placebo

Parameter (N = 238) (N = 234)

Sex, n (%)

Male 118 (49.6) 127 (54.3)

Female 120 (50.4) 107 (45.7)

Race, n (%)

White 216 (90.8) 197 (84.2)

Black or African American 2 (0.8) 6 (2.6)

Asian 6 (2.5) 20 (8.5)

Other 12 (5.0) 11 (4.7)

Not collected or reported 2 (0.8) 0 (0)

ECOG performance status, n (%)0 116 (48.7) 111 (47.4)1 101 (42.4) 106 (45.3)2 21 (8.8) 15 (6.4)3 0 (0) 2 (0.9)

Cytogenetic risk status at diagnosis, n (%)

Intermediate risk1 203 (85.3) 203 (86.6)

Poor risk2 35 (14.7) 31 (13.2)

Initial AML classification, n (%)

AML with recurrent genetic abnormalities 39 (16.4) 46 (19.7)

AML with myelodysplasia-related changes 49 (20.6) 42 (17.9)

Therapy related myeloid neoplasms 2 (0.8) 0 (0)

AML not otherwise specified 148 (62.2) 145 (62.0)

Missing 0 (0) 1 (0.4)

Type of AML, n (%)

Primary (de novo) 213 (89.5) 216 (92.3)

Secondary 25 (10.5) 18 (7.7)

MRD status at randomisation3, n (%)

Negative 133 (55.9) 111 (47.4)

Positive 103 (43.3) 116 (49.6)

Missing 2 (0.8) 7 (3.0)

AML = Acute myelogenous leukaemia; MDS = Myelodysplastic syndrome; CMML = Chronic myelomonocytic

Leukaemia; ECOG = Eastern cooperative oncology group; CR = Morphologic complete remission;

CRi = Morphologic CR with incomplete blood count recovery.1 Intermediate risk was defined as normal cytogenetics +8, t(9;11), or other undefined.2 Poor risk was defined as complex (≥ 3 abnormalities): -5; 5q-; -7; 7q-; 11q23 - non t(9;11); inv(3); t(3;3);t(6;9); or t(9;22). Source for Intermediate and Poor Risk: National comprehensive cancer network clinicalpractice guidelines in oncology for AML.3MRD status in bone marrow was measured during screening period by flow cytometric assay at a sensitivitylevel of 0.1%.

Most patients received consolidation therapy after induction therapy in both the Onureg (78%) andplacebo (82%) treatment arms; more than 90% of these patients in each treatment arm received 1 or2 cycles of consolidation therapy after induction therapy (Table 4).

Table 4: Consolidation therapy in study CC-486-AML-001

Parameter Onureg Placebo(N = 238) (N = 234)

Received consolidation therapy followinginduction

Yes, n (%) 186 (78.2) 192 (82.1)1 Cycle, n (%) 110 (46.2) 102 (43.6)2 Cycles, n (%) 70 (29.4) 77 (32.9)3 Cycles, n (%) 6 (2.5) 13 (5.6)

No, n (%) 52 (21.8) 42 (17.9)

CR/CRi status at randomisation

CR, n (%) 183 (76.9) 177 (75.6)

CRi, n (%) 50 (21.0) 44 (18.8)

Not in CR/CRi a, n (%) 5 (2.1) 11 (4.7)

Missing, n (%) 0 (0) 2 (0.9)

CR = Complete remission; CRi = Morphologic CR with incomplete blood count recovery.a These patients had baseline bone marrow of less than 5% blasts and both ANC < 1 x 109 and platelets< 100 x 109.

The efficacy of Onureg in adult patients with AML was established based on overall survival (OS)and relapse-free survival (RFS).

The efficacy results are summarised in the Table 5.

Table 5: CC-486-AML-001 efficacy results (ITT Population)

Endpoints Onureg Placebo(N = 238) (N = 234)

Overall survival

OS events, n (%) 158 (66.4) 171 (73.1)

Median OS, months (95% CI) 24.7 (18.7, 30.5) 14.8 (11.7, 17.6)

Hazard ratio (95% CI) 0.69 (0.55, 0.86)p-value 0.0009

Relapse-free survival

Events, n (%) 164 (68.9) 181 (77.4)

Median RFS, months (95% CI) 10.2 (7.9, 12.9) 4.8 (4.6, 6.4)

Hazard ratio (95% CI) 0.65 (0.52, 0.81)p-value 0.0001

Time to relapse

Relapsed, n (%) 154 (64.7) 179 (76.5)

Median time to relapse, months (95% CI) 10.2 (8.3, 13.4) 4.9 (4.6, 6.4)

Time to discontinuation from treatment

Treatment discontinued, n (%) 193 (81.1) 208 (88.9)

Median time to treatment discontinuation, 11.4 (9.8, 13.6) 6.1 (5.1, 7.4)months (95% CI)

Treatment discontinued - disease relapse, n (%) 143 (60.1) 180 (76.9)

CI = Confidence interval.

