Zynteglo

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynteglo 1.2-20 × 106 cells/mL dispersion for infusion.  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
2.1 General description 
 
Zynteglo (betibeglogene autotemcel) is a genetically modified autologous CD34+ cell enriched 
population that contains haematopoietic stem cells (HSC) transduced with lentiviral vector (LVV) 
encoding the βA-T87Q-globin gene. 
 
2.2 Qualitative and quantitative composition 
 
The finished product is composed of one or more infusion bags which contain a dispersion of 
1.2-20 × 106 cells/mL suspended in cryopreservative solution. Each infusion bag contains 
approximately 20 mL of Zynteglo. 
 
The quantitative information regarding strength, CD34+ cells, and dose for the medicinal product is 
provided in the Lot Information Sheet. The Lot Information Sheet is included inside the lid of the 
cryoshipper used to transport Zynteglo.   
 
Excipient with known effect 
 
Each dose contains 391-1564 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Dispersion for infusion. 
 
A clear to slightly cloudy, colourless to yellow or pink dispersion. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indication 
 
Zynteglo is indicated for the treatment of patients 12 years and older with transfusion-dependent 
β-thalassaemia (TDT) who do not have a β0/β0 genotype, for whom haematopoietic stem cell (HSC) 
transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not 
available (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Zynteglo must be administered in a qualified treatment centre by a physician(s) with experience in 
HSC transplantation and in the treatment of patients with TDT.  
 



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Patients are expected to enrol in a registry and will be followed in the registry in order to better 
understand the long-term safety and efficacy of Zynteglo.  
 
Posology 
 
The minimum recommended dose of Zynteglo is 5.0 × 106 CD34+ cells/kg. In clinical studies doses up 
to 20 × 106 CD34+ cells/kg have been administered. The minimum recommended dose is the same for 
adults and adolescents 12 years of age and older. 
 
Zynteglo is intended for autologous use (see section 4.4) and should only be administered once. 
 
Mobilisation and apheresis 
 
Patients are required to undergo HSC mobilisation followed by apheresis to obtain CD34+ stem cells 
which will be used for medicinal product manufacturing (see section 5.1 for a description of the 
mobilisation regimen used in clinical studies).  
 
The minimum target number of CD34+ cells to be collected is 12 × 106 CD34+ cells/kg. If the 
minimum dose of Zynteglo of 5.0 × 106 CD34+ cells/kg is not met after initial medicinal product 
manufacturing, the patient may undergo one or more additional cycles of mobilisation and apheresis, 
separated by at least 14 days, in order to obtain more cells for additional manufacture. 
 
A back-up collection of CD34+ stem cells of ≥1.5 × 106 CD34+ cells/kg (if collected by apheresis) or 
>1.0 × 108 TNC/kg (if collected by bone marrow harvest) is required. These cells must be collected 
from the patient and be cryopreserved prior to myeloablative conditioning and infusion with Zynteglo. 
The back-up collection may be needed for rescue treatment if there is: 1) compromise of Zynteglo 
after initiation of myeloablative conditioning and before Zynteglo infusion, 2) primary engraftment 
failure, or 3) loss of engraftment after infusion with Zynteglo (see section 4.4).  
 
Pre-treatment conditioning  
 
The treating physician should confirm that HSC transplantation is appropriate for the patient before 
myeloablative conditioning is initiated (see section 4.4).  
 
Full myeloablative conditioning must be administered before infusion of Zynteglo (see section 5.1 for 
a description of the myeloablative regimen used in clinical studies). It is recommended that patients 
maintain haemoglobin (Hb) ≥11 g/dL for at least 30 days prior to mobilisation and during 
myeloablative conditioning. Iron chelation should be stopped at least 7 days prior to myeloablative 
conditioning. Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for 
seizures should be considered (see section 5.1 for a description of the prophylaxis regimen used in 
clinical studies). 
 
Myeloablative conditioning should not begin until the complete set of infusion bag(s) constituting the 
dose of Zynteglo has been received and stored at the administration site, and the availability of the 
back-up collection is confirmed.  
 
Zynteglo administration 
 
See Method of Administration below and section 6.6 for details on Zynteglo administration and 
handling. 
 
After Zynteglo administration 
 
Any blood products required within the first 3 months after Zynteglo infusion should be irradiated.  
 
Restarting iron chelation after Zynteglo infusion may be necessary and should be based on clinical 
practice (see sections 4.5 and 5.1). Phlebotomy can be used in lieu of iron chelation, when appropriate. 



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Special populations 
 
Elderly 
Zynteglo has not been studied in patients >65 years of age. HSC transplantation must be appropriate 
for a patient with TDT to be treated with Zynteglo (see section 4.4). No dose adjustment is required. 
 
Renal impairment 
Zynteglo has not been studied in patients with renal impairment. Patients should be assessed for renal 
impairment defined as creatinine clearance ≤70 mL/min/1.73 m2 to ensure HSC transplantation is 
appropriate. No dose adjustment is required. 
 
Hepatic impairment 
Zynteglo has not been studied in patients with hepatic impairment. Patients should be assessed for 
hepatic impairment to ensure HSC transplantation is appropriate (see section 4.4.). No dose adjustment 
is required. 
 
Paediatric population 
The safety and efficacy of Zynteglo in children <12 years of age have not yet been established.  
 
Patients seropositive for human immunodeficiency virus (HIV) or human T-lymphotropic virus 
(HTLV) 
Zynteglo has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative 
serology test for HIV is necessary to ensure acceptance of apheresis material for Zynteglo 
manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for 
Zynteglo manufacturing.  
 
Method of administration  
 
Zynteglo is for intravenous use only (see section 6.6 for full details on the administration process). 
 
After completion of the 4-day course of myeloablative conditioning, there must be a minimum of 
48 hours of washout before Zynteglo infusion.  
 
Before infusion, it must be confirmed that the patient’s identity matches the unique patient information 
on the Zynteglo infusion bag(s). The total number of infusion bags to be administered should also be 
confirmed with the Lot Information Sheet (see section 4.4). 
 
Zynteglo infusion should be completed as soon as possible and no more than 4 hours after thawing. 
Each infusion bag should be administered in less than 30 minutes. In the event that more than one 
infusion bag is provided, all infusion bags must be administered. The entire volume of each infusion 
bag should be infused.  
 
Standard procedures for patient management after HSC transplantation should be followed after 
Zynteglo infusion. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Pregnancy and breast-feeding (see section 4.6). 
 
Previous treatment with HSC gene therapy. 
 
Contraindications to the mobilisation agents and the myeloablative conditioning agent must be 
considered. 
 



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4.4 Special warnings and precautions for use 
 
Traceability 
 
The traceability requirements of cell-based advanced therapy medicinal products must apply. To 
ensure traceability the name of the product, the batch number and the name of the treated patient 
should be kept for a period of 30 years. 
 
General 
 
Warnings and precautions of the mobilisation agents and the myeloablative conditioning agent must be 
considered. 
 
Patients treated with Zynteglo should not donate blood, organs, tissues or cells for transplantation at 
any time in the future. This information is provided in the Patient Alert Card which must be given to 
the patient after treatment.  
 
Zynteglo is intended solely for autologous use and must not be administered to other patients. Confirm 
that the patient’s identity matches the unique patient identification information on the Zynteglo 
infusion bag(s) and metal cassette(s). Do not infuse Zynteglo if the information on the patient specific 
label on the infusion bag(s) or metal cassette(s) do not match the intended patient. 
 
Risks associated with TDT and iron overload 
 
Patients with TDT experience iron overload due to chronic red blood cell (RBC) transfusions that can 
lead to end organ damage. HSC transplantation with myeloablative conditioning is not appropriate for 
patients with TDT who have evidence of severely elevated iron in the heart i.e., patients with cardiac 
T2* <10 msec by magnetic resonance imaging (MRI). MRI of the liver should be performed on all 
patients prior to myeloablative conditioning. It is recommended that patients with MRI results 
demonstrating liver iron content ≥15 mg/g undergo liver biopsy for further evaluation. If the liver 
biopsy demonstrates bridging fibrosis, cirrhosis, or active hepatitis, HSC transplantation with 
myeloablative conditioning is not appropriate. 
 
Risk of insertional oncogenesis 
 
No cases of leukaemia or lymphoma have been reported in clinical studies with Zynteglo in patients 
with TDT. There are no reports of LVV-mediated insertional mutagenesis resulting in oncogenesis. 
Nevertheless, there is a theoretical risk of leukaemia or lymphoma after treatment with Zynteglo.  
 
Patients should be monitored annually for leukaemia or lymphoma (including with a complete blood 
count) for 15 years post treatment with Zynteglo. If leukaemia or lymphoma is detected in any patient 
who received Zynteglo, blood samples should be collected for integration site analysis.   
 
Serological testing 
 
All patients should be tested for HIV-1/2 prior to mobilisation and apheresis to ensure acceptance of 
the apheresis material for Zynteglo manufacturing (see section 4.2).  
 
Interference with serology testing 
 
It is important to note that patients who have received Zynteglo are likely to test positive by 
polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false 
positive test for HIV. Therefore, patients who have received Zynteglo should not be screened for HIV 
infection using a PCR-based assay.  
 



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Engraftment failure as measured by neutrophil engraftment 
 
Treatment with Zynteglo involves the infusion and engraftment of CD34+ HSCs that have been 
genetically modified ex vivo with a LVV. In clinical trials, no patients failed to engraft bone marrow, 
as measured by neutrophil engraftment (N=45). Neutrophil engraftment occurred on 
median (min, max) Day 21.0 (13, 38) after medicinal product infusion. Failure of neutrophil 
engraftment is a short-term but potentially severe risk, defined as failure to achieve 3 consecutive 
absolute neutrophil counts (ANC) ≥500 cells/µL obtained on different days by Day 43 after infusion of 
Zynteglo. Patients who experience neutrophil engraftment failure should receive rescue treatment with 
the back-up collection (see section 4.2). 
 
Delayed platelet engraftment 
 
Platelet engraftment is defined as 3 consecutive platelet values ≥20 × 109/L obtained on different days 
after Zynteglo infusion, with no platelet transfusions administered for 7 days immediately preceding 
and during the evaluation period. Patients with TDT treated with Zynteglo who achieved platelet 
engraftment had a median (min, max) platelet engraftment on Day 42.0 (19, 191) in clinical trials 
(N=45). No correlation was observed between incidence of bleeding and delayed platelet engraftment. 
Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. 
Patients should be monitored for thrombocytopenia and bleeding according to standard guidelines. 
Platelet counts should be monitored according to medical judgment until platelet engraftment and 
platelet recovery are achieved. Blood cell count determination and other appropriate testing should be 
promptly considered whenever clinical symptoms suggestive of bleeding arise.  
 
Anti-retroviral and hydroxyurea use 
 
Patients should not take anti-retroviral medications or hydroxyurea from at least one month prior to 
mobilisation until at least 7 days after Zynteglo infusion (see section 4.5). If a patient requires 
anti-retrovirals for HIV prophylaxis, Zynteglo treatment, including mobilisation and apheresis of 
CD34+ cells through Zynteglo infusion, should be delayed until an HIV infection could be adequately 
ruled out according to local guidance for HIV testing. 
 
Sodium content 
 
This medicinal product contains 391-1564 mg sodium per dose equivalent to 20 to 78% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Patients should not take anti-retroviral medicinal products or hydroxyurea from at least one month 
prior to mobilisation until at least 7 days after Zynteglo infusion (see section 4.4). 
 
Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be 
considered. Iron chelators should be discontinued 7 days prior to initiation of conditioning. The 
Summary of Product Characteristics (SmPC) for the iron chelator and the myeloablative conditioning 
agent must be consulted for the recommendations regarding co-administration with CYP3A substrates. 
 
Some iron chelators are myelosuppressive. After Zynteglo infusion, avoid use of these iron chelators 
for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron 
chelators (see sections 4.2 and 5.1). 
 
No formal drug interaction studies have been performed. Zynteglo is not expected to interact with the 
hepatic cytochrome P-450 family of enzymes or drug transporters. 
 
There is no clinical experience with the use of erythropoiesis-stimulating agents in patients treated 
with Zynteglo. 
 



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The safety of immunisation with live viral vaccines during or following Zynteglo treatment has not 
been studied.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
 
There are insufficient exposure data to provide a precise recommendation on duration of contraception 
following treatment with Zynteglo. Women of childbearing potential and men capable of fathering a 
child must use a reliable method of contraception (intra-uterine device or combination of hormonal 
and barrier contraception) from start of mobilisation through at least 6 months after administration of 
Zynteglo. Consult the SmPC of the myeloablative conditioning agent for information on the need for 
effective contraception in patients who undergo conditioning.  
 
Pregnancy 
 
A negative serum pregnancy test must be confirmed prior to the start of mobilisation and re-confirmed 
prior to conditioning procedures and before medicinal product administration. 
 
No clinical data on exposed pregnancies are available. 
 
Reproductive and developmental toxicity studies with Zynteglo were not performed. Zynteglo must 
not be used during pregnancy because of myeloablative conditioning (see section 4.3). It is unknown 
whether Zynteglo transduced cells have the potential to be transferred in utero to a foetus. 
 
There is no opportunity for germline transmission of the βA-T87Q-globin gene after treatment with 
Zynteglo, therefore the likelihood that an offspring would have general somatic expression of the 
βA-T87Q-globin gene is considered negligible. 
 
Breast-feeding 
 
It is unknown whether Zynteglo is excreted in human milk. The effect of administration of Zynteglo to 
mothers on their breast-fed children has not been studied. 
 
Zynteglo must not be administered to women who are breast-feeding. 
 
Fertility 
 
There are no data on the effects of Zynteglo on human fertility. Effects on male and female fertility 
have not been evaluated in animal studies.  
 
Data are available on the risk of infertility with myeloablative conditioning. It is therefore advised to 
cryopreserve semen or ova before treatment if possible. 
 
4.7 Effects on ability to drive and use machines 
 
Zynteglo has no influence on the ability to drive or use machines. 
 
The effect of the mobilisation agents and the myeloablative conditioning agent on the ability to drive 
or use machines must be considered. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of Zynteglo was evaluated in 45 patients with TDT. The only serious adverse reaction 
attributed to Zynteglo was thrombocytopenia (2.2%). Given the small patient population and size of 



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cohorts, adverse reactions in the table below do not provide a complete perspective on the nature and 
frequency of these events.  
 
Tabulated list of adverse reactions 
 
Adverse reactions are listed by MedDRA body system organ class and by frequency convention. 
Frequencies are defined as: very common (≥1/10), and common (≥1/100 to <1/10). Within each 
frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 
 
Tables 1, 2, and 3 are lists of adverse reactions attributed to mobilisation/apheresis, myeloablative 
conditioning, and Zynteglo, respectively, experienced by patients with TDT in clinical trials with 
Zynteglo. 
 
Table 1 Adverse reactions attributed to mobilisation/apheresis 

System Organ Class (SOC) Very Common (≥10%) Common (≥1% - <10%) 
Blood and lymphatic system 
disorders 

Thrombocytopenia Splenomegaly, Leukocytosis 

Metabolism and nutrition 
disorders 

Hypocalcaemia Hypokalaemia, 
Hypomagnesaemia 

Psychiatric disorders  Agitation 
Nervous system disorders Headache, Peripheral sensory 

neuropathy 
Dizziness, Head discomfort, 
Paraesthesia 

Cardiac disorders  Cardiac flutter 
Vascular disorders  Hypotension 
Respiratory, thoracic and 
mediastinal disorders 

 Hypoxia, Epistaxis 

Gastrointestinal disorders Nausea Vomiting, Lip swelling, 
Abdominal pain, Abdominal 
pain upper, Paraesthesia oral  

Skin and subcutaneous tissue 
disorders 

 Rash, Hyperhidrosis 

Musculoskeletal and 
connective tissue disorders 

Bone pain Back pain, Musculoskeletal 
discomfort 

General disorders and 
administration site conditions 

 Pyrexia, Influenza like illness, 
Chest discomfort, Chest pain, 
Injection site reaction, Catheter 
site haemorrhage, Catheter site 
bruise, Injection site bruising, 
Fatigue, Non-cardiac chest 
pain, Catheter site pain, 
Injection site pain, Puncture 
site pain, Pain 

Investigations  Blood magnesium decreased 
Injury, poisoning and 
procedural complications 

 Citrate toxicity, Contusion, 
Procedural pain 

 



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Table 2 Adverse reactions attributed to myeloablative conditioning 
SOC Very Common (≥10%) Common (≥1% - <10%) 
Infections and infestations 
 

 Neutropenic sepsis, Systemic 
infection, Staphylococcal 
infection, Pneumonia, Lower 
respiratory tract infection, 
Urinary tract infection, 
Mucosal infection, Cellulitis, 
Vaginal infection, Rash 
pustular, Folliculitis, 
Gingivitis, Vulvovaginal 
candidiasis 

Blood and lymphatic system 
disorders 

Febrile neutropenia, 
Neutropenia, 
Thrombocytopenia, 
Leukopenia, Anaemia 

Lymphopenia, Leukocytosis, 
Monocyte count decreased, 
Neutrophilia, Mean cell 
haemoglobin concentration 
increased 

Endocrine disorders  Primary hypogonadism 
Metabolism and nutrition 
disorders 

Decreased appetite Hypocalcaemia, 
Hypokalaemia, Metabolic 
acidosis, Fluid overload, Fluid 
retention, Hypomagnesaemia, 
Hyponatraemia, 
Hypophosphataemia, 
Hyperphosphataemia 

Psychiatric disorders Insomnia Anxiety 
Nervous system disorders Headache Dizziness, Lethargy, 

Dysgeusia, Ageusia, Memory 
impairment 

Eye disorders  Conjunctival haemorrhage 
Ear and labyrinth disorders  Vertigo 
Cardiac disorders  Cardiac failure congestive, 

Atrial fibrillation  
Vascular disorders  Hypotension, Haematoma, Hot 

flush 
Respiratory, thoracic and 
mediastinal disorders 

Epistaxis, Pharyngeal 
inflammation 

Hypoxia, Pulmonary mass, 
Dyspnoea, Pleural effusion, 
Rales, Upper-airway cough 
syndrome, Cough, Laryngeal 
pain, Hiccups, Oropharyngeal 
pain  

Gastrointestinal disorders Stomatitis, Vomiting, Nausea, 
Diarrhoea, Gingival bleeding, 
Constipation, Abdominal pain, 
Anal inflammation  

Anal haemorrhage, Gastritis, 
Gastrointestinal inflammation, 
Abdominal distension, 
Abdominal pain upper, Anal 
fissure, Dyspepsia, Dysphagia, 
Oesophagitis, Haemorrhoids, 
Proctalgia, Lip dry 

Hepatobiliary disorders Veno-occlusive liver disease, 
Alanine aminotransferase 
increased, Aspartate 
aminotransferase increased, 
Blood bilirubin increased 

Cholecystitis, Cholelithiasis, 
Hepatomegaly, Jaundice, 
Transaminases increased, 
Gamma-glutamyltransferase 
increased 

Skin and subcutaneous tissue 
disorders 

Alopecia, Pruritus, Skin 
hyperpigmentation 

Petechiae, Ecchymosis, Pain of 
skin, Palpable purpura, 
Pigmentation disorder, Pruritus 



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SOC Very Common (≥10%) Common (≥1% - <10%) 
generalised, Purpura, Sweat 
gland disorder, Urticaria, Dry 
skin, Rash 

Musculoskeletal and 
connective tissue disorders 

 Bone pain, Myalgia, 
Pain in extremity, Back pain 

Renal and urinary disorders  Haematuria, Pollakiuria 
Reproductive system and breast 
disorders 

Vaginal haemorrhage Ovarian failure, Menstruation 
irregular, Premature 
menopause, Blood follicle 
stimulating hormone increased, 
Blood testosterone decreased 

General disorders and 
administration site conditions 

Pyrexia, Fatigue, Mucosal 
inflammation 

Face oedema, Hypothermia, 
Feeling cold, Pain, Xerosis 

Investigations  C-reactive protein increased, 
Aspergillus test positive, Blood 
potassium decreased, Weight 
decreased, Blood alkaline 
phosphatase decreased, Blood 
magnesium decreased, Forced 
expiratory flow decreased, 
Protein total decreased, Blood 
albumin decreased, 
Reticulocyte count decreased, 
Reticulocyte percentage 
decreased 

Injury, poisoning and 
procedural complications 

 Transfusion reaction, Skin 
abrasion 

 
Table 3 Adverse reactions attributed to Zynteglo 

SOC Very Common (≥10%) Common (≥1% - <10%) 
Blood and lymphatic system 
disorders 

 Thrombocytopenia,  
Leukopenia, Neutropenia 

Vascular disorders  Hot flush 
Respiratory, thoracic and 
mediastinal disorders 

 Dyspnoea 

Gastrointestinal disorders Abdominal pain  
Musculoskeletal and 
connective tissue disorders 

 Pain in extremity 

General disorders and 
administration site conditions 

 Non-cardiac chest pain 

 
Description of selected adverse reactions 
 
Bleeding 
 
Bleeding is a potential complication of thrombocytopenia subsequent to myeloablative conditioning 
and treatment with Zynteglo. The majority of all reported bleeding events were nonserious. A risk of 
bleeding exists before platelet engraftment and may continue after platelet engraftment in patients who 
have continued thrombocytopenia.    
 
Following platelet engraftment, all patients maintained platelet levels of ≥20 × 109/L. Median (min, 
max) times to unsupported platelet counts of ≥50 × 109/L  and ≥100 × 109/L were 51 (20, 268) days 
(N=45) and 63.5 (20, 1231) days (N=42), respectively (see section 4.4 for guidance on platelet 
monitoring and management). 
 



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Hepatic veno-occlusive disease 
 
Serious events of hepatic VOD occurred in 11.1% of patients following myeloablative conditioning; 
80% of these patients did not receive prophylaxis for VOD. All patients who experienced VOD 
received treatment with defibrotide and recovered. Patients with TDT may be at an increased risk of 
VOD following myeloablative conditioning compared with other patient populations.   
 
Infusion related reactions to Zynteglo 
 
Pre-medication for infusion reactions was managed at physician discretion. Infusion related reactions 
to Zynteglo were observed in 13.3% of patients and occurred on the day of Zynteglo infusion. All 
reactions resolved and the majority were mild. Events included abdominal pain, dyspnoea, hot flush, 
and non-cardiac chest pain in 11.1%, 2.2%, 2.2%, and 2.2% of patients, respectively.   
 
Paediatric population 
 
According to available data, the frequency, type, and severity of adverse reactions in adolescents 
12-17 years of age are similar to adults with the exception that VOD and pyrexia occurred more 
frequently in adolescents. 
 
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 
 
No data from clinical studies are available regarding overdose of Zynteglo.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other haematological agents, ATC code: B06AX02 
 
Mechanism of action 
 
Zynteglo adds functional copies of a modified β-globin gene into the patients’ HSCs through 
transduction of autologous CD34+ cells with BB305 LVV, thereby addressing the underlying genetic 
cause of the disease. After Zynteglo infusion, transduced CD34+ HSCs engraft in the bone marrow and 
differentiate to produce RBCs containing biologically active βA-T87Q-globin (a modified β-globin 
protein) that will combine with α-globin to produce functional Hb containing βA-T87Q-globin (HbAT87Q). 
βA-T87Q-globin can be quantified relative to other globin species in peripheral blood using high 
performance liquid chromatography. βA-T87Q-globin expression is designed to correct the β/α-globin 
imbalance in erythroid cells of patients with TDT and has the potential to increase total Hb to normal 
levels and eliminate dependence on chronic RBC transfusions. Following successful engraftment and 
achievement of transfusion independence, the effects of the product are expected to be life-long. 
 
Pharmacodynamic effects  
 
All patients with TDT with a non-β0/β0 genotype who received Zynteglo with at least 3 months of 
follow-up produced HbAT87Q (N=10, HGB-204; N=4, HGB-205; N=15, HGB-207; N=3, HGB-212). 
For patients with at least 6 months of follow-up, HbAT87Q generally increased steadily after Zynteglo 
infusion and stabilised by approximately Month 6. Patients had a Month 6 median (min, max) HbAT87Q 



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of 4.901 (1.03, 9.59) g/dL in the Phase 1/2 studies (N=14, HGB-204 and HGB-205) and 
9.409 (3.35, 10.60) g/dL in ongoing Phase 3 studies (N=16, HGB-207 and HGB-212).   
 
HbAT87Q remained generally stable through Month 24 with a median (min, max) of 
6.444 (1.10, 10.13) g/dL in the completed Phase 1/2 studies (N=14, HGB-204 and HGB-205) and 
8.766 (0.89, 11.40) g/dL in the ongoing Phase 3 studies (N=3, HGB-207). HbAT87Q continued to be 
stable at last follow-up through Month 60, demonstrating stable integration of the βA-T87Q-globin gene 
into long-term HSCs and stable expression of the βA-T87Q-globin gene in cells of the erythroid lineage.  
 
Clinical efficacy  
 
Efficacy was based on 32 adult and adolescent patients with TDT and a non-β0/β0 genotype treated 
with Zynteglo (N=10, HGB-204; N=4, HGB-205; N=15, HGB-207; N=3, HGB-212) (see Table 4). A 
few patients have been included in the clinical studies with genotypes characterised by low 
endogenous β-globin production phenotypically similar to patients with a β0/β0 genotype, such as 
patients homozygous for IVS-I-110 or IVS-I-5.  
 
Table 4 Baseline characteristics for non-β0/β0 patients with TDT ≥12 years of age treated 

with Zynteglo (Studies HGB-204, HGB-205, HGB-207, HGB-212, LTF-303)  
 

Study Total number 
of patients  

(young adults/ 
adolescents) 

 

Age 
(years) 

median (min, 
max) 

Pre-enrolment 
transfusion volumes 

(mL/kg/year) 
median (min, max) 

Pre-enrolment 
transfusion frequency 

(number/year) 
median (min, max) 

HGB-205 4 
(2) 

young adults/ 
adolescents* 

181.85 
(138.8, 197.3) 

12.50 
(10.5, 13.0)  

HGB-204 10 
(2) 

19.5 
(16, 34) 

151.28 
(140.0, 234.5) 

13.75 
(10.0, 16.5) 

HGB-207 15 
(6) 

20.0 
(12, 34) 

192.92 
(152.3, 251.3) 

17.50 
(11.5, 37.0) 

HGB-212 3 
(1) 

adults/ 
adolescents* 

175.51 
(170.7, 209.6) 

21.50 
(17.5, 39.5) 

*Age range is not provided to protect patient identity. 
 
Transfusion-dependent β-thalassaemia (TDT) 
 
Patients were considered to be transfusion-dependent if they had a history of transfusions of at least 
100 mL/kg/year of RBCs or with ≥8 transfusions of RBCs per year in the 2 years preceding enrolment. 
In the clinical studies, patients received a median (min, max) RBC transfusion volume of 
175.74 (138.8, 251.3) mL/kg/year and a median (min, max) number of 14.75 (10.0, 39.5) RBC 
transfusions per year.  
 
Adolescents were excluded from Phase 3 studies if they had a known and available HLA-matched 
related HSC donor. The median (min, max) age in the studies was 19.0 (12, 34) years, 56.3% were 
females, 59.4% were Asian, and 40.6% White/Caucasian. All patients had a Karnofsky/Lansky 
performance score ≥80 and the majority (18/32, 56.3%) had a performance score of 100 at baseline. 
Cardiac T2* at baseline was >20 msec. The median (min, max) serum ferritin at baseline was 
3778.7 (784, 22517) pmol/L and median (min, max) liver iron concentration was 6.75 (1.0, 41.0) mg/g 
(N=10, HGB-204; N=4, HGB-205; N=15, HGB-207; N=3, HGB-212). 
 
Mobilisation and apheresis 
 
All patients were administered G-CSF and plerixafor to mobilise stem cells prior to the apheresis 
procedure. The planned dose of G-CSF was 10 µg/kg/day in patients with a spleen, and 5 µg/kg/day in 
patients without a spleen, given on Days 1 through 5 of mobilisation in the morning. The planned dose 



13 

of plerixafor was 0.24 mg/kg/day, given on Days 4 and 5 of mobilisation in the evening. If a third day 
of collection was needed, plerixafor and G-CSF dosing was extended to Day 6. The dose of G-CSF 
was decreased by half if white blood cell (WBC) count was >100 × 109/L prior to the day of apheresis. 
For most patients, the minimum number of CD34+ cells to manufacture Zynteglo was collected with 
1 cycle of mobilisation and apheresis.  
 
Pre-treatment conditioning 
 
All patients received full myeloablative conditioning with busulfan prior to treatment with Zynteglo. 
The planned dose of busulfan was 3.2 mg/kg/day for patients ≥18 years as a 3-hour IV infusion daily 
for 4 days with a recommended target AUC0-24h of 3800-4500 µM*min. The planned dose of busulfan 
was 0.8 mg/kg for patients 12-17 years of age as a 2-hour IV infusion every 6 hours for a total of 
16 doses with a recommended target of AUC0-6h of 950-1125 µM*min. The busulfan SmPC was used 
for information on appropriate method for determination of patient weight-based dosing. Busulfan 
dose adjustments were made as needed based on pharmacokinetic monitoring. 
 
The median (min, max) busulfan dose was 3.50 (2.5, 5.0) mg/kg/day (N=32). AUC0-24h was measured 
during Day 1 and informed the dose for Day 3; the median (min, max) estimated daily AUC was 
4394.5 (3030, 9087) μM*min (N=32). All patients with non-β0/β0 genotypes received anti-seizure 
prophylaxis with agents other than phenytoin prior to initiating busulfan. Phenytoin was not used for 
anti-seizure prophylaxis because of its well understood induction of glutathione-S-transferase and 
cytochrome P450 and resultant increased clearance of busulfan, and because of the widespread 
availability of effective anti-seizure medications that do not affect busulfan metabolism. 
 
In HGB-207 and HGB-212 prophylaxis for VOD/hepatic sinusoidal obstruction syndrome was 
required per institutional practice with ursodeoxycholic acid or defibrotide.  
 
Zynteglo administration 
 
All patients were administered Zynteglo with a median (min, max) dose of 7.80 × 106 

(5.0, 19.4) CD34+ cells/kg as an intravenous infusion (N=32). 
 
After Zynteglo administration 
 
A total of 31.1% of patients (14/45; HGB-204, HGB-205, HGB-207, HGB-212) received G-CSF 
within 21 days after Zynteglo infusion. However, G-CSF use was not recommended for 21 days after 
Zynteglo infusion in Phase 3 studies.  
 
Studies HGB-204 and HGB-205 
 
HGB-204 and HGB-205 were Phase 1/2 open-label, single-arm 24-month studies that included 
22 patients with TDT treated with Zynteglo (N=18, HGB-204; N=4, HGB-205), of whom 14 had a 
non-β0/β0 genotype (N=10, HGB-204; N=4, HGB-205) and 8 had a β0/β0 genotype in HGB-204. All 
patients completed HGB-204 and HGB-205 and enrolled for long-term follow-up in the LTF-303 
study. The median (min, max) duration of follow-up of patients with a non-β0/β0 genotype was 
44.63 (35.8, 61.3) months. All patients remain alive at last follow-up.    
 
The primary endpoint was transfusion independence (TI) by Month 24, defined as a weighted average 
Hb ≥9 g/dL without any RBC transfusions for a continuous period of ≥12 months at any time during 
the study after infusion of Zynteglo. Of the patients with a non-β0/β0 genotype, 11/14 (78.6%, 95% CI 
49.2%-95.3%) achieved TI by Month 24 (Table 5). Among these 11 patients, the median (min, max) 
weighted average Hb during TI was 10.51 (9.3, 13.3) g/dL (Table 5).  
 
All patients who have achieved TI at any time have maintained TI at Month 36 with a min, max 
duration of TI of 28.3+, 57.6+ months (N=11). The median (min, max) time to last RBC transfusion 
was 0.46 (0.2, 5.8) months following Zynteglo infusion.  
 



14 

In the 3 patients who did not achieve TI, reductions of 100%, 86.9% and 26.8% in transfusion volume 
requirements and of 100%, 85.3% and 20.7% in transfusion frequency were observed between 
Month 6 through Month 24 visit when compared to their pre-study levels of RBC transfusions. 
Reductions in volume and frequency were maintained at last follow-up in LTF-303. 
 
The median (min, max) total Hb at Month 6 for patients who had not received a transfusion for the 
prior 60 days was 10.60 (7.6, 13.4) g/dL (N=11). Total Hb remained stable at Month 24 with a median 
(min, max) of 10.60 (8.8, 13.7) g/dL (N=12) and at Month 36 with a median (min, max) of 
10.60 (7.8, 13.5) g/dL (N=13).  
 
After Zynteglo infusion, patient iron chelation was managed at physician discretion. Of the 
14 non-β0/β0 patients treated in HGB-204 and HGB-205 that completed Month 6, 9 patients (64.3%) 
reported ongoing chelation use at last follow-up. The remaining 5 patients (35.7%) had stopped iron 
chelation, of whom 4 patients (28.6%) have stopped chelation for at least 6 months with median (min, 
max) time from stopping chelation to last follow-up of 26.40 (11.5, 42.2) months for these 4 patients. 
Additionally, of the 14 treated patients, 3 patients in HGB-205 (21.4%) received phlebotomy to 
remove iron. For the 11 patients that achieved TI, 4 patients (36.4%) stopped chelation for at least 
6 months and 3 patients (27.3%) received phlebotomy. 
 
At 48 months after infusion of Zynteglo for patients who achieved TI, the median reduction (min, 
max) in serum ferritin levels from baseline was 70.00% (39.2, 84.8) (N=5, HGB-204; N=2, 
HGB-205). The median reduction in liver iron content from baseline was 62.50%, ranging from an 
83.3% reduction to a 269.2% increase (N=5, HGB-204; N=2, HGB-205). 
 
Studies HGB-207 and HGB-212 
 
HGB-207 and HGB-212 are ongoing Phase 3 open-label, single-arm 24-month studies that are planned 
to include approximately 39 adults, adolescents, and children with TDT (N=23, HGB-207; 
N=16, HGB-212), of whom 29 have a non-β0/β0 genotype (N=23, HGB-207; N=6, HGB-212) and 
10 have a β0/β0 genotype in HGB-212. These studies are conducted with improved transduction 
compared to Phase 1/2 studies, resulting in increased average number of functional copies of the 
transgene (βA-T87Q-globin) integrated in the autologous CD34+ cells. Eighteen adults and adolescents 
with TDT with a non-β0/β0 genotype have been treated with Zynteglo in Phase 3 studies 
(N=15, HGB-207; N=3, HGB-212) and their median (min, max) duration of follow-up was 
15.92 (5.6, 26.3) months. All patients remain alive at last follow-up. 
 
The primary endpoint was transfusion independence (TI) by Month 24, defined as a weighted average 
Hb ≥9 g/dL without any RBC transfusions for a continuous period of ≥12 months at any time during 
the study after infusion of Zynteglo. Ten patients are evaluable for assessment of TI. Of these, 
9/10 (90.0%, 95% CI 55.5-99.7%) achieved TI at last follow-up. Among these 9 patients, the median 
(min, max) weighted average Hb during TI was 12.22 (11.4, 12.8) g/dL (Table 5).  
 
All patients who have achieved TI have maintained TI with a min, max duration of TI of 
12.1+, 21.3+ months (N=9). The median (min, max) time to last RBC transfusion was 
1.08 (0.5, 2.2) months following Zynteglo infusion.  
 
For the only patient who did not achieve TI, a reduction of 51.5% in transfusion volume requirements 
and a reduction of 43.4% in transfusion frequency were observed from Month 12 to Month 24 when 
compared to their pre-study levels of RBC transfusions.  
 
The median (min, max) total Hb at Month 6 for patients who had not received a transfusion for the 
prior 60 days was 11.85 (8.4, 13.3) g/dL (N=18). Total Hb remained stable at Month 24 with a median 
(min, max) of 12.85 (12.5, 13.2) g/dL (N=2). 
 
After Zynteglo infusion, patient iron chelation was managed at physician discretion. Of the 
18 non-β0/β0 patients treated in HGB-207 and HGB-212 that completed Month 6, 5 patients (27.8%) 
reported ongoing chelation use at last follow-up. The remaining 13 patients (72.2%) had stopped iron 



15 

chelation, of whom 9 patients (50.0%) have stopped chelation for at least 6 months with median (min, 
max) time from stopping chelation to last follow-up of 16.89 (6.9, 25.4) months for these 9 patients. 
Additionally, of the 18 treated patients, 5 patients in HGB-207 (27.8%) received phlebotomy to 
remove iron. For the 9 patients that achieved TI, 6 patients (66.7%) stopped chelation for at least 
6 months and 2 patients (22.2%) received phlebotomy. 
  
Exploratory analyses were performed to evaluate resolution of dyserythropoiesis, the fundamental 
pathophysiological characteristic of TDT, in the bone marrow. Bone marrow biopsies taken before 
treatment were consistent with a diagnosis of TDT, including a low myeloid/erythroid ratio (N=15, 
HGB-207; N=3, HGB-212), reflective of erythroid hyperplasia. For 9 patients who achieved TI and 
had a Month 12 bone marrow assessment, myeloid/erythroid ratios increased from a median (min, 
max) of 0.2 (0.1 to 0.7) at baseline to a median (min, max) of 0.83 (0.6 to 1.9) at Month 12 after 
Zynteglo infusion, suggesting that Zynteglo improves erythropoiesis in patients with TDT.  
 
Overall results 
 
Figure 1 Median total haemoglobin over time in non-β0/β0 TDT patients treated with 

Zynteglo who have achieved transfusion independence (Studies HGB-204, 
HGB-205, HGB-207, LTF-303) 

 
Bars represent interquartile ranges. 
Total Hb represents those without any acute or chronic RBC transfusions within 60 days prior to the 
measurement date. 
 



16 

Table 5 Efficacy outcomes for non-β0/β0 TDT patients treated with Zynteglo (Studies 
HGB-204, HGB-205, HGB-207, HGB-212, LTF-303) 

 
HbAT87Q at 
6 months 

(g/dL) 
n 

median 
(min, max) 

HbAT87Q at 
24 months 

(g/dL) 
n 

median 
(min, max) 

Hb at 
6 months* 

(g/dL) 
n 

median 
(min, max) 

Hb at 
24 months* 

(g/dL) 
n 

median 
(min, max) 

TI** 
n/N^  
(%) 

[95% CI] 

WA Hb 
during TI 

(g/dL) 
n 

median 
(min, max) 

Duration 
of TI 

(months) 
n 

median 
(min, max) 

HGB-205 
4 

7.543 
(4.94, 9.59) 

4 
8.147 
(6.72, 
10.13) 

4 
10.73 

(7.6, 13.4) 

4 
10.91 

(8.8, 13.6) 

3/4  
(75.0%) 
[19.4, 
99.4] 

3 
11.35 

(10.5, 13.0) 

3 
NR  

(38.2+, 
57.6+) 

HGB-204 
10 

4.153 
(1.03, 8.52) 

10 
5.418 

(1.10, 9.60) 

7 
9.20 

(7.7, 13.3) 

8 
10.35 

(9.1, 13.7) 

8/10 
(80.0%) 
[44.4, 
97.5] 

8 
10.27 

(9.3, 13.3) 

8 
NR  

(28.3+, 
51.3+) 

HGB-207 
13 

9.324 
(3.35, 
10.60) 

3 
8.766 
(0.89, 
11.40) 

15 
11.80 

(8.4, 13.3) 

2 
12.85 

(12.5, 13.2) 

9/10 
(90.0%) 
[55.5, 
99.7] 

9 
12.22 

(11.4, 12.8) 

9 
NR 

(12.1+, 
21.3+) 

HGB-212 
3 

10.094 
(5.06, 
10.33) 

NA*** 3 
12.10 

(8.5, 12.2) 

NA*** NA*** NA*** NA*** 

*Patients who have not received transfusions in the prior 60 days.  
**Transfusion independence (TI): a weighted average Hb ≥9 g/dL without any RBC transfusions for a 
continuous period of ≥12 months at any time during the study after medicinal product infusion. 
***No patients are currently evaluable for these endpoints.   
N^ represents the total number of patients evaluable for TI, defined as patients who have completed 
their parent study (i.e., 24 months of follow-up), or achieved TI, or will not achieve TI in their parent 
study.  
NR = Not reached. NA = Not applicable. Hb = Total Hb. WA Hb = Weighted average Hb. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zynteglo in one or more subsets of the paediatric population in β-thalassaemia (see section 4.2 for 
information on paediatric use). 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. The European Medicines Agency 
will review new information on this medicinal product at least every year and this SmPC will be 
updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Zynteglo is an autologous gene therapy medicinal product consisting of autologous cells that have 
been genetically modified ex vivo. The nature of Zynteglo is such that conventional studies on 
pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable. 
 



17 

5.3 Preclinical safety data 
 
Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have 
not been conducted. 
 
The pharmacology, toxicology and genotoxicity of the BB305 LVV used for transduction in the 
manufacture of Zynteglo were evaluated in vitro and in vivo. An in vitro immortalisation (IVIM) assay 
conducted with BB305 LVV-transduced mouse bone marrow cells (BMCs) showed minimal 
mutagenic potential (Fitness Score ≈ 0.1 × 10-4). Insertion site analysis (ISA) of pre-transplantation 
transduced mouse BMCs and human CD34+ HSCs showed no enrichment for insertion in or near 
cancer-related genes. A pharmacology, biodistribution, toxicity and genotoxicity study was conducted 
in a mouse model of β-thalassaemia. In this study, there was no evidence of toxicity, genotoxicity or 
oncogenesis (tumorigenicity) related to BB305 LVV integration, and no toxicity related to production 
of βA-T87Q-globin. ISA of post-transplantation BMCs demonstrated no preferred integration in the 
proximity of or within genes associated clinically (for gamma retroviral vectors) with either clonal 
dominance or leukaemia, and no evidence of clonal dominance was observed. Additional studies with 
human CD34+ HSCs administered to immunodeficient, myeloablated mice demonstrated no toxicity, 
tumorigenicity or genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Cryostor CS5 
Sodium chloride 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
Frozen: 1 year at ≤-140°C. 
Once thawed: maximum 4 hours at room temperature (20°C-25°C). 
 
6.4 Special precautions for storage 
 
Store in the vapour phase of liquid nitrogen at ≤-140°C until ready for thaw and administration.  
 
Keep the infusion bag(s) in the metal cassette(s).  
 
Do not re-freeze after thawing. 
 
6.5 Nature and contents of container  
 
20 mL fluorinated ethylene propylene infusion bag(s), each packed in a transparent pouch inside a 
metal cassette.  
 
Zynteglo is shipped from the manufacturing facility to the infusion centre storage facility in a 
cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal 
cassette contains one infusion bag with Zynteglo. A patient may have multiple infusion bags.  
 
6.6 Special precautions for disposal and other handling 
 
Irradiation could lead to inactivation of the product. 



18 

 
Precautions to be taken before handling or administering the medicinal product 

• This medicinal product contains genetically modified human blood cells. Healthcare 
professionals handling Zynteglo should take appropriate precautions (wearing gloves, 
protective clothing and eye protection) to avoid potential transmission of infectious diseases.   

 
Preparation for the infusion 

• Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from 
the metal cassette. 

• Confirm that Zynteglo is printed on the infusion bag(s). 
• Confirm that patient identity matches the unique patient identification information located on 

the Zynteglo infusion bag(s). Do not infuse Zynteglo if the information on the patient 
specific-label on the infusion bag does not match the intended patient. 

• Account for all infusion bags and confirm each infusion bag is within the expiry date using the 
accompanying Lot Information Sheet.  

• Each infusion bag should be inspected for any breaches of integrity before thawing and 
infusion. If an infusion bag is compromised, follow the local guidelines and contact bluebird 
bio immediately. 

 
Thaw and administration 

• Thaw Zynteglo at 37°C in a water bath or dry bath. Thawing of each infusion bag takes 
approximately 2 to 4 minutes. Do not overthaw the medicinal product. Do not leave the 
medicinal product unattended and do not submerge the infusion ports if thawed in a water 
bath. 

• After thaw, mix the medicinal product gently by massaging the infusion bag until all of the 
contents are uniform. Expose the sterile port on the infusion bag by tearing off a protective 
wrap covering the port.  

• Access the medicinal product infusion bag and infuse per the administration site’s standard 
procedures for administration of cell therapy products. Do not use an in-line blood filter or an 
infusion pump. 

• Do not sample, alter, or irradiate the medicinal product. 
• Administer each infusion bag of Zynteglo via intravenous infusion over a period of less than 

30 minutes. If more than one infusion bag is provided, administer each infusion bag 
completely before proceeding to thaw and infuse the next bag. 

• Infuse Zynteglo as soon as possible and no more than 4 hours after thawing. Flush all Zynteglo 
remaining in the infusion bag and any associated tubing with at least 50 mL of 0.9% sodium 
chloride solution to ensure as many cells as possible are infused into the patient. 

 
Precautions to be taken for the disposal of the medicinal product 
 
The medicinal product contains genetically-modified cells. Local guidelines on handling human-
derived material should be followed for unused medicinal products or waste material. All material that 
has been in contact with Zynteglo (solid and liquid waste) should be handled and disposed of as 
potentially infectious waste in accordance with local guidelines on handling human-derived material.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
bluebird bio (Netherlands) B.V. 
Stadsplateau 7 
WTC Utrecht 
3521AZ Utrecht 
The Netherlands 
 
 



19 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1367/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 May 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD month YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu <, and on the website of {name of MS Agency (link)}>.   



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 

SUBSTANCE(S) AND 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 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 

  



21 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
apceth Biopharma GmbH 
Haidgraben 5 
85521 Ottobrunn 
GERMANY 
 
Name and address of the manufacturer(s) responsible for batch release 
 
apceth Biopharma GmbH 
Haidgraben 5 
85521 Ottobrunn 
GERMANY 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to special and 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 (PSURs) 
 
The requirements for submission of PSURs 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. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (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. 

• Additional risk minimisation measures  
 
Prior to launch of Zynteglo in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational and controlled distribution programme, 



22 

including communication media, distribution modalities, and any other aspects of the programme, with 
the National Competent Authority.  
 
The educational and controlled distribution programme is aimed at providing information on the safe 
use of Zynteglo. 
 
The MAH shall ensure that in each Member State where Zynteglo is marketed, all healthcare 
professionals and patients/carers who are expected to prescribe, dispense and/or use Zynteglo have 
access to/are provided with the following educational package to be disseminated through professional 
bodies: 
 

• Physician educational material 
• Patient information pack 

 
The physician educational material should contain: 

o The Summary of Product Characteristics  
o Guide for healthcare professionals  
o Guide for handling and method of administration. 

 
• The Guide for healthcare professionals shall contain the following key elements: 

o Warnings and precautions of the mobilisation agents and the myeloablative conditioning 
agent must be considered. 

o Treatment with Zynteglo in the clinical trials was associated with delayed platelet 
engraftment. No correlation was observed between incidence of bleeding adverse events 
(AEs) and time to platelet engraftment. Precautions regarding bleeding consequences of 
thrombocytopenia need to be taken. Patients should be made aware of the risk of bleeding 
events that are not easily identifiable, such as internal bleeding.  

o Treatment with Zynteglo is in theory associated with the risk of insertional mutagenesis, 
potentially leading to development of malignancy. All patients must be advised on signs of 
leukaemia and to seek immediate medical attention if these signs are present. 

o A negative serology test for HIV is necessary to ensure acceptance of apheresis material 
for Zynteglo manufacturing. 

o The potential risk of loss of response to gene therapy may lead to loss of transfusion 
independence or increase transfusion needs for patients who did not reach transfusion-
independence. 

o All patients should receive annual monitoring of complete blood counts and total 
haemoglobin levels to monitor for leukaemia/lymphoma and maintenance of efficacy, 
respectively. 

o The short-term potential risk of treatment with Zynteglo represents failure of engraftment, 
which shall be managed by administration of rescue cells.  

o The need to explain and to ensure that patients understand: 
– potential risks of treatment with Zynteglo  
– signs of leukaemia/lymphoma and what action to take 
– content of patient’s guide 
– the need to carry the patient alert card and show it to every healthcare professional 
– enrolment in the drug product Registry. 

o Scope of the Registry and how to enrol patients. 
 

• The Guide to handling and method of administration for healthcare professionals shall 
contain the following key elements: 
o Instructions on receiving and storing of Zynteglo and how to check Zynteglo prior to 

administration 
o Instructions about the thawing of Zynteglo 
o Instructions on protective equipment and treatment of spills. 

 
The patient information pack should contain: 

o Package leaflet 



23 

o A patient/carer guide 
o A patient alert card. 

 
• The patient/carer guide shall contain the following key messages: 

o Treatment with Zynteglo is in theory associated with the risk of development of 
malignancy. Signs of leukaemia and the need to obtain urgent medical care if these signs 
are present.  

o Patient alert card and the need to carry it on their person and tell any treating healthcare 
professional that they were treated with Zynteglo. 

o The potential risk of loss of response to gene therapy may lead to loss of transfusion 
independence or increase transfusion needs for patients who did not reach transfusion-
independence. 

o The importance of annual check-ups. 
o Treatment with Zynteglo is associated with the risk of delayed platelet engraftment that 

could lead to an increased tendency for bleeding.  
o Signs and symptoms of bleeding and the need to contact the physician if any signs of 

unusual or prolonged bleeding or any other relevant signs are present. 
o Enrolment in the drug product Registry. 

 
• The patient alert card shall contain the following key messages: 

o Information of risk of delayed platelet engraftment, potentially leading to bleeds, and 
theoretical risks. 

o Statement that the patient was treated with gene therapy and should not donate blood, 
organs, tissues, or cells. 

o Statement that the patient was treated with Zynteglo, including LOT number and treatment 
date(s). 

o Details on reporting of adverse effects. 
o Information on the possibility of false positivity of certain commercial HIV tests because 

of Zynteglo. 
o Contact details where a health care professional can receive further information. 

 
The MAH shall ensure that in each Member State where Zynteglo is marketed, a system aimed to 
control distribution to Zynteglo beyond the level of control ensured by routine risk minimisation 
measures. The following requirements need to be fulfilled before the product is prescribed, 
manufactured, dispensed and used: 
 

• Zynteglo will only be available through bluebird bio qualified treatment centres to ensure 
traceability of the patient`s cells and manufactured drug product between the treating hospital 
and manufacturing site. The selection of the treatment centres will be conducted in 
collaboration with national health authorities as appropriate. 

 
• Obligation to conduct post-authorisation measures  
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
In order to further confirm the appropriateness of the acceptance criteria, the 
MAH should re-evaluate the acceptance criteria for attributes related to 
potency tests using batch release data and clinical results after 6 months 
follow-up of 20 patients treated with commercial batches.    

Interim report: 
at each annual 
renewal  
 
When 20 
patients have 
been treated 
with 6 months 
follow-up 



24 

Non interventional post-authorisation safety study (PASS): In order to further 
characterise and contextualise the long-term safety and efficacy of Zynteglo in 
patients 12 years and older with transfusion-dependent β-thalassaemia (TDT) 
who do not have a β0/β0 genotype, the MAH should conduct and submit the 
results of a study based on data from a product registry (REG-501) and use 
data on HLA-matched allogenic HSCT treated patients from an established 
European registry as a comparator group. 

Protocol 
submission: 
December 2020 
 
Interim results:  
- at each annual 
renewal  
- Dec. 2024 
- Dec. 2034 
 
Final results: 
Q4 2039 

 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 

THE CONDITIONAL MARKETING AUTHORISATION 
 
This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 
 

Description Due date 
In order to confirm the efficacy and safety of Zynteglo in patients 12 years and 
older with transfusion-dependent β-thalassaemia (TDT) who do not have a 
β0/β0 genotype, the MAH should submit interim and final data on Study 
HGB-207 

Interim results: 
at each annual 
renewal  
 
Final results: 
December 2021 

In order to confirm the efficacy and safety of Zynteglo in patients 12 years and 
older with transfusion-dependent β-thalassaemia (TDT) who do not have a 
β0/β0 genotype, the MAH should submit interim and final data from patients 
with a severe non-β0/β0 genotype such as IVS-I-110 included in Study 
HGB-212. 

Interim results: 
at each annual 
renewal  
 
Final results: 
December 2021 

In order to confirm the efficacy and safety of Zynteglo in patients 12 years and 
older with transfusion-dependent β-thalassaemia (TDT) who do not have a 
β0/β0 genotype, the MAH should submit interim data and the 5 years follow-up 
results of Study LTF-303. 

Interim results: 
at each annual 
renewal  
 
Final results: 
December 2024 

 
 
 
 
 
 
 
 
 
 
 
 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING – METAL CASSETTE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynteglo 1.2-20 × 106 cells/mL dispersion for infusion  
(betibeglogene autotemcel) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
A genetically modified autologous CD34+ cell enriched population that contains haematopoietic stem 
cells transduced with lentiviral vector encoding the βA-T87Q-globin gene with a strength of 1.2-20 × 106 
cell/mL.  
 
 
3. LIST OF EXCIPIENTS 
 
Also contains Cryostor CS5 and sodium chloride. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Dispersion for infusion 
 
20 mL 
See Lot Information Sheet for number of infusion bags and CD34+ cells per kg for this patient. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous 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 
 
For autologous use only. 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the vapour phase of liquid nitrogen at ≤-140°C until ready for thaw and administration. Keep 
infusion bag(s) in the metal cassette(s). Once thawed do not re-freeze. 



28 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
This medicine contains genetically-modified cells. Unused medicine must be disposed of in 
compliance with the local guidelines on handling human-derived material.  
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
bluebird bio (Netherlands) B.V. 
Stadsplateau 7 
WTC Utrecht 
3521AZ Utrecht 
The Netherlands 
Tel: +31 (0) 303 100 450 
e-mail: medinfo@bluebirdbio.com 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1367/001 
 
 
13. BATCH NUMBER, DONATION AND PRODUCT CODES 
 
Patient ID: 
COI ID: 
Last Name: 
First Name:  
Date of Birth: 
DIN: 
Lot:  
Bag ID: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 



29 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
INFUSION BAG  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Zynteglo 1.2-20 × 106 cells/mL dispersion for infusion  
(betibeglogene autotemcel) 
For intravenous use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER, DONATION AND PRODUCT CODES 
 
Patient ID: 
COI ID: 
Last Name  
First Name: 
Date of Birth: 
DIN: 
Lot:  
Bag ID: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
See Lot Information Sheet for number of infusion bags and CD34+ cells per kg for this patient. 
20 mL 
 
 
6. OTHER 

 
For autologous use only. 



30 

PARTICULARS TO APPEAR ON THE LOT INFORMATION SHEET INCLUDED WITH 
EACH SHIPMENT FOR ONE PATIENT 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zynteglo 1.2-20 × 106 cells/mL dispersion for infusion  
(betibeglogene autotemcel) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Zynteglo is a genetically modified autologous CD34+ cell enriched population that contains 
haematopoietic stem cells transduced with lentiviral vector encoding the βA-T87Q-globin gene. 
 
 
3. DONATION AND PRODUCT CODES 
 
PATIENT INFORMATION 
 
Name (Last, First): 
Date of Birth (DD/MM/YYYY): 
Weight at First Collection (kg):  
Patient ID: 
 
 
4. BATCH NUMBER, CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT, AND 
EXPIRY DATE 
 
INFORMATION ON SUPPLIED LOT(S) 
 
The following lot(s) was manufactured and included in the shipment: 

Lot 
Number / 
COI ID  

DIN 
(List all 

collections) 

Number of 
Infusion 

Bags 

Bag ID 
(List each 
infusion 

bag) 

Strength 
(× 106 

cells/mL) 

CD34+ 
Cells 
(× 106 
CD34+ 
cells) 

Expiry 
Date 

(DD/MM/
YYYY) 

       
       
       
       

 
 
5. DOSE OF THE MEDICINAL PRODUCT 
 
Total Number of Infusion Bags: __ 
Dose: {N.N} × 106 CD34+ cells/kg  
 
The minimum recommended dose of Zynteglo is 5.0 × 106 CD34+ cells/kg. In clinical studies doses up 
to 20 × 106 CD34+ cells/kg have been administered. 
 
 



31 

6. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
SAVE THIS DOCUMENT AND PREPARE TO HAVE IT AVAILABLE AT THE TIME OF 
ZYNTEGLO INFUSION. 
 
Read the package leaflet before use. 
For autologous use only. 
 
 
7. SPECIAL STORAGE CONDITIONS 
 
INSTRUCTIONS FOR STORAGE AND USE 
 
Store in the vapour phase of liquid nitrogen at ≤-140°C until ready for thaw and administration. Keep 
infusion bag(s) in the metal cassette(s). Once thawed do not re-freeze. 
 
 
8. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
This medicine contains genetically-modified cells. Unused medicine must be disposed of in 
compliance with the local guidelines on handling human-derived material. 
 
 
9. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
MARKETING AUTHORISATION HOLDER AND NUMBER 
 
bluebird bio (Netherlands) B.V. 
Stadsplateau 7 
WTC Utrecht 
3521AZ Utrecht 
The Netherlands 
e-mail: medinfo@bluebirdbio.com 
 
 
10. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1367/001 
  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



33 

Package leaflet: Information for the patient or carer 
Zynteglo 1.2-20 × 106 cells/mL dispersion for infusion 

betibeglogene autotemcel  
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
 
You will be given a Patient Alert Card which contains important safety information that you need to 
know about your treatment with Zynteglo. You should carry the Patient Alert Card with you at all 
times and show it to your doctor or nurse when you see them or if you are admitted to the hospital. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. See section 4. 
- Read the Patient Alert Card carefully and follow the instructions on it.  

 
What is in this leaflet 
1. What Zynteglo is and what it is used for  
2. What you need to know before you are given Zynteglo 
3. How Zynteglo is given 
4. Possible side effects  
5. How to store Zynteglo  
6. Contents of the pack and other information 
 
 
1. What Zynteglo is and what it is used for 
 
Zynteglo is used to treat a serious genetic disease called transfusion-dependent beta-thalassaemia 
(TDT), which includes the disease commonly known as beta-thalassaemia major, in people 12 years 
and older. People with this condition cannot make enough haemoglobin, a protein in the blood that 
carries oxygen. More specifically, people with TDT do not make enough of a part of the haemoglobin 
called beta-globin, due to a gene defect. Because of this defect, people with TDT are anaemic and need 
frequent blood transfusions to survive. 
 
Zynteglo is a type of medicine called gene therapy. It is made specifically for each patient, using the 
patient’s own (also called autologous) blood stem cells. Zynteglo works by adding functional copies of 
the beta-globin gene into these cells, so that the patient can make enough beta-globin to increase total 
haemoglobin, improve anaemia, and carry more oxygen around their body. This reduces or eliminates 
the need for blood transfusions. 
 
 
2. What you need to know before you are given Zynteglo 
 
You must not be given Zynteglo if you: 
- are allergic to any of the ingredients of this medicine (listed in section 6) 
- are pregnant or breast-feeding 
- have previously received gene therapy of your blood stem cells 
- are allergic to any of the ingredients in the medicines you will be given for mobilisation and 

chemotherapy (see section 3). 
 
Warnings and precautions  
Talk to your doctor before you are given Zynteglo. 
 



34 

Before treatment with Zynteglo, you will be given medicines know as mobilisation medicine and 
chemotherapy medicine (see sections 3 and 4 for more information on these medicines, including 
possible side effects). 
 
Before treatment with Zynteglo, your doctor will perform tests to make sure your heart and liver are 
functioning properly so you can be treated safely with Zynteglo.  
 
Zynteglo is made specifically for you, using your own blood stem cells.  
 
After you have been treated with Zynteglo, you will not be able to donate blood, organs, or tissues in 
the future. This is because Zynteglo is a gene therapy medicine.  
 
Adding a new gene into the DNA of your blood stem cells could theoretically cause leukaemia or 
lymphoma, although no patients have developed leukaemia or lymphoma in clinical trials with 
Zynteglo. After treatment with Zynteglo, you will be asked to enrol in a registry for at least 15 years in 
order to better understand the long-term effects of Zynteglo. During the long-term follow-up, your 
doctor will monitor you for any signs of leukaemia or lymphoma.  
 
Zynteglo is prepared using parts of the human immunodeficiency virus (HIV), which have been altered 
so that they cannot cause HIV infection. The modified virus is used to insert a functional beta-globin 
gene into your blood stem cells. Although this medicine will not give you HIV infection, having 
Zynteglo in your blood may cause a false positive HIV test result with some commercial tests that 
recognise a piece of HIV used to make Zynteglo. If you test positive for HIV following treatment, 
please contact your doctor or nurse.  
 
Before receiving Zynteglo you will be given chemotherapy in order to remove your existing bone 
marrow. If Zynteglo cannot be administered after chemotherapy or if the modified stem cells do not 
take hold (engraft) in your body, the doctor may give you an infusion of your own original blood stem 
cells that were collected and stored before the treatment started (see also section 3, How Zynteglo is 
given).  
 
After you receive Zynteglo, you may have a low number of platelets in your blood. This means that 
your blood may not be able to clot as well as normal and you may be prone to bleeding. You must get 
medical attention if you:  

• bump your head or have a head injury 
• have symptoms that could be from internal bleeding, such as unusual stomach or back pain, or 

severe headache 
• have abnormal bruising or bleeding (such as bruising without injury, blood in your urine, 

stool, vomit, or cough up blood). 
Your doctor will tell you when your platelet count has recovered to normal levels. 
 
Other medicines and Zynteglo  
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
You should not take hydroxyurea (a medicine for blood disorders) or any medicines for HIV infection 
from at least one month before you undergo mobilisation until at least 7 days after Zynteglo infusion 
(see also section 3, How Zynteglo is given). 
 
You should stop taking medicines to remove iron from your body (so-called chelating agents: 
deferoxamine, deferiprone and/or deferasirox) 7 days before you start the chemotherapy before the 
infusion of Zynteglo (see section 3, How Zynteglo is given). Your doctor will advise you if and when 
you should start taking these medicines after Zynteglo infusion.  
 
Talk to your doctor if you need to have any vaccinations.  
 



35 

Pregnancy, breast-feeding and fertility 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, tell 
your doctor before you are given this medicine. 
 
If you are a woman, you will be given a pregnancy test before starting mobilisation, before you are 
given chemotherapy, and before Zynteglo treatment in order to confirm that you are not pregnant. 
 
Women who could become pregnant and men capable of fathering a child must start using a reliable 
method of contraception from before their blood stem cells are collected and continue until at least 6 
months after receiving Zynteglo.  Reliable methods of contraception include intra-uterine device or a 
combination of oral contraceptive (also know as the pill) and condoms. 
 
The added gene from Zynteglo will not be passed on to your children. Your children are still at risk of 
inheriting your original beta-globin gene. 
 
You should not be given Zynteglo if you are breast-feeding. It is not known whether the ingredients of 
Zynteglo can pass into breast milk. 
 
It may no longer be possible for you to become pregnant or father a child after receiving chemotherapy 
medicine. If you are concerned about having children, you should discuss this with your doctor before 
treatment. Options may include providing reproductive material for storage in a tissue bank to use at a 
later time. For men, this may be sperm or testicular tissue. For women, this may be eggs (oocytes) or 
ovarian tissue. 
 
Driving and using machines 
Zynteglo has no influence on the ability to drive or use machines. However, the mobilisation and 
chemotherapy medicines may cause dizziness and fatigue. Avoid driving or using machines if you feel 
dizzy, tired or unwell. 
 
Sodium content 
This medicine contains 391-1564 mg sodium (main component of cooking/table salt) in each dose. 
This is equivalent to 20-78% of the recommended maximum daily dietary intake of sodium for an 
adult. 
 
 
3. How Zynteglo is given 
 
Zynteglo is given by a drip (infusion) into a vein. It can only be given in a specialised hospital by 
doctors who are experienced in treating patients with TDT, administering bone marrow transplants, 
and using gene therapy medicines. 
 
Zynteglo can only be made if enough of the right kind of blood stem cells can be collected from your 
blood (CD34+ blood stem cells). Approximately 2 months before treatment with Zynteglo, you will be 
given a mobilisation medicine that will move your blood stem cells from your bone marrow into your 
blood stream. The blood stem cells can then be collected by a machine that separates blood 
components (apheresis machine). It may take more than 1 day to collect enough blood stem cells to 
make Zynteglo and to store as replacement cells if Zynteglo cannot be given or does not work. 
 

Time What happens Why 
Approximately 2 months 
before Zynteglo infusion 

Mobilisation medicine is given To move the blood stem cells 
from your bone marrow into 
your blood stream. 

Approximately 2 months 
before Zynteglo infusion 

Blood stem cells are collected  To make Zynteglo and to serve 
as replacement cells if needed. 

At least 6 days before Zynteglo 
infusion 

A chemotherapy medicine is 
given for 4 days in a hospital 

To prepare your bone marrow 
for treatment with Zynteglo. 



36 

Time What happens Why 
Start of Zynteglo treatment Zynteglo is given by a drip 

(infusion) into a vein. This will 
take place in a hospital and will 
take less than 30 minutes for 
each infusion bag. The number 
of bags will vary by patient. 

To add blood stem cells 
containing functional copies of 
the beta-globin into your bone 
marrow. 

After Zynteglo infusion You will remain in the hospital 
for approximately 3-6 weeks 

To recover and be monitored 
until your doctor is satisfied 
that it is safe for you to leave 
the hospital. 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Some side effects observed in clinical studies with Zynteglo are related to mobilisation and blood stem 
cell collection or to the chemotherapy medicine used to prepare your bone marrow for treatment with 
Zynteglo.  
 
You should discuss possible side effects due to the mobilisation medicines and chemotherapy medicine 
with your doctor. You should also read the package leaflets for these medicines. 
 
Mobilisation and blood stem cell collection 
Most of these side effects occur during or within a few days after mobilisation and blood stem cell 
collection but can occur later. Tell your doctor immediately if side effects become severe or serious.  
 
Very common side effects (may affect more than 1 in 10 people) 

• a low level of blood platelets, which may reduce the ability of blood to clot 
• bone pain 
• numbness and pain in hands and feet 
• feeling sick (nausea) 
• headache 
• low blood calcium level 

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

• bleeding  
• low oxygen level in blood  
• low blood pressure 
• abdominal pain 
• back pain 
• bone or muscle pain 
• chest pain or discomfort 
• other pain 
• agitation  
• abnormal blood test results (decrease in magnesium and potassium, too much citrate, or 

increase in white blood cells) 
• abnormal heart rhythm  
• bruising, bleeding or pain from catheter or injection site 
• injection site reaction  
• bruising   
• dizziness, tiredness 
• head discomfort 
• excessive sweating 



37 

• flu like illness 
• lip swelling 
• tingling or numbness of the hands, feet, or mouth 
• fever 
• rash 
• enlarged spleen which may result in pain in your upper left belly or left shoulder 
• vomiting  

 
Chemotherapy medicine 
Tell your doctor immediately if you get any of the following side effects after receiving 
chemotherapy medicine. They usually happen within the first few days and several weeks after 
receiving chemotherapy medicine, but can also develop much later. 
 
Very common (may affect more than 1 in 10 people) 

• Pain in the right upper abdomen under the ribs, yellowing of eyes or skin, rapid weight gain, 
swelling of arms, legs and abdomen, and trouble breathing. These may be signs of a serious 
liver condition called veno-occlusive disease. 

• Prolonged bleeding or bleeding without injury such as nosebleeds, bleeding from gums, or 
vaginal bleeding. 

 
Other possible side effects 
 
Tell your doctor immediately if side effects become severe or serious. 
 
Very common side effects (may affect more than 1 in 10 people) 

• low level of red and white blood cells, sometimes with a fever 
• increase of certain enzymes in the blood which may indicate a problem with your liver 
• a low level of blood platelets, which may reduce the ability of blood to clot 
• unusual hair loss or thinning 
• stomach pain, constipation, diarrhoea 
• feeling sick (nausea), being sick (vomiting) 
• fever 
• soreness of the mouth 
• inflammation of the throat 
• dark patches on skin 
• soreness of the rectum area 
• trouble sleeping 
• decreased appetite 
• headache 
• tiredness 
• itchy skin 
• soreness and swelling of the digestive tract lining which runs from the mouth to the anus 

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

• life-threatening inflammatory response to an infection along with low white blood cell count 
• heart failure 
• infections which may make you feel warm, chilly, or sweaty 
• mass in the lungs 
• enlarged abdomen 
• enlarged liver 
• difficulty breathing  
• abdominal pain 
• bleeding or bruising  
• blood in urine 
• yellowing of eyes or skin 



38 

• small tear in tissue that lines the anus 
• dizziness, or sensation of feeling off balance or like the room is spinning 
• memory problems  
• anxiety  
• positive test for Aspergillus (lung disease caused by fungus) 
• changes and abnormalities in heart rhythm 
• pain, including in back, bone, skin, limbs, anus, or muscles 
• vaginal yeast infection 
• heartburn 
• inflammation of the gallbladder 
• gallstones 
• cough 
• abnormal sense of taste or loss of taste 
• difficulty swallowing 
• swelling of the face 
• feeling cold 
• excess water in the body 
• inflammation or infection of hair follicles 
• decrease in speed of air leaving your lungs 
• stomach discomfort with nausea and vomiting 
• inflammation in the digestive tract 
• gum disease 
• piles (haemorrhoids) 
• hiccups 
• low blood pressure 
• low body temperature 
• low oxygen level in blood 
• pain in mouth, throat or larynx (voice box) 
• lack of energy 
• irregular menstruation 
• loss of function or decreased function of your ovaries or testes 
• premature menopause  
• spots on skin from bleeding under the skin 
• skin that is discoloured, blotchy, or darker or lighter than normal  
• fluid in or around the lung 
• hot flush 
• increased frequency of urination 
• dry, itchy skin  
• dry lips 
• rash sometimes with lesions or pus  
• inflamed skin lesions 
• skin abrasion/scrape 
• sweat gland disorder 
• transfusion reaction 
• weight decreased 
• abnormal liver tests 
• increased concentration of haemoglobin in cells 
• changes in magnesium, calcium, potassium, phosphate, albumin, protein, sodium in blood 
• increase in blood test for inflammation 
• excess acid in the body not removed by the kidneys 
• increase or decrease in white blood cells 
• low number of immature (not fully developed) red blood cells  
• increase in female hormones 
• decreased testosterone 



39 

 
Zynteglo 
Most side effects occur during or within a few days after treatment with Zynteglo but can occur later. 
Tell your doctor immediately if side effects become severe or serious. 
 
Very common side effects (may affect more than 1 in 10 people) 

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

• low level of blood platelets, which may reduce the ability of blood to clot 
• low level of white blood cells 
• shortness of breath 
• chest pain not due to a heart problem 
• flushing (redness and warmth of skin) 
• pain in legs 

 
Reporting of side effects 
If you get any side effects, talk to your doctor 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 Zynteglo 
 
This information is intended for doctors only. 
 
As this medicine will be given by a qualified doctor, they are responsible for the correct storage of the 
medicine before and during its use, as well as for its correct disposal.  
 
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 outer container label(s) and 
infusion bag label(s). 
 
Store at ≤-140°C for up to a year. Do not thaw the product until it is ready to be used. Once thawed 
store at room temperature (20°C-25°C) and use within 4 hours. 
 
This medicine contains genetically-modified cells. Unused medicine must be disposed of in 
compliance with the local guidelines on handling human-derived material.  
 
 
6. Contents of the pack and other information 
 
What Zynteglo contains  
- The active substance of Zynteglo consists of your own blood stem cells that contain functional 

copies of the beta-globin gene that can be measured in your blood. The concentration is 
1.2-20 × 106 CD34+ cells (blood stem cells) per millilitre. 

- The other ingredients are a solution used to preserve frozen cells and sodium chloride. See section 
2, Sodium content. 

 
What Zynteglo looks like and contents of the pack 
Zynteglo is a clear to slightly cloudy, colourless to yellow or pink dispersion of cells that is supplied in 
one or more clear infusion bags, each packed in a transparent pouch inside a closed metal container.  
 



40 

Your name and date of birth, as well as coded information identifying you as the patient, are printed 
onto each infusion bag and each metal container. 
 
Marketing Authorisation Holder and Manufacturer 
bluebird bio (Netherlands) B.V.  
Stadsplateau 7  
WTC Utrecht  
3521AZ Utrecht  
The Netherlands  
medinfo@bluebirdbio.com 
 
Manufacturer 
apceth Biopharma GmbH  
Haidgraben 5 
85521 Ottobrunn 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:  
 
Deutschland 
bluebird bio (Germany) GmbH 
Tel: +49 (0) 893 803 7456 (0800 181 0702) 
 

Italia 
bluebird bio (Italy) S.r.l. 
Tel: +39 029 475 9755 (800 728 026) 
 

France 
bluebird bio (France) SAS 
Tél: +33 (0)1 85 14 97 89 (0800 914 510) 
 

Nederland 
bluebird bio (Netherlands) B.V. 
Tel: +31 (0) 303 100 450 

Ελλάδα/ Κύπρος 
bluebird bio Greece Single Member L.L.C. 
Τηλ: +30 21 0300 5938 
 

United Kingdom 
bluebird bio (UK) Limited 
Tel: +44 (0) 207 660 0754 
 (0800-069-8046) 

België/Belgique/Belgien, България, Česká 
republika, Danmark, Eesti, España, Hrvatska, 
Ireland, Ísland, Latvija, Lietuva, 
Luxembourg/Luxemburg, Magyarország, 
Malta, Norge, Österreich, Polska, Portugal, 
România, Slovenija, Slovenská republika, 
Suomi/Finland, Sverige 
bluebird bio (Netherlands) B.V. 
Tél/Tel/Teл/Tlf/ Sími/Puh:  
+31 (0) 303 100 450 
medinfo@bluebirdbio.com   
 

 
 

This leaflet was last revised in <{MM/YYYY}> 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine.  
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu<, and on the website of {name of MS Agency (link)}>. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 
----------------------------------------------------------------------------------------------------------------- 
 



41 

The following information is intended for healthcare professionals only:  
 
Zynteglo is shipped from the manufacturing facility to the infusion centre storage facility in a 
cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal 
cassette contains one infusion bag with Zynteglo. A patient may have multiple infusion bags. The 
infusion bag(s) must be kept inside the metal cassette(s) until ready to thaw and use. 
 
Confirm that Zynteglo is printed on the infusion bag(s). Confirm that patient identity matches the 
unique patient information located on the infusion bag(s) and metal cassette(s) prior to infusion. 
Account for all infusion bags and confirm each infusion bag of Zynteglo is within the expiry date 
using the accompanying Lot Information Sheet.  
 
Inspect each infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag 
is compromised, follow the local guidelines on handling human-derived material and contact bluebird 
bio immediately. 
 
Zynteglo is intended solely for autologous use.  
 
After carefully removing the outer metal container, thaw each infusion bag at 37°C in a water bath or 
dry bath for approximately 2-4 minutes. Do not overthaw the medicinal product. Do not leave the 
medicinal product unattended and do not submerge the infusion ports if thawed in a water bath. After 
thaw, mix the medicinal product gently by massaging the infusion bag until all of the contents are 
uniform. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the 
port. Access the infusion bag and infuse per the administration site’s standard procedures for 
administration of cell therapy products. Do not use an in-line blood filter or an infusion pump. Do not 
sample, alter, or irradiate the medicinal product.  
 
Administer each infusion bag via intravenous infusion over a period of less than 30 minutes. If more 
than one infusion bag is provided, administer each infusion bag completely before proceeding to thaw 
and infuse the next bag.  
 
Zynteglo must not be re-frozen. Infuse as soon as possible and no more than 4 hours after thawing.  
 
Flush all Zynteglo remaining in the infusion bag and any associated tubing with at least 50 mL of 
0.9% sodium chloride solution to ensure as many cells as possible are infused into the patient. 
 
This medicinal product contains genetically-modified cells. Local guidelines on handling and waste of 
human-derived material applicable for such products should be followed. 
 
Healthcare professionals handling Zynteglo should take standard precautions (wearing gloves, 
protective clothing and eye protection) to avoid potential transmission of infectious diseases. 
 
Work surfaces and material which have potentially been in contact with Zynteglo must be 
decontaminated with a viricidal disinfectant according to the manufacturer's instructions.  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASEB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USEC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATIOND. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCTE. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET