Azacitidine Celgene

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Azacitidine Celgene 25 mg/mL powder for suspension for injection 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each vial contains 100 mg azacitidine. After reconstitution, each mL of suspension contains 25 mg 

azacitidine. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Powder for suspension for injection. 

 

White lyophilised powder. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Azacitidine Celgene is indicated for the treatment of adult patients who are not eligible for 

haematopoietic 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 10-29 % marrow blasts without 
myeloproliferative disorder, 

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

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

4.2 Posology and method of administration 

 

Azacitidine Celgene treatment should be initiated and monitored under the supervision of a physician 

experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics 

for nausea and vomiting. 

 

Posology 

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline 

haematology laboratory values, is 75 mg/m2 of body surface area, injected subcutaneously, daily for 

7 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 continued 

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. 

 

Laboratory tests 

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation 

of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to 

initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each 

treatment cycle. 

 



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Dose adjustment due to haematological toxicity 

Haematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets 

≤ 50.0 x 109/l and/or absolute neutrophil count (ANC) ≤ 1 x 109/l. 

 

Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at 

least half of the difference of nadir and the baseline count plus the nadir count (i.e. blood count at 

recovery ≥ nadir count + (0.5 x [baseline count – nadir count]). 

 

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

ANC ≥ 1.5 x 109/l, and platelets ≥ 75.0 x 109/l) prior to the first treatment 

If haematological toxicity is observed following Azacitidine Celgene treatment, the next cycle of the 

therapy should be delayed 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, the dose should be reduced according to the following table. Following dose modifications, 

the cycle duration should return to 28 days. 

 

Nadir counts % Dose in the next cycle, if recovery* is 

not achieved within 14 days ANC (x 109/l) Platelets (x 109/l) 

≤ 1.0 ≤ 50.0 50 % 

> 1.0 > 50.0 100 % 

*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 

 

Patients with reduced baseline blood counts (i.e. WBC < 3.0 x 109/l or ANC < 1.5 x 109/l or platelets 

< 75.0 x 109/l) prior to the first treatment 

Following Azacitidine Celgene treatment, if the decrease in WBC or ANC or platelets from that prior 

to treatment is ≤ 50 %, or greater than 50 % but with an improvement in any cell line differentiation, 

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 no 

improvement in cell line differentiation, the next cycle of Azacitidine Celgene therapy should be 

delayed 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, bone 

marrow cellularity should be determined. If the bone marrow cellularity is > 50 %, no dose 

adjustments should be made. If bone marrow cellularity is ≤ 50 %, treatment should be delayed and 

the dose 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 days 

15-50 % 100 % 50 % 

< 15 % 100 % 33 % 

*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 

 

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

 

Special populations 

Elderly patients 

No specific dose adjustments are recommended for the elderly. Because elderly patients are more 

likely to have decreased renal function, it may be useful to monitor renal function. 

 

Patients with renal impairment 

Azacitidine can be administered to patients with renal impairment without initial dose adjustment (see 

section 5.2). If unexplained reductions in serum bicarbonate levels to less than 20 mmol/l occur, the 

dose should be reduced by 50 % on the next cycle. If unexplained elevations in serum creatinine or 

blood 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 should 

be reduced by 50 % on the next treatment cycle (see section 4.4). 

 



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Patients with hepatic impairment 

No formal studies have been conducted in patients with hepatic impairment (see section 4.4). Patients 

with severe hepatic organ impairment should be carefully monitored for adverse events. No specific 

modification to the starting dose is recommended for patients with hepatic impairment prior to starting 

treatment; subsequent dose modifications should be based on haematology laboratory values. 

Azacitidine Celgene is contraindicated in patients with advanced malignant hepatic tumours (see 

sections 4.3 and 4.4). 

 

Paediatric population 

The safety and efficacy of Azacitidine Celgene in children aged 0-17 years have not yet been 

established. No data are available. 

 

Method of administration 

Reconstituted Azacitidine Celgene should be injected subcutaneously into the upper arm, thigh or 

abdomen. Injection sites should be rotated. New injections should be given at least 2.5 cm from the 

previous site and never into areas where the site is tender, bruised, red, or hardened. 

 

After reconstitution, the suspension should not be filtered. For instructions on reconstitution of the 

medicinal product before administration, see section 6.6. 

 

4.3 Contraindications 

 

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). 

 

4.4 Special warnings and precautions for use 

 

Haematological toxicity 

Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly 

during the first 2 cycles (see section 4.8). Complete blood counts should be performed as needed to 

monitor response and toxicity, but at least prior to each treatment cycle. After administration of the 

recommended dose for the first cycle, the dose for subsequent cycles should be reduced or its 

administration delayed based on nadir counts and haematological response (see section 4.2). Patients 

should be advised to promptly report febrile episodes. Patients and physicians are also advised to be 

observant for signs and symptoms of bleeding. 

 

Hepatic impairment 

No formal studies have been conducted in patients with hepatic impairment. Patients with extensive 

tumour burden due to metastatic disease have been reported to experience progressive hepatic coma 

and 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 (see 

section 4.3). 

 

Renal impairment 

Renal abnormalities ranging from elevated serum creatinine to renal failure and death were reported in 

patients treated with intravenous azacitidine in combination with other chemotherapeutic agents. In 

addition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mmol/L in association 

with an alkaline urine and hypokalaemia (serum potassium < 3 mmol/L) developed in 5 subjects with 

chronic myelogenous leukaemia (CML) treated with azacitidine and etoposide. If unexplained 

reductions in serum bicarbonate (< 20 mmol/L) or elevations of serum creatinine or BUN occur, the 

dose 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. 