Prespecified subgroup analyses of OS and RFS showed a consistent treatment effect for Onuregacross demographic and disease-related subgroups including baseline cytogenetic risk, the number ofprior consolidation cycles received, and CR/CRi status.

The Kaplan-Meier curves display the OS (see Figure 1) and RFS (see Figure 2) results.

Figure 1: Kaplan-Meier curve for overall survival: Onureg versus placebo (ITT

Population)1.0 Stratified HR: 0.69 (95% CI:0.55-0.86)

Stratified Log_rank p-value: 0.00090.90.80.70.6

Median OS: 24.70.5

Median OS: 14.80.40.30.20.10.0

Time (months) from randomisation

ONUREG

Placebo

Number at risk

ONUREG

Placebo

Figure 2: Kaplan-Meier curve for relapse free survival: Onureg versus placebo (ITT

Population)1.0

Stratified HR: 0.65 (95% CI:0.52-0.81)

Stratified Log_rank p-value: 0.00010.90.80.70.6

Median RFS: 10.20.5

Median RFS: 4.80.40.30.20.10.0

Time (months) from randomisation

ONUREG Placebo

Number at risk

ONUREG

Placebo

In patients who had their dose schedule extended to 300 mg for 21 days due to disease relapse, themedian OS (22.8 months for Onureg and 14.6 months for placebo) and median RFS (7.4 months for

Onureg and 4.6 months for placebo) were comparable to the overall study results.

Survival probability Survival probability

Onureg demonstrated a favorable treatment effect for OS compared with placebo in both minimalresidual disease (MRD)-positive and MRD-negative patients. The treatment effect for OS was morepronounced in MRD-positive patients (HR = 0.69; 95% CI: 0.51, 0.93) than in MRD-negative patients(HR = 0.81; 95% CI: 0.59, 1.12).

Health related quality of life (HRQoL)

HRQoL was assessed using the Functional assessment of chronic illness therapy-fatigue scale(FACIT - fatigue scale) and the Five dimensions three levels (EQ-5D-3L) health utility index andvisual analogue scale (VAS). At baseline, patients had a low level of fatigue and good level of HRQoLthat were generally comparable to those of the general population of similar age. This level of HRQoLwas maintained over time with Onureg, as compared to baseline, as well as to placebo. Both the timeto definitive deterioration and the proportion of patients experiencing clinically meaningfuldeterioration was found to be similar between those receiving Onureg and placebo. Overall, thefindings demonstrate that HRQoL was similar between Onureg treatment and placebo arms, with noclinically meaningful deterioration over time.

Exposure was generally linear with dose-proportional increases in systemic exposure; high intersubjectvariability was observed. The geometric mean (coefficient of variation [%CV]) Cmax and AUC valuesafter oral administration of a 300 mg single dose were 145.1 ng/mL (63.7) and 241.6 ng h/mL (64.5),respectively. Multiple dosing at the recommended dose regimen did not result in drug accumulation.

Absorption of azacitidine was rapid, with a median Tmax of 1 hour post dose. Mean oral bioavailabilityrelative to subcutaneous (SC) administration was approximately 11%.

The impact of food on the exposure of Onureg was minimal. Therefore, Onureg can be administeredwith or without food.

After oral administration, the geometric mean apparent volume of distribution was 12.6 L/kg for a70 kg person. The plasma protein binding of azacitidine was 6 to 12%.

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450isoenzymes (CYPs). Azacitidine undergoes spontaneous hydrolysis and deamination mediated bycytidine deaminase.

The geometric mean apparent clearance was 1242 L/hour and the geometric mean half-life wasapproximately 0.5 hours. Following intravenous administration of 14C azacitidine to 5 cancer patients,the cumulative urinary excretion was 85% of the radioactive dose. Faecal excretion accounted for <1%of administered radioactivity over 3 days. Mean excretion of radioactivity in urine followingsubcutaneous administration of 14C-azacitidine was 50%. The amount of unchanged azacitidinerecovered in urine relative to dose was < 2% following either subcutaneous (SC) or oraladministration. Faecal excretion has not been measured following oral administration.

The epigenetic regulatory effect of azacitidine on DNA global methylation reduction in the blood wassustained with prolonged exposure of 300 mg daily administered for 14 or 21 days of a 28-day cycle inmyeloid cancers including AML patients from a Phase 1/2 study. A positive correlation was observedbetween azacitidine plasma exposure and the pharmacodynamic effect of reduction in global DNAmethylation in blood.

In a population pharmacokinetics (PK) analysis from 286 AML patients, age (46 to 93 years) did nothave clinically meaningful effects on the PK of Onureg. Therefore, dose modification for Onureg isnot required, regardless of patient age.

No formal studies have been conducted in patients with hepatic impairment. Hepatic impairment isunlikely to affect the PK to a clinically relevant extent since azacitidine undergoes spontaneoushydrolysis and deamination mediated by cytidine deaminase. A population PK analysis determinedthat AST (8 to 155 U/L), ALT (5 to 185 U/L) and mild hepatic impairment (BIL ≤ ULN and

AST > ULN, or BIL 1 to 1.5 × ULN and any AST) did not have clinically meaningful effects on the

PK of azacitidine. The effects of moderate to severe hepatic impairment (BIL > 1.5 × ULN and any

AST) on the PK of azacitidine is unknown.

In patients with cancer, the PK of azacitidine in 6 patients with normal renal function(CLcr >80 mL/min) and 6 patients with severe renal impairment (CLcr <30 mL/min) were comparedfollowing daily subcutaneous dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal impairmentincreased azacitidine exposure by approximately 70% after single and 41% after multiplesubcutaneous administrations. This increase in exposure was not correlated with an increase in adverseevents.

A population PK analysis following a 300 mg dose of Onureg determined that patients with mild(CLcr: ≥ 60 to < 90 mL/min), moderate (CLcr: ≥ 30 to < 60 mL/min), and severe (CLcr: < 30 mL/min)renal impairment had 19%, 25%, and 38% increases in azacitidine plasma AUC, respectively. Theeffect of severe renal impairment on Onureg was similar to the above referenced clinical renalimpairment study with injectable azacitidine (~40% increase in AUC). The exposure of azacitidine(AUC) is approximately 75% lower after oral administration relative to the exposure achievedfollowing SC administration; therefore, an increase in exposure of approximately 40% following oraladministration is still considered safe and tolerable. Thus, no dose adjustment of Onureg isrecommended in patients with mild, moderate, or severe renal impairment.

The effects of race/ethnicity on the PK of Onureg is unknown.

In a 14-day oral toxicity study in dogs, mortality occurred at doses of 8 and 16 mg/m2/day. Themaximum tolerated dose (MTD) was 4 mg/m2/day. At 1 or all doses, pancytopenia correlated withbone marrow hypoplasia, lymphoid depletion, gland/lumen dilation and single cell necrosis in mucosalcrypts of small and large intestines and/or centrilobular hepatocellular vacuolation were observed. Atthe MTD, these findings were partially or completely resolved after 3 weeks. Following parenteralazacitidine administrations at comparable dose ranges, mortality and similar target organ toxicitieswere observed in rodents, dogs and monkeys. Non-clinical data from repeat-dose toxicity studies withazacitidine revealed no special hazard for humans.

Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammaliancell systems in vitro. The potential carcinogenicity of azacitidine was evaluated in mice and rats.

Azacitidine induced tumours of the haematopoietic system in female mice, when administeredintraperitoneally 3 times per week for 52 weeks. An increased incidence of tumours in thelymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidineadministered intraperitoneally for 50 weeks. A tumorigenicity study in rats revealed an increasedincidence of testicular tumours.

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death(increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis.

Developmental abnormalities in the brain have been detected in mice given azacitidine on or beforeclosure of the hard palate. In rats, azacitidine caused no adverse reactions when givenpre-implantation, but it was clearly embryotoxic when given during organogenesis. Foetalabnormalities during organogenesis in rats included: Central nervous system (CNS) anomalies(exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) andothers (microphthalmia, micrognathia, gastroschisis, oedema, and rib abnormalities).

Administration of azacitidine to male mice prior to mating with untreated female mice resulted indecreased fertility and loss of offspring during subsequent embryonic and postnatal development.

Treatment of male rats resulted in decreased weight of the testes and epididymides, decreased spermcounts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos inmated females (see section 4.6).

Tablet content

Croscarmellose sodium (E468)

Magnesium stearate (E572)

Mannitol (E421)

Silicified microcrystalline cellulose (E460, E551)

Onureg 200 mg tablet coating

Opadry II pink containing:

Hypromellose (E464)

Titanium dioxide (E171)

Lactose monohydrate

Polyethylene glycol/macrogols (E1521)

Triacetin (E1518)

Iron oxide red (E172)

Onureg 300 mg tablet coating

Opadry II brown containing:

Hypromellose (E464)

Titanium dioxide (E171)

Lactose monohydrate

Polyethylene glycol/macrogols (E1521)

Triacetin (E1518)

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

The film-coated tablets are packaged in nylon (OPA)/polyvinyl chloride (PVC) aluminium blisterswith push through aluminium foil.

Pack size of 7 or 14 film-coated tablets.

Not all pack sizes may be marketed.

Onureg is a cytotoxic medicinal product. If powder from the film-coated tablets makes contact withthe skin, the skin should be washed immediately and thoroughly with soap and water. If the powdercomes in contact with mucous membranes, the area should be thoroughly flushed with water.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

Onureg 200 mg film-coated tablets

EU/1/21/1556/001

EU/1/21/1556/002

Onureg 300 mg film-coated tablets

EU/1/21/1556/003

EU/1/21/1556/004

Date of first authorisation: 17 June 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.