AZACITIDINE BETAPHARM 25mg / ml powder for injection suspension medication leaflet

Azacitidine betapharm 25 mg/mL powder for suspension for injection

Each vial of powder contains 100 mg azacitidine.

After reconstitution, each mL of suspension contains 25 mg azacitidine.

For the full list of excipients, see section 6.1.

Powder for suspension for injection.

White to off-white lyophilised powder.

Azacitidine betapharm is indicated for the treatment of adult patients who are not eligible forhaematopoietic stem cell transplantation (HSCT) with:

* intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International

Prognostic Scoring System (IPSS),

* chronic myelomonocytic leukaemia (CMML) with 10 % to 29 % marrow blasts withoutmyeloproliferative disorder,

* acute myeloid leukaemia (AML) with 20 % to 30 % blasts and multi-lineage dysplasia,according to World Health Organization (WHO) classification,

* AML with > 30 % marrow blasts according to the WHO classification.

Azacitidine betapharm treatment should be initiated and monitored under the supervision of aphysician experienced in the use of chemotherapeutic agents. Patients should be premedicated withanti-emetics for nausea and vomiting.

The recommended starting dose for the first treatment cycle, for all patients regardless of baselinehaematology laboratory values, is 75 mg/m2 of body surface area, injected subcutaneously, daily for7 days, followed by a rest period of 21 days (28-day treatment cycle).

It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continuedfor as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematologic response/toxicity and renal toxicities (see section 4.4);a delay in starting the next cycle or a dose reduction as described below may be necessary.

Azacitidine betapharm should not be used interchangeably with oral azacitidine. Due to differences inthe exposure, the dose and schedule recommendations for oral azacitidine are different from those forinjectable azacitidine. Healthcare professionals are recommended to verify the name of the medicinalproduct, dose and administration route.

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation oftherapy and prior to each treatment cycle. Complete blood counts should be performed prior toinitiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to eachtreatment cycle.

Haematological toxicity is defined as the lowest count reached (nadir) in a given cycle ifplatelets ≤ 50.0 × 109/L and/or absolute neutrophil count (ANC) ≤ 1 × 109/L.

Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of atleast half of the absolute difference of nadir and the baseline count plus the nadir count (i.e. bloodcount at recovery ≥ nadir count + (0.5 × [|baseline count - nadir count|]).

Patients without reduced baseline blood counts (i.e. White Blood Cells (WBC) ≥ 3.0 × 109/L and

ANC ≥ 1.5 × 109/L, and platelets ≥ 75.0 × 109/L) prior to the first treatment

If haematological toxicity is observed following Azacitidine betapharm treatment, the next cycle of thetherapy should be delayed until the platelet count and the ANC have recovered. If recovery is achievedwithin 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within14 days, the dose should be reduced according to the following table. Following dose modifications,the cycle duration should return to 28 days.

Cycle Nadir count Dose in the next cycle, if recovery* is not

ANC (× 109/L) Platelets (× 109/L) achieved within 14 days (%)≤ 1.0 ≤ 50.0 50 %> 1.0 > 50.0 100 %

*Recovery = counts ≥ nadir count + (0.5 × [baseline count - nadir count])

Patients with reduced baseline blood counts (i.e. WBC < 3.0 × 109/L or ANC < 1.5 × 109/L orplatelets < 75.0 × 109/L) prior to the first treatment

Following Azacitidine betapharm treatment, if the decrease in WBC or ANC or platelets from thatprior to treatment is ≤ 50 %, or greater than 50 % but with an improvement in any cell linedifferentiation, the next cycle should not be delayed and no dose adjustment made.

If the decrease in WBC or ANC or platelets is greater than 50 % from that prior to treatment, with noimprovement in cell line differentiation, the next cycle of Azacitidine betapharm therapy should bedelayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days,no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, bonemarrow cellularity should be determined. If the bone marrow cellularity is > 50 %, no doseadjustments should be made. If bone marrow cellularity is ≤ 50 %, treatment should be delayed and thedose reduced according to the following table:

Bone marrow cellularity Dose in the next cycle if recovery is not achieved within 14 days (%)

Recovery* ≤ 21 days Recovery* > 21 days15-50 % 100 % 50 %< 15 % 100 % 33 %

*Recovery = counts ≥ nadir count + (0.5 × [baseline count - nadir count])

Following dose modifications, the next cycle duration should return to 28 days.

No specific dose adjustments are recommended for the elderly. Because elderly patients are morelikely to have decreased renal function, it may be useful to monitor renal function.

Azacitidine can be administered to patients with renal impairment without initial dose adjustment (seesection 5.2). If unexplained reductions in serum bicarbonate levels to less than 20 mmol/L occur, thedose should be reduced by 50 % on the next cycle. If unexplained elevations in serum creatinine orblood urea nitrogen (BUN) to ≥ 2-fold above baseline values and above upper limit of normal (ULN)occur, the next cycle should be delayed until values return to normal or baseline and the dose shouldbe reduced by 50 % on the next treatment cycle (see section 4.4).

No formal studies have been conducted in patients with hepatic impairment (see section 4.4). Patientswith severe hepatic organ impairment should be carefully monitored for adverse events. No specificmodification to the starting dose is recommended for patients with hepatic impairment prior to startingtreatment; subsequent dose modifications should be based on haematology laboratory values.

Azacitidine betapharm is contraindicated in patients with advanced malignant hepatic tumours (seesections 4.3 and 4.4).

The safety and efficacy of Azacitidine betapharm in children aged 0 to 17 years have not yet beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

Azacitidine betapharm is for subcutaneous use. Reconstituted Azacitidine betapharm should beinjected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated. Newinjections should be given at least 2.5 cm from the previous site and never into areas where the site istender, bruised, red, or hardened.

After reconstitution, the suspension should not be filtered. For instructions on reconstitution of themedicinal product before administration, see section 6.6.

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

Advanced malignant hepatic tumours (see section 4.4).

Breast-feeding (see section 4.6).

Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularlyduring the first 2 cycles (see section 4.8). Complete blood counts should be performed as needed tomonitor response and toxicity, but at least prior to each treatment cycle. After administration of therecommended dose for the first cycle, the dose for subsequent cycles should be reduced or itsadministration delayed based on nadir counts and haematological response (see section 4.2). Patientsshould be advised to promptly report febrile episodes. Patients and physicians are also advised to beobservant for signs and symptoms of bleeding.

No formal studies have been conducted in patients with hepatic impairment. Patients with extensivetumour burden due to metastatic disease have been reported to experience progressive hepatic comaand death during azacitidine treatment, especially in such patients with baseline serum albumin< 30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumours (seesection 4.3).

Renal abnormalities ranging from elevated serum creatinine to renal failure and death were reported inpatients treated with intravenous azacitidine in combination with other chemotherapeutic agents. Inaddition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mmol/L in associationwith an alkaline urine and hypokalaemia (serum potassium < 3 mmol/L) developed in 5 subjects withchronic myelogenous leukaemia (CML) treated with azacitidine and etoposide. If unexplainedreductions in serum bicarbonate (< 20 mmol/L) or elevations of serum creatinine or BUN occur, thedose should be reduced or administration delayed (see section 4.2).

Patients should be advised to report oliguria and anuria to the health care provider immediately.

Although no clinically relevant differences in the frequency of adverse reactions were noted betweensubjects with normal renal function compared to those with renal impairment, patients with renalimpairment should be closely monitored for toxicity since azacitidine and/or its metabolites areprimarily excreted by the kidney (see section 4.2).

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation oftherapy and prior to each treatment cycle. Complete blood counts should be performed prior toinitiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to eachtreatment cycle, see also section 4.8.

Patients with a history of severe congestive heart failure, clinically unstable cardiac disease orpulmonary disease were excluded from the pivotal registration studies (AZA PH GL 2003 CL 001 and

AZA-AML-001) and therefore the safety and efficacy of azacitidine in these patients has not beenestablished. Recent data from a clinical trial in patients with a known history of cardiovascular orpulmonary disease showed a significantly increased incidence of cardiac events with azacitidine (seesection 4.8). It is therefore advised to exercise caution when prescribing azacitidine to these patients.

Cardiopulmonary assessment before and during the treatment should be considered.

Necrotising fasciitis, including fatal cases, have been reported in patients treated with azacitidine.

Azacitidine therapy should be discontinued in patients who develop necrotising fasciitis andappropriate treatment should be promptly initiated.

The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment.

These patients should be monitored closely and appropriate precautions taken.

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported inpatients receiving injectable azacitidine. Differentiation syndrome may be fatal and symptoms andclinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema,peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renaldysfunction (see section 4.8). Treatment with high-dose IV corticosteroids and haemodynamicmonitoring should be considered at first onset of symptoms or signs suggestive of differentiationsyndrome. Temporary discontinuation of injectable azacitidine should be considered until resolution ofsymptoms and if resumed, caution is advised.

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), andglutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo aretherefore considered unlikely.

Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes areunlikely (see section 5.2).

No interaction studies have been performed.

Women of childbearing potential have to use effective contraception during and for at least 6 monthsafter treatment. Men should be advised not to father a child while receiving treatment and must useeffective contraception during and for at least 3 months after treatment.

There are no adequate data from the use of azacitidine in pregnant women. Studies in mice haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Based onresults from animal studies and its mechanism of action, azacitidine should not be used duringpregnancy, especially during the first trimester, unless clearly necessary. The advantages of treatmentshould be weighed against the possible risk for the foetus in every individual case.

It is unknown whether azacitidine/metabolites are excreted in human milk. Due to the potential seriousadverse reactions in the nursing child, breast-feeding is contraindicated during azacitidine therapy.

There are no human data on the effect of azacitidine on fertility. In animals, adverse reactions withazacitidine use on male fertility have been documented (see section 5.3). Before starting treatment,male patients should be advised to seek counselling on sperm storage.

Azacitidine has minor or moderate influence on the ability to drive and use machines. Fatigue has beenreported with the use of azacitidine. Therefore, caution is recommended when driving or operatingmachines.

Adult population with MDS, CMML and AML (20 % to 30 % marrow blasts)

Adverse reactions considered to be possibly or probably related to the administration of azacitidinehave occurred in 97% of patients.

The most common serious adverse reactions noted from the pivotal study (AZA PH GL 2003 CL 001)included febrile neutropenia (8.0 %) and anaemia (2.3 %), which were also reported in the supportingstudies (CALGB 9221 and CALGB 8921). Other serious adverse reactions from these 3 studiesincluded infections such as neutropenic sepsis (0.8 %) and pneumonia (2.5 %) (some with fataloutcome), thrombocytopenia (3.5 %), hypersensitivity reactions (0.25 %) and haemorrhagic events(e.g. cerebral haemorrhage [0.5 %], gastrointestinal haemorrhage [0.8 %] and intracranial haemorrhage[0.5 %]).

The most commonly reported adverse reactions with azacitidine treatment were haematologicalreactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3 to 4),gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 1 to 2) or injection sitereactions (77.1 %; usually Grade 1 to 2).

Adult population aged 65 years or older with AML with > 30 % marrow blasts

The most common serious adverse reactions (≥ 10 %) noted from AZA-AML-001 within theazacitidine treatment arm included febrile neutropenia (25.0 %), pneumonia (20.3 %), and pyrexia(10.6 %). Other less frequently reported serious adverse reactions in the azacitidine treatment armincluded sepsis (5.1 %), anaemia (4.2 %), neutropenic sepsis (3.0 %), urinary tract infection (3.0 %),thrombocytopenia (2.5 %), neutropenia (2.1 %), cellulitis (2.1 %), dizziness (2.1 %) and dyspnoea(2.1 %).

The most commonly reported (≥ 30 %) adverse reactions with azacitidine treatment weregastrointestinal events, including constipation (41.9 %), nausea (39.8 %), and diarrhoea (36.9 %;usually Grade 1 to 2), general disorders and administration site conditions including pyrexia (37.7 %;usually Grade 1 to 2) and haematological events, including febrile neutropenia (32.2 %) andneutropenia (30.1 %; usually Grade 3-4).

Table 1 below contains adverse reactions associated with azacitidine treatment obtained from the mainclinical studies in MDS and AML and post marketing surveillance.

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 in any of the main clinical studies.

Table 1: Adverse reactions reported in patients with MDS or AML treated with azacitidine(clinical studies and post- marketing)

System organ Very common Common Uncommon Rare Not knownclass

Infections and pneumonia* sepsis* (including necrotisinginfestations (including bacterial, bacterial, viral and fasciitis *viral and fungal), fungal), neutropenicnasopharyngitis sepsis*, respiratorytract infection(includes upper andbronchitis), urinarytract infection,cellulitis,diverticulitis, oralfungal infection,sinusitis,pharyngitis, rhinitis,herpes simplex, skininfection

Neoplasms Differ-benign, malignant entiation-and unspecified syndrome*,a(including cystsand polyps)

Blood and febrile pancytopenia*, bonelymphatic system neutropenia*, marrow failuredisorders neutropenia,leukopenia,thrombocytopenia,anaemia

Immune system hypersensitivitydisorders reactions

System organ Very common Common Uncommon Rare Not knownclass

Metabolism and anorexia, decreased dehydration tumournutrition appetite, lysisdisorders hypokalemia syndrome

Psychiatric insomnia confusional state,disorders anxiety

Nervous system dizziness, headache intracranialdisorders haemorrhage*,syncope,somnolence,lethargy

Eye disorders eye haemorrhage,conjunctivalhaemorrhage

Cardiac disorders pericardial effusion pericarditis

Vascular hypotension*,disorders hypertension,orthostatichypotension,haematoma

Respiratory, dyspnoea, epistaxis pleural effusion, interstitialthoracic and dyspnoea exertional, lung diseasemediastinal pharyngolaryngealdisorders pain

Gastrointestinal diarrhoea, vomiting, gastrointestinaldisorders constipation, nausea, haemorrhage*abdominal pain (includes mouth(includes upper and haemorrhage),abdominal haemorrhoidaldiscomfort) haemorrhage,stomatitis, gingivalbleeding, dyspepsia

Hepatobiliary hepatic failure*,disorders progressivehepatic coma

Skin and petechiae, pruritus purpura, alopecia, acute febrile cutaneoussubcutaneous (includes urticaria, erythema, neutrophilic vasculitistissue disorders generalised), rash, rash macular dermatosis,ecchymosis pyodermagangrenosum

Musculoskeletal arthralgia, muscle spasms,and connective musculoskeletal myalgiatissue disorders pain (includes back ,bone and pain inextremity)

Renal and renal failure*, renal tubularurinary disorders haematuria, acidosiselevated serumcreatinine

General disorders pyrexia*, fatigue, bruising, injectionand asthenia, chest pain, haematoma, site necrosisadministration injection site induration, rash,site conditions erythema, injection pruritus,site pain, injection inflammation,site reaction discoloration,(unspecified) nodule and

System organ Very common Common Uncommon Rare Not knownclasshaemorrhage (atinjection site),malaise, chills,catheter sitehaemorrhage

Investigations weight decreased

* = rarely fatal cases have been reporteda = see section 4.4

The most commonly reported (≥ 10 %) haematological adverse reactions associated with azacitidinetreatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, andwere usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles,after which they occur with less frequency in patients with restoration of haematological function.

Most haematological adverse reactions were managed by routine monitoring of complete blood countsand delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factorsupport (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required.

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adversereactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patientsreceiving azacitidine, some with a fatal outcome. Infections may be managed with the use of anti-infectives plus growth factor support (e.g. G-CSF) for neutropenia.

Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such asgastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should bemonitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.

Serious hypersensitivity reactions have been reported in patients receiving azacitidine. In case of ananaphylactic-like reaction, treatment with azacitidine should be immediately discontinued andappropriate symptomatic treatment initiated.

The majority of skin and subcutaneous adverse reactions were associated with the injection site. Noneof these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in thepivotal studies. The majority of adverse reactions occurred during the first 2 cycles of treatment andtended to decrease with subsequent cycles. Subcutaneous adverse reactions such as injection siterash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitantmedicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatorymedicinal products (NSAIDs). These cutaneous reactions have to be distinguished from soft tissueinfections, sometimes occurring at injection site. Soft tissue infections, including cellulitis andnecrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the postmarketing setting. For clinical management of infectious adverse reactions, see section 4.8 infections.

The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatmentincluded constipation, diarrhoea, nausea and vomiting. These adverse reactions were managedsymptomatically with anti-emetics for nausea and vomiting; anti-diarrhoeals for diarrhoea, andlaxatives and/or stool softeners for constipation.

Renal abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis,renal failure and death were reported in patients treated with azacitidine (see section 4.4).

Patients with extensive tumour burden due to metastatic disease have been reported to experiencehepatic failure, progressive hepatic coma and death during azacitidine treatment (see section 4.4).

Data from a clinical trial allowing enrolment of patients with known history of cardiovascular orpulmonary disease showed an increase in cardiac events in patients with newly diagnosed AMLtreated with azacitidine (see section 4.4).

There is limited safety information available with azacitidine in patients ≥ 85 years (with 14 [5.9 %]patients ≥ 85 years treated in study AZA-AML-001).

In Study AZA-JMML-001, 28 paediatric patients (1 month to less than 18 years of age) were treatedwith azacitidine for MDS (n = 10) or juvenile myelomonocytic leukaemia (JMML) (n = 18) (seesection 5.1).

All 28 patients experienced at least 1 adverse event and 17 (60.7%) experienced at least 1 treatment-related event. The most commonly reported adverse events in the overall paediatric population werepyrexia, haematologic events including anaemia, thrombocytopenia and febrile neutropenia, andgastrointestinal events including constipation and vomiting.

Three (3) subjects experienced a treatment emergent event leading to drug discontinuation (pyrexia,disease progression and abdominal pain).

In Study AZA-AML-004, 7 paediatric patients (aged 2 to 12 years) were treated with azacitidine for

AML in molecular relapse after first complete remission [CR1] (see section 5.1).

All 7 patients experienced at least 1 treatment-related adverse event. The most commonly reportedadverse events were neutropenia, nausea, leukopenia, thrombocytopenia, diarrhoea and increasedalanine aminotransferase (ALT). Two patients experienced a treatment-related event leading to doseinterruption (febrile neutropenia, neutropenia).

No new safety signals were identified in the limited number of paediatric patients treated withazacitidine during the course of the clinical study. The overall safety profile was consistent with that ofthe adult population.

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.

One case of overdose with azacitidine was reported during clinical trials. A patient experienceddiarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2,almost 4 times the recommended starting dose.

In the event of overdose, the patient should be monitored with appropriate blood counts and shouldreceive supportive treatment, as necessary. There is no known specific antidote for azacitidineoverdose.

Pharmacotherapeutic group: Antineoplastic agents, pyrimidine analogues; ATC code: L01BC07

Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms includingcytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. Thecytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA,

RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damagepathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidineinto DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA.

DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation,differentiation and death pathways may result in gene re-expression and restoration of cancer-suppressing functions to cancer cells. The relative importance of DNA hypomethylation versuscytotoxicity or other activities of azacitidine to clinical outcomes has not been established.

Adult population (MDS, CMML and AML [20 % to 30 % marrow blasts])

The efficacy and safety of Azacitidine were studied in an international, multicentre, controlled, open-label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in adultpatients with: intermediate-2 and high-risk MDS according to the International Prognostic Scoring

System (IPSS), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blastsin transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) accordingto the French American British (FAB) classification system. RAEB-T patients (21 % to 30 % blasts)are now considered to be AML patients under the current WHO classification system. Azacitidine plusbest supportive care (BSC) (n = 179) was compared to conventional care regimens (CCR). CCRconsisted of BSC alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard inductionchemotherapy plus BSC (n = 25). Patients were pre-selected by their physician to 1 of the 3 CCR priorto randomisation. Patients received this pre-selected regimen if not randomised to Azacitidine. As partof the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group(ECOG) performance status of 0 to 2. Patients with secondary MDS were excluded from the study.

The primary endpoint of the study was overall survival. Azacitidine was administered at asubcutaneous dose of 75 mg/m2 daily for 7 days, followed by a rest period of 21 days (28-daytreatment cycle) for a median of 9 cycles (range = 1 to 39) and a mean of 10.2 cycles. Within the

Intent to Treat population (ITT), the median age was 69 years (range 38 to 88 years).

In the ITT analysis of 358 patients (179 azacitidine and 179 CCR), Azacitidine treatment wasassociated with a median survival of 24.46 months versus 15.02 months for those receiving CCRtreatment, a difference of 9.4 months, with a stratified log-rank p-value of 0.0001. The hazard ratio(HR) for the treatment effect was 0.58 (95 % CI: 0.43, 0.77). The two-year survival rates were 50.8 %in patients receiving azacitidine versus 26.2 % in patients receiving CCR (p < 0.0001).

KEY: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = hazardratio

The survival benefits of Azacitidine were consistent regardless of the CCR treatment option (BSCalone, low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in thecontrol arm.

When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survivalwere observed in all groups (good, intermediate, poor cytogenetics, including monosomy 7).

On analyses of age subgroups, an increase in median overall survival was observed for all groups(< 65 years, ≥ 65 years and ≥ 75 years).

Azacitidine treatment was associated with a median time to death or transformation to AML of13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 monthswith a stratified log-rank p-value of 0.0025.

Azacitidine treatment was also associated with a reduction in cytopenias, and their related symptoms.

Azacitidine treatment led to a reduced need for red blood cell (RBC) and platelet transfusions. Of thepatients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0 % of thesepatients became RBC transfusion independent during the treatment period, compared with 11.4 % ofthe patients in the combined CCR groups (a statistically significant (p < 0.0001) difference of 33.6 %(95 % CI: 22.4, 44.6). In patients who were RBC transfusion dependent at baseline and becameindependent, the median duration of RBC transfusion independence was 13 months in the azacitidinegroup.

Response was assessed by the investigator or by the Independent Review Committee (IRC). Overallresponse (complete remission [CR] + partial remission [PR]) as determined by the investigator was29 % in the azacitidine group and 12 % in the combined CCR group (p = 0.0001). Overall response(CR + PR) as determined by the IRC in AZA PH GL 2003 CL 001 was 7 % (12/179) in the azacitidinegroup compared with 1 % (2/179) in the combined CCR group (p = 0.0113). The differences betweenthe IRC and investigator assessments of response were a consequence of the International Working

Group (IWG) criteria requiring improvement in peripheral blood counts and maintenance of theseimprovements for a minimum of 56 days. A survival benefit was also demonstrated in patients that hadnot achieved a complete/partial response following azacitidine treatment. Haematologicalimprovement (major or minor) as determined by the IRC was achieved in 49 % of patients receivingazacitidine compared with 29 % of patients treated with combined CCR (p < 0.0001).

In patients with one or more cytogenetic abnormalities at baseline, the percentage of patients with amajor cytogenetic response was similar in the azacitidine and combined CCR groups. Minorcytogenetic response was statistically significantly (p = 0.0015) higher in the azacitidine group (34 %)compared with the combined CCR group (10 %).

Adult population aged 65 years or older with AML with > 30 % marrow blasts

The results presented below represent the intent-to-treat population studied in AZA-AML-001 (seesection 4.1 for the approved indication).

The efficacy and safety of azacitidine was studied in an international, multicentre, controlled, open-label, parallel group Phase 3 study in patients 65 years and older with newly diagnosed de novo orsecondary AML with > 30 % bone marrow blasts according to the WHO classification, who were noteligible for HSCT. Azacitidine plus BSC (n = 241) was compared to CCR. CCR consisted of BSCalone (n = 45), low- dose cytarabine plus BSC (n = 158), or standard intensive chemotherapy withcytarabine and anthracycline plus BSC (n = 44). Patients were pre-selected by their physician to 1 ofthe 3 CCRs prior to randomisation. Patients received the pre-selected regimen if not randomised toazacitidine. As part of the inclusion criteria, patients were required to have an ECOG performancestatus of 0 to 2 and intermediate- or poor-risk cytogenetic abnormalities. The primary endpoint of thestudy was overall survival.

Azacitidine was administered at a SC dose of 75 mg/m2/day for 7 days, followed by a rest period of21 days (28 day treatment cycle), for a median of 6 cycles (range: 1 to 28), BSC- only patients for amedian of 3 cycles (range: 1 to 20), low-dose cytarabine patients for a median of 4 cycles (range 1 to25) and standard intensive chemotherapy patients for a median of 2 cycles (range: 1 to 3, inductioncycle plus 1 or 2 consolidation cycles).

The individual baseline parameters were comparable between the azacitidine and CCR groups. Themedian age of the subjects was 75.0 years (range: 64 to 91 years), 75.2 % were Caucasian and 59.0 %were male. At baseline 60.7 % were classified as AML not otherwise specified, 32.4 % AML withmyelodysplasia-related changes, 4.1 % therapy-related myeloid neoplasms and 2.9 % AML withrecurrent genetic abnormalities according to the WHO classification.

In the ITT analysis of 488 patients (241 azacitidine and 247 CCR), azacitidine treatment wasassociated with a median survival of 10.4 months versus 6.5 months for those receiving CCRtreatment, a difference of 3.8 months, with a stratified log-rank p-value of 0.1009 (two- sided). Thehazard ratio for the treatment effect was 0.85 (95 % CI= 0.69, 1.03). The one-year survival rates were46.5 % in patients receiving azacitidine versus 34.3 % in patients receiving CCR.

The Cox PH model adjusted for pre-specified baseline prognostic factors defined a HR for azacitidineversus CCR of 0.80 (95 % CI= 0.66, 0.99; p = 0.0355).

In addition, although the study was not powered to demonstrate a statistically significant differencewhen comparing azacitidine to the preselection CCR treatment groups, the survival of azacitidinetreated patients was longer when compared to CCR treatment options BSC alone, low-dose cytarabineplus BSC and were similar when compared to standard intensive chemotherapy plus BSC.

In all pre- specified subgroups age [(< 75 years & ≥ 75 years), gender, race, ECOG performance status(0 or 1 & 2) , baseline cytogenetic risk (intermediate & poor) , geographic region, WHO classificationof AML (including AML with myelodysplasia-related changes), baseline WBC count (≤ 5 × 109/L& > 5 × 109/L), baseline bone marrow blasts (≤ 50 % & > 50 %) and prior history of MDS] there was atrend in OS benefit in favour of azacitidine. In a few pre-specified subgroups, the OS HR reachedstatistical significance including patients with poor cytogenetic risk, patients with AML withmyelodysplasia-related changes, patients < 75 years, female patients and white patients.

Haematologic and cytogenetic responses were assessed by the investigator and by the IRC with similarresults. Overall response rate (complete remission [CR] + complete remission with incomplete bloodcount recovery [CRi]) as determined by the IRC was 27.8 % in the azacitidine group and 25.1 % in thecombined CCR group (p = 0.5384). In patients who achieved CR or CRi, the median duration ofremission was 10.4 months (95 % CI = 7.2, 15.2) for the azacitidine subjects and 12.3 months (95 %

CI = 9.0, 17.0) for the CCR subjects. A survival benefit was also demonstrated in patients that had notachieved a complete response for azacitidine compared to CCR.

Azacitidine treatment improved peripheral blood counts and led to a reduced need for RBC andplatelet transfusions. A patient was considered RBC or platelet transfusion dependent at baseline if thesubject had one or more RBC or platelet transfusions during the 56 days (8 weeks) on or prior torandomisation, respectively. A patient was considered RBC or platelet transfusion independent duringthe treatment period if the subject had no RBC or platelet transfusions during any consecutive 56 daysduring the reporting period, respectively.

Of the patients in the azacitidine group who were RBC transfusion dependent at baseline, 38.5 %(95 % CI = 31.1, 46.2) of these patients became RBC transfusion independent during the treatmentperiod, compared with 27.6 % of (95 % CI = 20.9, 35.1) patients in the combined CCR groups. Inpatients who were RBC transfusion dependent at baseline and achieved transfusion independence ontreatment, the median duration of RBC transfusion independence was 13.9 months in the azacitidinegroup and was not reached in the CCR group.

Of the patients in the azacitidine group who were platelet transfusion dependent at baseline, 40.6 %(95 % CI = 30.9, 50.8) of these patients became platelet transfusion independent during the treatmentperiod, compared with 29.3 % of (95 % CI = 19.7, 40.4) patients in the combined CCR groups. Inpatients who were platelet transfusion dependent at baseline and achieved transfusion independence ontreatment, the median duration of platelet transfusion independence was 10.8 months in the azacitidinegroup and 19.2 months in the CCR group.

Health-Related Quality of Life (HRQoL) was assessed using the European Organisation for Researchand Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). HRQoL data couldbe analysed for a subset of the full trial population. While there are limitations in the analysis, theavailable data suggest that patients do not experience meaningful deterioration in quality of life duringtreatment with azacitidine.

Study AZA-JMML-001 was a Phase 2, international, multicentre, open-label study to evaluate thepharmacokinetics, pharmacodynamics, safety and activity of azacitidine prior to HSCT in paediatricpatients with newly diagnosed advanced MDS or JMML. The primary objective of the clinical studywas to evaluate the effect of azacitidine betapharm on response rate at Cycle 3, Day 28.

Patients (MDS, n = 10; JMML, n = 18, 3 months to 15 years; 71% male) were treated with intravenousazacitidine 75 mg/m², daily on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and amaximum of 6 cycles.

Enrolment in the MDS study arm was stopped after 10 MDS patients due to a lack of efficacy: noconfirmed responses were recorded in these 10 patients.

In the JMML study arm, 18 patients (13 PTPN11, 3 NRAS, 1 KRAS somatic mutations and 1 clinicaldiagnosis of neurofibromatosis type 1 [NF-1]) were enrolled. Sixteen patients completed 3 cycles oftherapy and 5 of them completed 6 cycles. A total of 11 JMML patients had a clinical response at

Cycle 3, Day 28, of these 11 subjects, 9 (50%) subjects had a confirmed clinical response (3 subjectswith cCR and 6 subjects with cPR). Among the cohort of JMML patients treated with azacitidine, 7(43.8%) patients had a sustained platelet response (counts ≥ 100 × 109/L) and 7 (43.8%) patientsrequired transfusions at HSCT. 17 of 18 patients proceeded to HSCT.

Because of the study design (small patient numbers and various confounding factors), it cannot beconcluded from this clinical study whether azacitidine prior to HSCT improves survival outcome in

JMML patients.

Study AZA-AML-004 was a Phase 2, multicentre, open-label study to evaluate the safety,pharmacodynamics and efficacy of azacitidine compared to no anti-cancer treatment in children andyoung adults with AML in molecular relapse after CR1.

Seven patients (median age 6.7 years [range 2 to 12 years]; 71.4% male) were treated with intravenousazacitidine 100 mg/m2, daily on Days 1 to 7 of each 28-day cycle for a maximum of 3 cycles.

Five patients had minimal residual disease (MRD) assessment at Day 84 with 4 patients achievingeither molecular stabilization (n = 3) or molecular improvement (n = 1) and 1 patient had clinicalrelapse. Six of 7 patients (90% [95% CI = 0.4, 1.0]) treated with azacitidine underwent HSCT.

Due to the small sample size, the efficacy of azacitidine in paediatric AML cannot be established.

See section 4.8 for safety information.

Following subcutaneous administration of a single 75 mg/m2 dose, azacitidine was rapidly absorbedwith peak plasma concentrations of 750 ng/mL ± 403 ng/mL occurring at 0.5 h after dosing (the firstsampling point). The absolute bioavailability of azacitidine after subcutaneous relative to intravenousadministration (single 75 mg/m2 doses) was approximately 89 % based on the area under the curve(AUC).

Area under the curve and maximum plasma concentration (Cmax) of subcutaneous administration ofazacitidine were approximately proportional within the 25 to 100 mg/m2 dose range.

Following intravenous administration, the mean volume of distribution was 76 L ± 26 L, and systemicclearance was 147 L/h ± 47 L/h.

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), andglutathione transferases (GSTs).

Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Inhuman liver S9 fractions, formation of metabolites was independent of NADPH implying thatazacitidine metabolism was not mediated by cytochrome P450 isoenzymes. An in vitro study ofazacitidine with cultured human hepatocytes indicates that at concentrations of 1.0 µM to 100 µM (i.e.

up to approximately 30-fold higher than clinically achievable concentrations), azacitidine does notinduce CYP 1A2, 2C19, or 3A4 or 3A5. In studies to assess inhibition of a series of P450 isoenzymes(CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) azacitidine up to 100 μM did not produceinhibition. Therefore, CYP enzyme induction or inhibition by azacitidine at clinically achievableplasma concentrations is unlikely.

Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) after subcutaneousadministration of 41 ± 8 minutes. No accumulation occurs after subcutaneous administration of75 mg/m2 azacitidine once daily for 7 days. Urinary excretion is the primary route of elimination ofazacitidine and/or its metabolites. Following intravenous and subcutaneous administration of 14C-azacitidine, 85 and 50 % of the administered radioactivity was recovered in urine respectively,while < 1 % was recovered in faeces.

The effects of hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics ofazacitidine have not been formally studied.

In Study AZA-JMML-001, pharmacokinetic analysis was determined from 10 MDS and 18 JMMLpaediatric patients on Day 7 of Cycle 1 (see section 5.1). The median age (range) of the MDS patientswas 13.3 (1.9-15) years and 2.1 (0.2-6.9) years for JMML patients.

Following intravenous administration of a 75 mg/m2 dose, azacitidine rapidly reached Cmax within0.083 hours in both MDS and JMML populations. The geometric mean Cmax were 1797.5 and1066.3 ng/mL, and the geometric mean AUC0-∞ were 606.9 and 240.2 ng∙h/mL, for MDS and JMMLpatients, respectively. The geometric mean volume of distribution in MDS and JMML subjects were103.9 and 61.1 L, respectively. It appeared that the total plasma exposure of azacitidine was higher in

MDS subjects; however, moderate to high between-patient variability was noted for both AUC and

Cmax.

The geometric mean t½ were 0.4 and 0.3 hours, and the geometric mean clearances were 166.4 and148.3 L/h for MDS and JMML, respectively.

Pharmacokinetic data from Study AZA-JMML-001 were pooled together and compared topharmacokinetic data from 6 adult subjects with MDS administered 75 mg/m2 azacitidineintravenously in Study AZA-2002-BA-002. Mean Cmax and AUC0-t of azacitidine were similar betweenadult patients and paediatric patients after intravenous administration (2750 ng/mL versus 2841 ng/mLand 1025 ng∙h/mL versus 882.1 ng∙h/mL, respectively).

In Study AZA-AML-004, pharmacokinetic analysis was determined from 6 of the 7 paediatricpatients, which had at least one measurable postdose pharmacokinetic concentration (see section 5.1).

The median age (range) of the AML patients was 6.7 (2-12) years.

Following multiple doses of 100 mg/m2, the geometric means for Cmax and AUC0-tau on Cycle 1 Day 7were 1557 ng/mL and 899.6 ng∙h/mL, respectively, with high inter-subject variability (CV% of201.6% and 87.8%, respectively) observed. Azacitidine rapidly reached Cmax, with a median time of0.090 hours post-intravenous administration and declined with a geometric mean t1/2 of 0.380 hours.

The geometric means for clearance and volume of distribution were 127.2 L/h and 70.2 L,respectively.

Pharmacokinetic (azacitidine) exposure observed in children with AML at molecular relapse after CR1was comparable to exposure from pooled data of 10 children with MDS and 18 children with JMMLand also comparable to azacitidine exposure in adults with MDS.

Renal impairment has no major effect on the pharmacokinetic exposure of azacitidine after single andmultiple subcutaneous administrations. Following subcutaneous administration of a single 75 mg/m2dose, mean exposure values (AUC and Cmax) from subjects with mild, moderate and severe renalimpairment were increased by 11 % to 21 %, 15 % to 27 %, and 41 % to 66 %, respectively, comparedto normal renal function subjects. However, exposure was within the same general range of exposuresobserved for subjects with normal renal function. Azacitidine can be administered to patients withrenal impairment without initial dose adjustment provided these patients are monitored for toxicitysince azacitidine and/or its metabolites are primarily excreted by the kidney.

Pharmacogenomics

The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not beenformally investigated.

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 given pre-implantation, but it was clearly embryotoxic when given during organogenesis. Foetal abnormalitiesduring organogenesis in rats included: CNS anomalies (exencephaly/encephalocele), limb anomalies(micromelia, club foot, syndactyly, oligodactyly) and others (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).

Mannitol (E 421)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years.

When Azacitidine betapharm is reconstituted using water for injections that has not been refrigerated,chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at25 °C for 45 minutes and at 2 °C to 8 °C for 8 hours.

The shelf life of the reconstituted medicinal product can be extended by reconstituting withrefrigerated (2 °C to 8 °C) water for injections. When Azacitidine betapharm is reconstituted usingrefrigerated (2 °C to 8 °C) water for injections, the chemical and physical in-use stability of thereconstituted medicinal product has been demonstrated at 2 °C to 8 °C for 22 hours.

From a microbiological point of view, the reconstituted product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand must not be longer than 8 hours at 2 °C to 8 °C when reconstituted using water for injections thathas not been refrigerated or not longer than 22 hours when reconstituted using refrigerated (2 °C to8 °C) water for injections.

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Clear glass vial (type I) sealed with bromobutyl rubber stopper and flip-off-seal, containing 100 mg ofazacitidine.

Pack size: 1 vial

Azacitidine betapharm is a cytotoxic medicinal product and, as with other potentially toxiccompounds, caution should be exercised when handling and preparing azacitidine suspensions.

Procedures for proper handling and disposal of anticancer medicinal products should be applied.

If reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash withsoap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

Azacitidine betapharm should be reconstituted with water for injections. The shelf life of thereconstituted medicinal product can be extended by reconstituting with refrigerated (2 °C to 8 °C)water for injections. Details on storage of the reconstituted product are provided below.

1. The following supplies should be assembled:

Vial (s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol wipes;5 mL injection syringe(s) with needle(s).

2. 4 mL of water for injections should be drawn into the syringe, making sure to purge any airtrapped within the syringe.

3. The needle of the syringe containing the 4 mL of water for injections should be inserted throughthe rubber top of the azacitidine vial followed by injection of the water for injections into thevial.

4. Following removal of the syringe and needle, the vial should be vigorously shaken until auniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudysuspension, free of agglomerates. The product should be discarded if it contains large particlesor agglomerates. Do not filter the suspension after reconstitution since this could remove theactive substance. It must be taken into account that filters are present in some adaptors, spikesand closed systems; therefore such systems should not be used for administration of themedicinal product after reconstitution.

5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vialshould then be turned upside down, making sure the needle tip is below the level of the liquid.

The plunger should then be pulled back to withdraw the amount of medicinal product requiredfor the proper dose, making sure to purge any air trapped within the syringe. The syringe withneedle should then be removed from the vial and the needle disposed of.

6. A fresh subcutaneous needle (recommended 25-gauge) should then be firmly attached to thesyringe. The needle should not be purged prior to injection, in order to reduce the incidence oflocal injection site reactions.

7. When more than 1 vial is needed all the above steps for preparation of the suspension should berepeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, itmay not be feasible to withdraw all of the suspension from the vial.

8. The contents of the dosing syringe must be re-suspended immediately prior to administration.

The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior toadministration to reach a temperature of approximately 20 °C to 25 °C. If the elapsed time islonger than 30 minutes, the suspension should be discarded appropriately and a new doseprepared. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudysuspension is achieved. The product should be discarded if it contains large particles oragglomerates.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

The total dose, according to the body surface area (BSA) can be calculated as follows:

Total dose (mg) = dose (mg/m2) × BSA (m2)

The following table is provided only as an example of how to calculate individual azacitidine dosesbased on an average BSA value of 1.8 m2.

Dose mg/m2 Total dose based on BSA Number of vials required Total volume of(% of recommended value of 1.8 m2reconstituted suspensionstarting dose) required75 mg/m2 (100 %) 135 mg 2 vials 5.4 mL37.5 mg/m2 (50 %) 67.5 mg 1 vial 2.7 mL25 mg/m2 (33 %) 45 mg 1 vial 1.8 mL

Reconstituted Azacitidine betapharm should be injected subcutaneously (insert the needle at a 45° to90° angle) using a 25-gauge needle into the upper arm, thigh or abdomen.

Doses greater than 4 mL should be injected into two separate sites.

Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous siteand never into areas where the site is tender, bruised, red, or hardened.

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

betapharm Arzneimittel GmbH

Kobelweg 9586156 Augsburg

Germany

EU/1/19/1416/001

Date of first authorisation: 24 March 2020

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

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