Azacitidine Accord

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Azacitidine Accord 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 or cake. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Azacitidine Accord 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 Accord 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 Accord 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 Accord 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 Accord 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 



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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). 
 
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 Accord is contraindicated in patients with advanced malignant hepatic tumours (see 
sections 4.3 and 4.4). 
 
Paediatric population 
The safety and efficacy of azacitidine in children aged 0-17 years have not yet been established. No 
data are available. 
 
Method of administration 
Reconstituted Azacitidine Accord 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 



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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. 
 
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 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 



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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 breast-feeding child, breast-feeding is contraindicated during azacitidine 
therapy. 
 
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 



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

  necrotisi
ng 
fasciitis 
* 

Blood and 
lymphatic system 
disorders 

febrile 

neutropenia*, 
neutropenia, 
leukopenia, 
thrombocytopenia
, 
anaemia 

pancytopenia*, 

bone marrow 
failure 

   

Immune system 
disorders 

  hypersensitiv
ity 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 

   



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System Organ 

Class 

Very common Common Uncommon Rare Not 
Known 

Eye disorders  eye haemorrhage, 

conjunctival 
haemorrhage 

   

Cardiac disorders  pericardial 
effusion 

pericarditis   

Vascular disorders  hypotension*, 

hypertension, 
orthostatic 
hypotension, 
haematoma 

   

Respiratory, 
thoracic and 
mediastinal 
disorders 

dyspnoea, 

epistaxis 

pleural effusion, 

dyspnoea 
exertional, 
pharyngolaryngea
l 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, 

bruising, 
haematoma, 
induration, rash, 
pruritus, 
inflammation, 

 injection site 
necrosis 

(at injection site) 

 



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System Organ 

Class 

Very common Common Uncommon Rare Not 
Known 

injection site 
reaction 
(unspecified) 

discoloration, 
nodule and 
haemorrhage (at 
injection site), 
malaise, chills, 
catheter site 
hemorrhage 

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. 
 
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. 



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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 study 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. 
 
4.9 Overdose 
 
One case of overdose with azacitidine was reported during clinical studies. 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]) 

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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). 
 

 
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). 
 



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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. 
 
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 



13 

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. 
 

 
 
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 



14 

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. 
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 



15 

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. 
 
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. 



16 

 
6.3 Shelf life 
 
Unopened powder vial 
3 years 
 
After reconstitution 
When Azacitidine Accord 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 60 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 Accord 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 rubber stopper and aluminium seal with 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 Accord 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 Accord 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. 



17 

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 
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 Accord 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. 
 



18 

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. 
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center,  
Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona, Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1413/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
 
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./


19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS 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. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Accord Healthcare Limited 
Sage House  
319, Pinner Road 
North Harrow 
Middlesex HA1 4HF 
United Kingdom 
 
Accord Healthcare Polska Sp.z.o.o. 
ul. Lutomierska 50,  
95-200, Pabianice, 
Poland 
 
Laboratori Fundació Dau 
C/ C, 12-14 Pol. Ind. 
Zona Franca, Barcelona, 08040, 
Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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 product 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 Accord 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 
 
 
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 SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



24 

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 
 
Accord Healthcare S.L.U.  
World Trade Center,  
Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona, Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1413/001 
 
 
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 Accord 25 mg/mL powder for suspension for injection 
azacitidine 
Subcutaneous use (SC) 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg 
 
 
6. OTHER 
 
 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



27 

Package leaflet: Information for the user 
 

Azacitidine Accord 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 Accord is and what it is used for 
2. What you need to know before you use Azacitidine Accord  
3. How to use Azacitidine Accord 
4. Possible side effects  
5. How to store Azacitidine Accord  
6. Contents of the pack and other information 
 
 
1. What Azacitidine Accord is and what it is used for 
 
What Azacitidine Accord is 
Azacitidine Accord is an anti-cancer agent which belongs to a group of medicines called ‘anti-
metabolites’. Azacitidine Accord contains the active substance ‘azacitidine’. 
 
What Azacitidine Accord is used for 
Azacitidine Accord 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 Accord works 
Azacitidine Accord 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 Accord works or why 
this medicine has been prescribed for you. 
 
 
2. What you need to know before you use Azacitidine Accord 
 
Do not use Azacitidine Accord 
- 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 Accord: 
- 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 Accord 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 Accord is not recommended for use in children and adolescents below the age of 18. 
 
Other medicines and Azacitidine Accord 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
This is because Azacitidine Accord may affect the way some other medicines work. Also, some other 
medicines may affect the way Azacitidine Accord works. 
 
Pregnancy, breast-feeding and fertility 
 
Pregnancy 
You should not use Azacitidine Accord 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 Accord. It is not known if this medicine passes 
into human milk. 
 
Fertility 
Men should not father a child while receiving treatment with Azacitidine Accord. 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 Accord 
 
Before giving you Azacitidine Accord, 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 Accord 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. 

 
Common side effects (may affect up to 1 in 10 people) 
- Bleeding inside your head. 



30 

- 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). 

 
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, 



31 

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 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 Accord 
 
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 Accord. They are also 
responsible for preparing and disposing of any unused Azacitidine Accord 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 60 minutes. 
 
When using later on  
If the Azacitidine Accord 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 Accord 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 Accord 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). 
 
What Azacitidine Accord looks like and contents of the pack 
Azacitidine Accord 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 Accord.  
 
Marketing Authorisation Holder  
Accord Healthcare S.L.U.  

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


32 

World Trade Center,  
Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona, Spain 
 
Manufacturer 
Accord Healthcare Limited,  
Sage House, 319 Pinner Road, North Harrow,  
Middlesex, HA1 4HF,  
United Kingdom 
 
Or 
Accord Healthcare Polska Sp.z o.o. 
ul. Lutomierska 50,  
95-200 Pabianice 
Poland 
 
Or 
Laboratori Fundació Dau 
C/ C, 12-14 Pol. Ind. 
Zona Franca, Barcelona, 08040,  
Spain 
 
This leaflet was last revised in {MM/YYYY}. 
 
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. 



33 

------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Recommendations for safe handling 
Azacitidine Accord 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 Accord 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 
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. 

 



34 

Storage of the reconstituted product 
 
For immediate use 
The Azacitidine Accord suspension may be prepared immediately before use and the reconstituted 
suspension should be administered within 60 minutes. If elapsed time is greater than 60 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 

 
Method of administration 
Do not filter the suspension after reconstitution. 
 
Reconstituted Azacitidine Accord should be injected subcutaneously (insert the needle at a 
45-90oangle) 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. 
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 


	ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS 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