 



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Although no clinically relevant differences in the frequency of adverse reactions were noted between 

subjects with normal renal function compared to those with renal impairment, patients with renal 

impairment should be closely monitored for toxicity since azacitidine and/or its metabolites are 

primarily excreted by the kidney (see section 4.2). 

 

Laboratory tests 

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation 

of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to 

initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each 

treatment cycle, see also section 4.8. 

 

Cardiac and pulmonary disease 

Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or 

pulmonary 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 been 

established. Recent data from a clinical trial in patients with a known history of cardiovascular or 

pulmonary disease showed a significantly increased incidence of cardiac events with azacitidine (see 

section 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 

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

Azacitidine Celgene therapy should be discontinued in patients who develop necrotising fasciitis and 

appropriate treatment should be promptly initiated. 

 

Tumour lysis syndrome 

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. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 

isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and 

glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are 

therefore considered unlikely. 

 

Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are 

unlikely (see section 5.2). 

 

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

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential / Contraception in males and females 

Women of childbearing potential and men have to use effective contraception during and up to 

3 months after treatment. 

 

Pregnancy 

There are no adequate data from the use of azacitidine in pregnant women. Studies in mice have 

shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Based on 

results from animal studies and its mechanism of action, azacitidine should not be used during 

pregnancy, especially during the first trimester, unless clearly necessary. The advantages of treatment 

should be weighed against the possible risk for the foetus in every individual case. 

 

Breast-feeding 

It is unknown whether azacitidine/metabolites are excreted in human milk. Due to the potential serious 

adverse reactions in the nursing child, breast-feeding is contraindicated during azacitidine therapy. 



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Fertility 

There are no human data on the effect of azacitidine on fertility. In animals, adverse reactions with 

azacitidine use on male fertility have been documented (see section 5.3). Men should be advised not to 

father a child while receiving treatment and must use effective contraception during and up to 

3 months after treatment. Before starting treatment, male patients should be advised to seek 

counselling on sperm storage. 

 

4.7 Effects on ability to drive and use machines 

 

Azacitidine has minor or moderate influence on the ability to drive and use machines. Fatigue has 

been reported with the use of azacitidine. Therefore, caution is recommended when driving or 

operating machines. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

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

Adverse reactions considered to be possibly or probably related to the administration of azacitidine 

have 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 supporting 

studies (CALGB 9221 and CALGB 8921). Other serious adverse reactions from these 3 studies 

included infections such as neutropenic sepsis (0.8%) and pneumonia (2.5%) (some with fatal 

outcome), 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 haematological 

reactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4), 

gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 1-2) or injection site 

reactions (77.1 %; usually Grade 1-2). 

 

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 the 

azacitidine 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 arm 

included 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 were 

gastrointestinal events, including constipation (41.9%), nausea (39.8%), and diarrhoea (36.9%), 

(usually Grade 1-2), general disorders and administration site conditions including pyrexia (37.7%; 

usually Grade 1-2) and haematological events, including febrile neutropenia (32.2%) and neutropenia 

(30.1%), (usually Grade 3-4). 

 

Tabulated list of adverse reactions 

Table 1 below contains adverse reactions associated with azacitidine treatment obtained from the main 

clinical studies in MDS and AML and post marketing surveillance. 

 



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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 be 

estimated from the available data). Within each frequency grouping, undesirable effects are presented 

in order of decreasing seriousness. Adverse reactions are presented in the table below according to the 

highest frequency observed in any of the main clinical studies. 

 

Table 1: ADRs reported in patients with MDS or AML treated with azacitidine (clinical 

studies and post- marketing) 

 
System Organ 

Class 

Very common 

 

Common 

 

Uncommon 

 

Rare Not 

Known 

Infections and 

infestations 

pneumonia* 

(including bacterial, 

viral and fungal), 

nasopharyngitis 

sepsis* (including 

bacterial, viral and 

fungal), 

neutropenic sepsis*, 

respiratory tract 

infection (includes 

upper and 

bronchitis), urinary 

tract infection, 

cellulitis, 

diverticulitis, oral 

fungal infection, 

sinusitis, 

pharyngitis, rhinitis, 

herpes simplex, 

skin infection  

  necrotising 

fasciitis * 

Blood and 

lymphatic system 

disorders 

febrile 

neutropenia*, 

neutropenia, 

leukopenia, 

thrombocytopenia, 

anaemia  

pancytopenia*, 

bone marrow 

failure 

   

Immune system 

disorders 

  hypersensitivity 

reactions 

  

Metabolism and 

nutrition 

disorders 

anorexia, 

decreased appetite, 

hypokalemia 

 

dehydration   tumour 

lysis 

syndrome 

 

Psychiatric 

disorders 

insomnia confusional state, 

anxiety 

 

   

Nervous system 

disorders 

dizziness, headache intracranial 

haemorrhage*, 

syncope, 

somnolence, 

lethargy 

   

Eye disorders  eye haemorrhage, 

conjunctival 

haemorrhage  

   

Cardiac 

disorders 

 pericardial effusion pericarditis   

Vascular 

disorders 

 hypotension*, 

hypertension, 

orthostatic 

hypotension, 

haematoma 

   



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System Organ 

Class 

Very common 

 

Common 

 

Uncommon 

 

Rare Not 

Known 

Respiratory, 

thoracic and 

mediastinal 

disorders 

dyspnoea, 

epistaxis 

pleural effusion, 

dyspnoea 

exertional, 

pharyngolaryngeal 

pain 

 interstitial 

lung 

disease 

 

Gastrointestinal 

disorders 

diarrhoea, vomiting, 

constipation, 

nausea, abdominal 

pain (includes upper 

and abdominal 

discomfort) 

gastrointestinal 

haemorrhage* 

(includes mouth 

haemorrhage), 

haemorrhoidal 

haemorrhage, 

stomatitis, gingival 

bleeding, dyspepsia 

   

Hepatobiliary 

disorders 

  hepatic failure*, 

progressive 

hepatic coma 

  

Skin and 

subcutaneous 

tissue disorders 

petechiae, pruritus 

(includes 

generalized), rash, 

ecchymosis  

purpura, alopecia, 

urticaria, erythema, 

rash macular 

acute febrile 

neutrophilic 

dermatosis, 

pyoderma 

gangrenosum 

  

Musculoskeletal 

and connective 

tissue disorders 

arthralgia, 

musculoskeletal 

pain (includes back, 

bone and pain in 

extremity) 

muscle spasms, 

myalgia  

   

Renal and 

urinary 

disorders 

 renal failure*, 

haematuria, 

elevated serum 

creatinine 

renal tubular 

acidosis 

  

General 

disorders and 

administration 

site conditions 

pyrexia*, fatigue, 

asthenia, chest pain, 

injection site 

erythema, injection 

site pain, injection 

site reaction 

(unspecified) 

 

bruising, 

haematoma, 

induration, rash, 

pruritus, 

inflammation, 

discoloration, 

nodule and 

haemorrhage (at 

injection site), 

malaise, chills, 

catheter site 

hemorrhage 

 injection 

site 

necrosis 

(at 

injection 

site) 

 

Investigations weight decreased      

* = rarely fatal cases have been reported 

 

Description of selected adverse reactions 

Haematologic adverse reactions 

The most commonly reported (≥ 10%) haematological adverse reactions associated with azacitidine 

treatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, and 

were 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 counts 

and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factor 

support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required. 

 



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Infections 

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse 

reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients 

receiving 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 

Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as 

gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be 

monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-

related thrombocytopenia. 

 

Hypersensitivity 

Serious hypersensitivity reactions have been reported in patients receiving azacitidine. In case of an 

anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and 

appropriate symptomatic treatment initiated. 

 

Skin and subcutaneous tissue adverse reactions 

The majority of skin and subcutaneous adverse reactions were associated with the injection site. None 

of these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in the 

pivotal studies. The majority of adverse reactions occurred during the first 2 cycles and tended to 

decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site 

rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant 

medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory 

medicinal products (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue 

infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and 

necrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the post 

marketing setting. For clinical management of infectious adverse reactions, see section 4.8 Infections. 

 

Gastrointestinal adverse reactions 

The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment 

included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed 

symptomatically with anti-emetics for nausea and vomiting; anti-diarrhoeals for diarrhoea, and 

laxatives and/or stool softeners for constipation. 

 

Renal adverse reactions 

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). 

 

Hepatic adverse reactions 

Patients with extensive tumour burden due to metastatic disease have been reported to experience 

hepatic failure, progressive hepatic coma and death during azacitidine treatment (see section 4.4). 

 

Cardiac events 

Data from a clinical trial allowing enrolment of patients with known history of cardiovascular or 

pulmonary disease showed a statistically significant increase in cardiac events in patients with newly 

diagnosed AML treated with azacitidine (see section 4.4). 

 

Elderly population 

There is limited safety information available with azacitidine in patients ≥85 years (with 14 [5.9%] 

patients ≥85 years in AZA-AML-001 study). 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


10 

 

4.9 Overdose 

 

One case of overdose with azacitidine was reported during clinical trials. A patient experienced 

diarrhoea, 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 should 

receive supportive treatment, as necessary. There is no known specific antidote for 

azacitidine overdose. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

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

 

Mechanism of action 

Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including 

cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The 

cytotoxic 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 damage 

pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine 

into 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 versus 

cytotoxicity or other activities of azacitidine to clinical outcomes has not been established. 

 

Clinical efficacy and safety 

 

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

The efficacy and safety of azacitidine were studied in an international, multicenter, controlled, open-

label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in adult 

patients 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 blasts 

in transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) according 

to the French American British (FAB) classification system. RAEB-T patients (21-30 % blasts) are 

now considered to be AML patients under the current WHO classification system. Azacitidine plus 

best supportive care (BSC) (n = 179) was compared to conventional care regimens (CCR). CCR 

consisted of BSC alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard induction 

chemotherapy plus BSC (n = 25). Patients were pre-selected by their physician to 1 of the 3 CCR prior 

to randomisation. Patients received this pre-selected regimen if not randomised to azacitidine. As part 

of the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group 

(ECOG) performance status of 0-2. Patients with secondary MDS were excluded from the study. The 

primary endpoint of the study was overall survival. Azacitidine was administered at a subcutaneous 

dose of 75 mg/m2 daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle) for a 

median of 9 cycles (range = 1-39) 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 was 

associated with a median survival of 24.46 months versus 15.02 months for those receiving CCR 

treatment, a difference of 9.4 months, with a stratified log-rank p-value of 0.0001. The hazard ratio 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). 

 



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Log-Rank p = 0.0001 
HR = 0.58 [95% CI: 0.43-0.77] 

Deaths: AZA = 82, CCR = 113 

Time (months) from Randomization 

P
ro

p
o

rt
io

n
 S

u
rv

iv
in

g
 

# at risk 

months 

months 

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

HR = hazard ratio 

 

The survival benefits of azacitidine were consistent regardless of the CCR treatment option (BSC 

alone, low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in the 

control arm. 

 

When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survival 

were 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 of 

13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months 

with 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 the 

patients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0 % of these 

patients became RBC transfusion independent during the treatment period, compared with 11.4 % of 

the 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 became 

independent, the median duration of RBC transfusion independence was 13 months in the 

azacitidine group. 

 



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Response was assessed by the investigator or by the Independent Review Committee (IRC). Overall 

response (complete remission [CR] + partial remission [PR]) as determined by the investigator was 

29 % 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 azacitidine 

group compared with 1 % (2/179) in the combined CCR group (p = 0.0113). The differences between 

the 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 these 

improvements for a minimum of 56 days. A survival benefit was also demonstrated in patients that 

had not achieved a complete/partial response following azacitidine treatment. Haematological 

improvement (major or minor) as determined by the IRC was achieved in 49 % of patients receiving 

azacitidine 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 a 

major cytogenetic response was similar in the azacitidine and combined CCR groups. Minor 

cytogenetic 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 (see 

section 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 or 

secondary AML with >30% bone marrow blasts according to the WHO classification, who were not 

eligible for HSCT. Azacitidine plus BSC (n=241) was compared to CCR. CCR consisted of BSC 

alone (n=45), low-dose cytarabine plus BSC (n=158), or standard intensive chemotherapy with 

cytarabine and anthracycline plus BSC (n=44). Patients were pre-selected by their physician to 1 of the 

3 CCRs prior to randomization. Patients received the pre-selected regimen if not randomised to 

azacitidine. As part of the inclusion criteria, patients were required to have an ECOG performance 

status of 0-2 and intermediate- or poor-risk cytogenetic abnormalities. The primary endpoint of the 

study was overall survival. 

 

Azacitidine was administered at a SC dose of 75mg/m2/day for 7 days, followed by a rest period of 

21 days (28 day treatment cycle), for a median of 6 cycles (range: 1 to 28), BSC- only patients for a 

median of 3 cycles (range: 1 to 20), low-dose cytarabine patients for a median of 4 cycles (range 1 to 

25) and standard intensive chemotherapy patients for a median of 2 cycles (range: 1 to 3, induction 

cycle plus 1 or 2 consolidation cycles). 

 

The individual baseline parameters were comparable between the azacitidine and CCR groups. The 

median 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 with 

myelodysplasia-related changes, 4.1% therapy-related myeloid neoplasms and 2.9% AML with 

recurrent genetic abnormalities according to the WHO classification. 

 

In the ITT analysis of 488 patients (241 azacitidine and 247 CCR), azacitidine treatment was 

associated with a median survival of 10.4 months versus 6.5 months for those receiving CCR 

treatment, a difference of 3.8 months, with a stratified log-rank p-value of 0.1009 (two- sided). The 

hazard ratio for the treatment effect was 0.85 (95% CI= 0.69, 1.03). The one-year survival rates were 

46.5% in patients receiving azacitidine versus 34.3% in patients receiving CCR. 

 



13 

 
The Cox PH model adjusted for pre-specified baseline prognostic factors defined a HR for azacitidine 

versus 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 difference 

when comparing azacitidine to the preselection CCR treatment groups, the survival of azacitidine 

treated patients was longer when compared to CCR treatment options BSC alone, low-dose cytarabine 

plus 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 classification 

of AML (including AML with myelodysplasia-related changes), baseline WBC count (≤ 5 x109/L & 

>5 x 109/L), baseline bone marrow blasts (≤ 50% & > 50%) and prior history of MDS] there was a 

trend in OS benefit in favour of azacitidine. In a few pre-specified subgroups, the OS HR reached 

statistical significance including patients with poor cytogenetic risk, patients with AML with 

myelodysplasia-related changes, patients < 75 years, female patients and white patients. 

 

Haematologic and cytogenetic responses were assessed by the investigator and by the IRC with similar 

results. Overall response rate (complete remission [CR] + complete remission with incomplete blood 

count recovery [CRi]) as determined by the IRC was 27.8% in the azacitidine group and 25.1% in the 

combined CCR group (p = 0.5384). In patients who achieved CR or CRi, the median duration of 

remission 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 not 

achieved a complete response for azacitidine compared to CCR. 

 

Azacitidine treatment improved peripheral blood counts and led to a reduced need for RBC and 

platelet transfusions. A patient was considered RBC or platelet transfusion dependent at baseline if the 

subject had one or more RBC or platelet transfusions during the 56 days (8 weeks) on or prior to 

randomization, respectively. A patient was considered RBC or platelet transfusion independent during 

the treatment period if the subject had no RBC or platelet transfusions during any consecutive 56 days 

during 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 treatment 

period, compared with 27.6% of (95% CI = 20.9, 35.1) patients in the combined CCR groups. In 

patients who were RBC transfusion dependent at baseline and achieved transfusion independence on 

treatment, the median duration of RBC transfusion independence was 13.9 months in the azacitidine 

group and was not reached in the CCR group. 



14 

 

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 treatment 

period, compared with 29.3% of (95% CI = 19.7, 40.4) patients in the combined CCR groups. In 

patients who were platelet transfusion dependent at baseline and achieved transfusion independence on 

treatment, the median duration of platelet transfusion independence was 10.8 months in the azacitidine 

group and 19.2 months in the CCR group. 

 

Health- Related Quality of Life (HRQoL) was assessed using the European Organization for Research 

and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). HRQoL data could 

be analysed for a subset of the full trial population. While there are limitations in the analysis, the 

available data suggest that patients do not experience meaningful deterioration in quality of life during 

treatment with azacitidine. 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following subcutaneous administration of a single 75 mg/m2 dose, azacitidine was rapidly absorbed 

with peak plasma concentrations of 750 ± 403 ng/mL occurring at 0.5 h after dosing (the first 

sampling point). The absolute bioavailability of azacitidine after subcutaneous relative to intravenous 

administration (single 75 mg/m2 doses) was approximately 89% based on area under the curve (AUC). 

 

Area under the curve and maximum plasma concentration (Cmax) of subcutaneous admiminstration of 

azacitidine were approximately proportional within the 25 to 100 mg/m2 dose range. 

 

Distribution 

Following intravenous administration, the mean volume of distribution was 76 ± 26 L, and systemic 

clearance was 147 ± 47 L/h. 

 

Biotransformation 

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 

isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and 

glutathione transferases (GSTs). 

 

Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. In 

human liver S9 fractions, formation of metabolites was independent of NADPH implying that 

azacitidine metabolism was not mediated by cytochrome P450 isoenzymes. An in vitro study of 

azacitidine 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 not 

induce 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 produce 

inhibition. Therefore, CYP enzyme induction or inhibition by azacitidine at clinically achievable 

plasma concentrations is unlikely. 

 

Elimination 

Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) after subcutaneous 

administration of 41 ± 8 minutes. No accumulation occurs after subcutaneous administration of 

75 mg/m2 azacitidine once daily for 7 days. Urinary excretion is the primary route of elimination of 

azacitidine 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. 

 

Special populations 

The effects of hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics of 

azacitidine have not been formally studied. 

 



15 

Renal impairment 

Renal impairment has no major effect on the pharmacokinetic exposure of azacitidine after single and 

multiple subcutaneous administrations. Following subcutaneous administration of a single 75 mg/m2 

dose, mean exposure values (AUC and Cmax) from subjects with mild, moderate and severe renal 

impairment were increased by 11-21%, 15-27%, and 41-66%, respectively, compared to normal renal 

function subjects. However, exposure was within the same general range of exposures observed for 

subjects with normal renal function. Azacitidine can be administered to patients with renal impairment 

without initial dose adjustment provided these patients are monitored for toxicity since azacitidine 

and/or its metabolites are primarily excreted by the kidney. 

 

Pharmacogenomics 

The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been 

formally investigated. 

 

5.3 Preclinical safety data 

 

Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian 

cell 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 administered 

intraperitoneally 3 times per week for 52 weeks. An increased incidence of tumours in the 

lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine 

administered intraperitoneally for 50 weeks. A tumorigenicity study in rats revealed an increased 

incidence 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 before 

closure 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 abnormalities 

during 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 in 

decreased 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 sperm 

counts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in 

mated females (see section 4.4). 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Mannitol (E421) 

 

6.2 Incompatibilities 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. 

 

6.3 Shelf life 

 

Unopened powder vial: 

4 years 

 



16 

After reconstitution: 

When Azacitidine Celgene 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 at 

25 °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 with 

refrigerated (2 °C to 8 °C) water for injections. When Azacitidine Celgene is reconstituted using 

refrigerated (2 °C to 8 °C) water for injections, the chemical and physical in-use stability of the 

reconstituted 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 not 

used immediately, in-use storage times and conditions prior to use are the responsibility of the user 

and must not be longer than 8 hours at 2 °C to 8 °C when reconstituted using water for injections that 

has not been refrigerated or not longer than 22 hours when reconstituted using refrigerated (2 °C to 

8 °C) water for injections. 

 

6.4 Special precautions for storage 

 

Unopened vials 

This medicinal product does not require any special storage conditions. 

 

Reconstituted suspension 

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

 

6.5 Nature and contents of container 

 

Colourless type I glass vial sealed with butyl elastomeric stopper and aluminium seal with 

polypropylene plastic button, containing 100 mg of azacitidine. 

 

Pack size: 1 vial 

 

6.6 Special precautions for disposal and other handling 

 

Recommendations for safe handling 

Azacitidine Celgene is a cytotoxic medicinal product and, as with other potentially toxic compounds, 

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 with 

soap and water. If it comes into contact with mucous membranes, flush thoroughly with water. 

 

Reconstitution procedure 

Azacitidine Celgene should be reconstituted with water for injections. The shelf life of the 

reconstituted 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 air 

trapped within the syringe. 

3. The needle of the syringe containing the 4 mL of water for injections should be inserted through 

the rubber top of the azacitidine vial followed by injection of the water for injections into 

the vial. 



17 

4. Following removal of the syringe and needle, the vial should be vigorously shaken until a 

uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain 

25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy 

suspension, free of agglomerates. The product should be discarded if it contains large particles 

or agglomerates. Do not filter the suspension after reconstitution since this could remove the 

active substance. It must be taken into account that filters are present in some adaptors, spikes 

and closed systems; therefore such systems should not be used for administration of the 

medicinal product after reconstitution. 

5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vial 

should 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 required 

for the proper dose, making sure to purge any air trapped within the syringe. The syringe with 

needle 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 the 

syringe. The needle should not be purged prior to injection, in order to reduce the incidence of 

local injection site reactions. 

7. When more than 1 vial is needed all the above steps for preparation of the suspension should be 

repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose 

150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it 

may 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 to 

administration to reach a temperature of approximately 20 °C-25 °C. If the elapsed time is 

longer than 30 minutes, the suspension should be discarded appropriately and a new dose 

prepared. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy 

suspension is achieved. The product should be discarded if it contains large particles or 

agglomerates. 

 

Storage of the reconstituted product 

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

 

Calculation of an individual dose 

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

 

Total dose (mg) = Dose (mg/m2) x BSA (m2) 

 

The following table is provided only as an example of how to calculate individual azacitidine doses 

based on an average BSA value of 1.8 m2. 

 

Dose mg/m2 

(% of recommended 

starting dose) 

Total dose based on 

BSA value of 1.8 m2 

Number of vials 

required 

Total volume of 

reconstituted 

suspension required 

75 mg/m2 (100 %) 135 mg 2 vials 5.4 mL 

37.5 mg/m2 (50 %) 67.5 mg 1 vial 2.7 mL 

25 mg/m2 (33 %) 45 mg 1 vial 1.8 mL 

 

Method of administration 

Reconstituted Azacitidine Celgene should be injected subcutaneously (insert the needle at a 45-90o 

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 site 

and 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 local 

requirements. 



18 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Celgene Europe B.V. 

Winthontlaan 6 N  

3526 KV Utrecht  

Netherlands  

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1382/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation:  

Date of latest renewal:  

 

 

10. DATE OF REVISION OF THE TEXT 

 

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

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

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


19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



20 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Celgene Distribution B.V. 

Winthontlaan 6 N  

3526 KV Utrecht  

Netherlands 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Update Reports 
The requirements for submission of periodic safety update reports for this medicinal are set out in the 

list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 

and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 



21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Azacitidine Celgene 25 mg/mL powder for suspension for injection 

Azacitidine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains100 mg azacitidine. After reconstitution, each mL suspension contains 25 mg 

azacitidine. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains mannitol. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for suspension for injection. 

1 vial – 100 mg 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

For single use only. Shake the suspension vigorously before administration. 

Subcutaneous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Cytotoxic 

 

 

8. EXPIRY DATE 

 

EXP 

 

Read the leaflet for the shelf life of the reconstituted medicine. 

 

 



24 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Any unused medicinal product or waste material should be disposed of in accordance with the local 

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Celgene Europe B.V. 

Winthontlaan 6 N  

3526 KV Utrecht  

Netherlands  

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1382/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



25 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Azacitidine Celgene 25 mg/mL powder for suspension for injection 

Azacitidine 

Subcutaneous use 

 

 

2. METHOD OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

100 mg 

 

 

6. OTHER 

 

Cytotoxic 



26 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



27 

Package leaflet: Information for the user 

 

Azacitidine Celgene 25 mg/mL powder for suspension for injection 

Azacitidine 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet: 

1. What Azacitidine Celgene is and what it is used for 

2. What you need to know before you use Azacitidine Celgene 

3. How to use Azacitidine Celgene 

4. Possible side effects 

5 How to store Azacitidine Celgene 

6. Contents of the pack and other information 

 

 

1. What Azacitidine Celgene is and what it is used for 

 

What Azacitidine Celgene is 

Azacitidine Celgene is an anti-cancer agent which belongs to a group of medicines called ‘anti-

metabolites’. Azacitidine Celgene contains the active substance ‘azacitidine’. 

 

What Azacitidine Celgene is used for 

Azacitidine Celgene is used in adults who are not able to have a stem cell transplantation to treat: 

• higher-risk myelodysplastic syndromes (MDS). 

• chronic myelomonocytic leukaemia (CMML). 

• acute myeloid leukaemia (AML). 
 

These are diseases which affect the bone marrow and can cause problems with normal blood cell 

production. 

 

How Azacitidine Celgene works 

Azacitidine Celgene works by preventing cancer cells from growing. Azacitidine becomes 

incorporated into the genetic material of cells (ribonucleic acid (RNA) and deoxyribonucleic acid 

(DNA)). It is thought to work by altering the way the cell turns genes on and off and also by 

interfering with the production of new RNA and DNA. These actions are thought to correct problems 

with the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic 

disorders, and to kill cancerous cells in leukaemia. 

Talk to your doctor or nurse if you have any questions about how Azacitidine Celgene works or why 

this medicine has been prescribed for you. 

 

 

2. What you need to know before you use Azacitidine Celgene 

 

Do not use Azacitidine Celgene 

• if you are allergic to azacitidine or any of the other ingredients of this medicine (listed in 
section 6). 

• if you have advanced liver cancer. 

• if you are breast-feeding. 
 



28 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before using Azacitidine Celgene: 

• if you have decreased counts of platelets, red or white blood cells. 

• if you have kidney disease. 

• if you have liver disease. 

• if you have ever had a heart condition or heart attack or any history of lung disease. 
 

Blood test 

You will have blood tests before you begin treatment with Azacitidine Celgene and at the start of each 

period of treatment (called a ‘cycle’). This is to check that you have enough blood cells and that your 

liver and kidneys are working properly. 

 

Children and adolescents 

Azacitidine Celgene is not recommended for use in children and adolescents below the age of 18. 

 

Other medicines and Azacitidine Celgene 

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 

This is because Azacitidine Celgene may affect the way some other medicines work. Also, some other 

medicines may affect the way Azacitidine Celgene works. 

 

Pregnancy, breast-feeding and fertility 

 

Pregnancy 

You should not use Azacitidine Celgene during pregnancy as it may be harmful to the baby. 

Use an effective method of contraception during and up to 3 months after treatment. 

Tell your doctor straight away if you become pregnant during treatment. 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. 

 

Breast-feeding 

You should not breast-feed when using Azacitidine Celgene. It is not known if this medicine passes 

into human milk. 

 

Fertility 

Men should not father a child while receiving treatment with Azacitidine Celgene. Use an effective 

method of contraception during and up to 3 months after treatment with this medicine. 

 

Talk to your doctor if you wish to conserve your sperm before starting this treatment. 

 

Driving and using machines 

Do not drive or use any tools or machines if you experience side effects, such as tiredness. 

 

 

3. How to use Azacitidine Celgene 

 

Before giving you Azacitidine Celgene, your doctor will give you another medicine to prevent nausea 

and vomiting at the start of each treatment cycle. 

 

• The recommended dose is 75 mg per m2 body surface area. Your doctor will decide your dose 
of this medicine, depending on your general condition, height and weight. Your doctor will 

check your progress and may change your dose if necessary. 

• Azacitidine Celgene is given every day for one week, followed by a rest period of 3 weeks. This 
“treatment cycle” will be repeated every 4 weeks. You will usually receive at least 6 treatment 

cycles. 

 



29 

This medicine will be given to you as an injection under the skin (subcutaneously) by a doctor or 

nurse. It may be given under the skin on your thigh, tummy or upper arm. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Tell your doctor straight away if you notice any of the following side effects: 

• Drowsiness, shaking, jaundice, abdominal bloating and easy bruising. These may be 
symptoms of liver failure and can be life-threatening. 

• Swelling of the legs and feet, back pain, reduced passing of water, increased thirst, rapid 
pulse, dizziness and nausea, vomiting or reduced appetite and feelings of confusion, 

restlessness or fatigue. These may be symptoms of kidney failure and can be life-threatening. 

• A fever. This could be due to an infection as a result of having low levels of white blood cells, 
which can be life-threatening. 

• Chest pain or shortness of breath which may be accompanied with a fever. This may be due 
to an infection of the lung called “pneumonia”, and can be life-threatening. 

• Bleeding. Such as blood in the stools due to bleeding in the stomach or gut, or such as bleeding 
inside your head. These may be symptoms of having low levels of platelets in your blood. 

• Difficulty breathing, swelling of the lips, itching or rash. This may be due to an allergic 
(hypersensitivity) reaction. 

 

Other side effects include: 

 

Very common side effects (may affect more than 1 in 10 people) 

• Reduced red blood count (anaemia). You may feel tired and pale. 

• Reduced white blood cell count. This may be accompanied by a fever. You are also more likely 
to get infections. 

• A low blood platelet count (thrombocytopenia). You are more prone to bleeding and bruising. 

• Constipation, diarrhoea, nausea, vomiting. 

• Pneumonia. 

• Chest pain, being short of breath. 

• Tiredness (fatigue). 

• Injection site reaction including redness, pain or a skin reaction. 

• Loss of appetite. 

• Joint aches. 

• Bruising. 

• Rash. 

• Red or purple spots under your skin. 

• Pain in your belly (abdominal pain). 

• Itching. 

• Fever. 

• Sore nose and throat. 

• Dizziness. 

• Headache. 

• Having trouble sleeping (insomnia). 

• Nosebleeds (epistaxis). 

• Muscle aches. 

• Weakness (asthenia). 

• Weight loss. 

• Low levels of potassium in your blood. 
 



30 

Common side effects (may affect up to 1 in 10 people) 

• Bleeding inside your head. 

• An infection of the blood caused by bacteria (sepsis). This may be due to low levels of white 
cells in your blood. 

• Bone marrow failure. This can cause low levels of red and white blood cells and platelets. 

• A type of anaemia where your red and white blood cells and platelets are reduced. 

• An infection in your urine. 

• A viral infection causing cold sores (herpes). 

• Bleeding gums, bleeding in the stomach or gut, bleeding from around your back passage due to 
piles (haemorrhoidal haemorrhage), bleeding in your eye, bleeding under your skin, or into your 

skin (haematoma). 

• Blood in your urine. 

• Ulcers of your mouth or tongue. 

• Changes to your skin at the injection site. These include swelling, a hard lump, bruising, 
bleeding into your skin (haematoma), rash, itching and changes in the skin colour. 

• Redness of your skin. 

• Skin infection (cellulitis). 

• An infection of the nose and throat, or sore throat. 

• Sore or runny nose or sinuses (sinusitis). 

• High or low blood pressure (hypertension or hypotension). 

• Being short of breath when you move. 

• Pain in your throat and voicebox. 

• Indigestion. 

• Lethargy. 

• Feeling generally unwell. 

• Anxiety. 

• Being confused. 

• Hair loss. 

• Kidney failure. 

• Dehydration. 

• White coating covering tongue, inner cheeks, and sometimes on the roof of your mouth, gums 
and tonsils (oral fungal infection). 

• Fainting. 

• A fall in blood pressure when standing (orthostatic hypotension) leading to dizziness when 
moving to a standing or sitting position. 

• Sleepiness, drowsiness (somnolence). 

• Bleeding due to a catheter line. 

• A disease affecting the gut which can result in fever, vomiting and stomach pain (diverticulitis). 

• Fluid around the lungs (pleural effusion). 

• Shivering (chills). 

• Muscle spasms. 

• Raised itchy rash on the skin (urticaria). 

• Collection of fluid around the heart (pericardial effusion).. 
 

Uncommon side effects (may affect up to 1 in 100 people) 

• Allergic (hypersensitivity) reaction. 

• Shaking. 

• Liver failure. 

• Large plum-coloured, raised painful patches on the skin with fever. 

• Painful skin ulceration (pyoderma gangrenosum). 

• Inflammation of the lining around the heart (pericarditis). 
 



31 

Rare side effects (may affect up to 1 in 1,000 people) 

• Dry cough. 

• Painless swelling in the finger tips (clubbing). 

• Tumour lysis syndrome - Metabolic complications that can occur during treatment of cancer and 
sometimes even without treatment. These complications are caused by the product of dying 

cancer cells and may include the following: changes to blood chemistry; high potassium, 

phosphorus, uric acid, and low calcium consequently leading to changes in kidney function, 

heartbeat, seizures, and sometimes death. 

 

Not known (frequency cannot be estimated from the available data) 

• Infection of the deeper layers of skin, which spreads quickly, damaging the skin and tissue, which 
can be life-threatening (necrotizing fasciitis). 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Azacitidine Celgene 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the vial label and the carton. The 

expiry date refers to the last day of that month. 

 

Your doctor, pharmacist or nurse are responsible for storing Azacitidine Celgene. They are also 

responsible for preparing and disposing of any unused Azacitidine Celgene correctly. 

 

For unopened vials of this medicine – there are no special storage conditions. 

 

When using immediately 

Once the suspension has been prepared it should be administered within 45 minutes. 

 

When using later on 

If the Azacitidine Celgene suspension is prepared using water for injections that has not been 

refrigerated, the suspension must be placed in the refrigerator (2 °C – 8 °C) immediately after it is 

prepared and kept refrigerated for up to a maximum of 8 hours. 

If the Azacitidine Celgene suspension is prepared using water for injections that has been stored in the 

refrigerator (2 °C – 8 °C), the suspension must be placed in the refrigerator (2 °C – 8 °C) immediately 

after it is prepared and kept refrigerated for up to a maximum of 22 hours. 

 

The suspension should be allowed up to 30 minutes prior to administration to reach room temperature 

(20 °C – 25 °C). 

 

If large particles are present in the suspension it should be discarded. 

 

 

6. Contents of the pack and other information 

 

What Azacitidine Celgene contains 

• The active substance is azacitidine. One vial contains 100 mg azacitidine. After reconstitution 
with 4 mL of water for injections, the reconstituted suspension contains 25 mg/mL azacitidine. 

• The other ingredient is mannitol (E421). 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

What Azacitidine Celgene looks like and contents of the pack 

Azacitidine Celgene is a white powder for suspension for injection and is supplied in a glass vial 

containing 100 mg of azacitidine. Each pack contains one vial of Azacitidine Celgene. 

 

Marketing Authorisation Holder 

Celgene Europe B.V. 

Winthontlaan 6 N  

3526 KV Utrecht  

Netherlands  

 

Manufacturer 

Celgene Distribution B.V. 

Winthontlaan 6 N  

3526 KV Utrecht  

Netherlands 

 

 

This leaflet was last revised in 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

-------------------------------------------------------------------------------------------------------------------------- 

 

The following information is intended for healthcare professionals only: 

 

Recommendations for safe handling 

Azacitidine Celgene is a cytotoxic medicinal product and, as with other potentially toxic compounds, 

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 with 

soap and water. If it comes into contact with mucous membranes, flush thoroughly with water. 

 

Incompatibilities 

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

below (see “Reconstitution Procedure”). 

 

Reconstitution procedure 

Azacitidine Celgene should be reconstituted with water for injections. The shelf life of the 

reconstituted 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 air 

trapped within the syringe. 

3. The needle of the syringe containing the 4 mL of water for injections should be inserted through 

the rubber top of the azacitidine vial followed by injection of the water for injections into 

the vial. 

4. Following removal of the syringe and needle, the vial should be vigorously shaken until a 

uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain 

25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy 

suspension, free of agglomerates. The product should be discarded if it contains large particles 

or agglomerates. Do not filter the suspension after reconstitution since this could remove the 

active substance. It must be taken into account that filters are present in some adaptors, spikes 

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


33 

and closed systems; therefore such systems should not be used for administration of the 

medicinal product after reconstitution. 

5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vial 

should 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 required 

for the proper dose, making sure to purge any air trapped within the syringe. The syringe with 

needle 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 the 

syringe. The needle should not be purged prior to injection, in order to reduce the incidence of 

local injection site reactions. 

7. When more than 1 vial is needed all the above steps for preparation of the suspension should be 

repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose 

150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it 

may 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 temperature of the suspension at the time of injection should be approximately 20 ºC-25 ºC. 

To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension 

is achieved. The product should be discarded if it contains large particles or agglomerates. 

 

Storage of the reconstituted product 

For immediate use 

The Azacitidine Celgene suspension may be prepared immediately before use and the reconstituted 

suspension should be administered within 45 minutes. If elapsed time is greater than 45 minutes, the 

reconstituted suspension should be discarded appropriately and a new dose prepared. 

 

For later use 

When reconstituting using water for injections that has not been refrigerated, the reconstituted 

suspension must be placed in a refrigerator (2 °C to 8 °C) immediately after reconstitution, and kept in 

the refrigerator for a maximum of 8 hours. If the elapsed time in the refrigerator is greater than 

8 hours, the suspension should be discarded appropriately and a new dose prepared. 

 

When reconstituting using refrigerated (2 °C to 8 °C) water for injections, the reconstituted suspension 

must be placed in a refrigerator (2 °C to 8 °C) immediately after reconstitution, and kept in a 

refrigerator for a maximum of 22 hours. If the elapsed time in the refrigerator is greater than 22 hours, 

the suspension should be discarded appropriately and a new dose prepared. 

 

The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to 

administration to reach a temperature of approximately 20 ºC-25 ºC. If the elapsed time is longer than 

30 minutes, the suspension should be discarded appropriately and a new dose prepared. 

 

Calculation of an individual dose 

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

 

Total dose (mg) = Dose (mg/m2) x BSA (m2) 

 

The following table is provided only as an example of how to calculate individual azacitidine doses 

based on an average BSA value of 1.8 m2. 

 

Dose mg/m2 

(% of recommended 

starting dose) 

Total dose based on 

BSA value of 1.8 m2 

Number of vials 

required 

Total volume of 

reconstituted 

suspension required 

75 mg/m2 (100 %) 135 mg 2 vials 5.4 mL 

37.5 mg/m2 (50 %) 67.5 mg 1 vial 2.7 mL 

25 mg/m2 (33 %) 45 mg 1 vial 1.8 mL 

 



34 

Method of administration 

Do not filter the suspension after reconstitution. 

 

Reconstituted Azacitidine Celgene should be injected subcutaneously (insert the needle at a 45-90° 

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 site 

and 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 local 

requirements. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET