Qarziba

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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 
 
Qarziba 4.5 mg/mL concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 mL of concentrate contains 4.5 mg dinutuximab beta. 
Each vial contains 20 mg dinutuximab beta in 4.5 mL. 
 
Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody produced in a mammalian 
cell line (CHO) by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion 
Clear, colourless liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Qarziba is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months and 
above, who have previously received induction chemotherapy and achieved at least a partial response, 
followed by myeloablative therapy and stem cell transplantation, as well as patients with history of 
relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of 
relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable 
measures. 
 
In patients with a history of relapsed/refractory disease and in patients who have not achieved a 
complete response after first line therapy, Qarziba should be combined with interleukin-2 (IL-2). 
 
4.2 Posology and method of administration 
 
Qarziba is restricted to hospital-use only and must be administered under the supervision of a 
physician experienced in the use of oncological therapies. It must be administered by a healthcare 
professional prepared to manage severe allergic reactions including anaphylaxis in an environment 
where full resuscitation services are immediately available. 
 
Posology 
Treatment with Qarziba consists of 5 consecutive courses, each course comprising 35 days. The 
individual dose is determined based on the body surface area and should be a total of 100 mg/m2 per 
course. 
 



 

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Two modes of administration are possible: 
• a continuous infusion over the first 10 days of each course (a total of 240 hours) at the daily 

dose of 10 mg/m2 
• or five daily infusions of 20 mg/m2 administered over 8 hours, on the first 5 days of each course  
 
When IL-2 is combined with Qarziba, it should be administered as subcutaneous injections of 
6×106 IU/m2/day, for 2 periods of 5 consecutive days, resulting in an overall dose of 60×106 IU/m2 per 
course. The first 5-day course should start 7 days prior to the first infusion of dinutuximab beta and the 
second 5-day course should start concurrently with dinutuximab beta infusion (days 1 to 5 of each 
dinutuximab beta course). 
 
Prior to starting each treatment course, the following clinical parameters should be evaluated and 
treatment should be delayed until these values are reached:  
• pulse oximetry > 94% on room air 
• adequate bone marrow function: absolute neutrophil count ≥ 500/µL, platelet count 

≥ 20,000/µL, haemoglobin > 8.0 g/dL 
• adequate liver function: alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) 

< 5 times upper limit of normal (ULN) 
• adequate renal function: creatinine clearance or glomerular filtration rate (GRF) 

> 60 mL/min/1.73 m2 
 
Dose modification of dinutuximab beta 

Based on the physician’s evaluation of the severity of adverse drug reactions to dinutuximab beta, 
patients may undergo a dose reduction of 50% or a temporary interruption of the infusion. As a 
consequence, either the infusion period is prolonged or, if tolerated by the patient, the infusion rate 
may be increased up to 3 mL/h (continuous infusion), in order to administer the total dose. 
 

Recommended dose modifications for dinutuximab beta 
Adverse reaction  Severity Treatment modification 

Any Grade 1 – 2 Decrease infusion rate to 50%, 
After resolution, resume infusion at 
original rate 

Hypersensitivity 
reaction 

e.g. hypotension Interrupt infusion and administer 
supportive measures, 
After resolution, resume infusion at 
original rate 

Dilated pupils with sluggish light reflex +/- photophobia Interrupt infusion, 
After resolution, resume infusion at 
50% rate 

Any Grade ≥ 3 Interrupt infusion and administer 
supportive measures, 
Resume infusion at 50% rate if ADR 
resolves or improves to Grade 1 – 2, 
After resolution, increase to original 
rate 

 Recurrent Discontinue infusion, 
Resume next day if ADR resolves 

Hypersensitivity 
reaction 

e.g. bronchospasm, angioedema Interrupt infusion immediately and 
treat appropriately (see section 4.4), 
Resume treatment for subsequent 
courses 

Capillary leak 
syndrome 

 Interrupt infusion and administer 
supportive measures, 
Resume at 50% rate if ADR resolves 
or improves to Grade 1 – 2 

 



 

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Treatment with dinutuximab beta should be permanently discontinued if the following toxicities occur: 
• grade 3 or 4 anaphylaxis 
• prolonged grade 2 peripheral motor neuropathy 
• grade 3 peripheral neuropathy 
• grade 3 vision eye toxicity 
• grade 4 hyponatremia (< 120 mEq/L) despite appropriate fluid management 
• recurrent or grade 4 capillary leak syndrome (requires ventilator support) 
 

Renal and hepatic impairment 

There are no data in patients with renal and hepatic impairment (see section 5.2). 
 
Paediatric population 

The safety and efficacy of Qarziba in children aged less than 12 months have not yet been established. 
No data are available.  
 
Method of administration  
Qarziba is for intravenous infusion. The solution should be administered via a peripheral or central 
intravenous line. Other intravenously co-administered agents should be delivered via a separate 
infusion line (see section 6.6). 
 
For continuous infusions, the solution is administered at a rate of 2 mL per hour (48 mL per day) using 
an infusion pump. 
 
For 8-hour daily infusions, the solution is administered at a rate of approximately 13 mL per hour.  
 
Pre-medication should always be considered before starting each infusion (see section 4.4). 
 
For instructions on dilution 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. 
 
Acute grade 3 or 4, or extensive chronic graft-versus-host disease (GvHD) 
 
4.4 Special warnings and precautions for use 
 

Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Pain 
Neuropathic pain usually occurs at the beginning of the treatment and premedication with analgesics, 
including intravenous opioids, prior to each infusion of dinutuximab beta is required. A triple therapy, 
including nonopioid analgesics (according to WHO guidelines), gabapentin and opioids, is 
recommended for pain treatment. The individual dose may vary widely. 
 

Nonopioid analgesics 

Nonopioid analgesics should be used permanently during the treatment, e.g. paracetamol or ibuprofen. 
 



 

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Gabapentin 

The patient should be primed with 10 mg/kg/day, starting 3 days prior to dinutuximab beta infusion. 
The daily dose of gabapentin is increased to 2×10 mg/kg/day orally, the next day and to 
3×10 mg/kg/day orally, the day before the onset of dinutuximab beta infusion and thereafter. The 
maximum single dose of gabapentin is 300 mg. This dosing schedule should be maintained for as long 
as required by the patient. 
Oral gabapentin should be tapered off after weaning off intravenous morphine infusion, at the latest 
after dinutuximab beta infusion therapy has stopped. 
 
Opioids 

Treatment with opioids is standard with dinutuximab beta. The first infusion day and course usually 
requires a higher dose than subsequent days and courses.  
 
• Before initiation of a continuous intravenous morphine infusion, a bolus infusion of 0.02 to 

0.05 mg/kg/hour morphine should be started 2 hours before dinutuximab beta infusion. 
• Subsequently, a dosing rate of 0.03 mg/kg/hour is recommended concomitantly with 

dinutuximab beta infusion. 
• With daily infusions of dinutuximab beta, morphine infusion should be continued at a decreased 

rate (e.g. 0.01 mg/kg/h) for 4 hours after the end of dinutuximab beta infusion. 
• With continuous infusion, in response to the patient’s pain perception, it may be possible to 

wean off morphine over 5 days by progressively decreasing its dosing rate (e.g. to 
0.02 mg/kg/hour, 0.01 mg/kg/hour, 0.005 mg/kg/hour).  

• If continous morphine infusion is required for more than 5 days, treatment should be gradually 
reduced by 20% per day after the last day of dinutuximab beta infusion. 

 
After weaning off intravenous morphine, in case of severe neuropathic pain, oral morphine sulphate 
(0.2 to 0.4 mg/kg every 4 to 6 hours) can be administered on demand. For moderate neuropathic pain, 
oral tramodol may be administered. 
 
Hypersensitivity reactions 
Severe infusion-related reactions, including cytokine release syndrome (CRS), anaphylactic and 
hypersensitivity reactions, may occur despite the use of premedication. Occurrence of a severe 
infusion related reaction (including CRS) requires immediate discontinuation of dinutuximab beta 
therapy and may necessitate emergency treatment. 
 
Cytokine release syndrome frequently manifests itself within minutes to hours of initiating the first 
infusion and is characterised by systemic symptoms such as fever, hypotension and urticaria.  
 
Anaphylactic reactions may occur as early as within a few minutes of the first infusion with 
dinutuximab beta and are commonly associated with bronchospasm and urticaria. 
 
Premedication 

Antihistamine premedication (e.g. diphenhydramine) should be administered by intravenous injection 
approximately 20 minutes before starting each dinutuximab beta infusion. It is recommended that 
antihistamine administration be repeated every 4 to 6 hours as required during dinutuximab infusion.  
 
Patients should be closely monitored for anaphylaxis and allergic reactions, particularly during the 
first and second treatment course. 
 
Treatment of hypersensitivity reactions 

Intravenous antihistamine, epinephrine (adrenaline) and prednisolone for intravenous administration 
should be immediately available at the bedside during administration of dinutuximab beta to manage 
life-threatening allergic reactions. It is recommended that treatment for such reactions include 
prednisolone administered by intravenous bolus, and epinephrine administered by intravenous bolus 
every 3 to 5 minutes as necessary, according to clinical response. In case of bronchial and/or 
pulmonary hypersensitivity reaction, inhalation with epinephrine (adrenaline) is recommended and 
should be repeated every 2 hours, according to clinical response. 



 

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Capillary leak syndrome (CLS) 
CLS is characterised by a loss of vascular tone and extravasation of plasma proteins and fluid into the 
extravascular space. CLS usually develops within hours after initiation of treatment, while clinical 
symptoms (i.e. hypotension, tachycardia) are reported to occur after 2 to 12 hours. Careful monitoring 
of circulatory and respiratory function is required. 
 
Neurological disorders of the eye 
Eye disorders may occur as dinutuximab beta binds to optic nerve cells. No dose modification is 
necessary in the case of an impaired visual accommodation that is correctable with eye glasses, as long 
as this is judged to be tolerable. 
Treatment must be interrupted in patients who experience Grade 3 vision toxicity (i.e. subtotal vision 
loss per toxicity scale). In case of any eye problems, patients should be referred promptly to an 
ophtalmology specialist. 
 
Peripheral neuropathy 
Occasional occurrences of peripheral neuropathy have been reported with Qarziba. Cases of motor or 
sensory neuropathy lasting more than 4 days must be evaluated and non-inflammatory causes, such as 
disease progression, infections, metabolic syndromes and concomitant medication, should be 
excluded. 
 
Treatment should be permanently discontinued in patients experiencing any objective prolonged 
weakness attributable to dinutuximab beta administration. For patients with moderate (Grade 2) 
neuropathy (motor with or without sensory), treatment should be interrupted and may be resumed after 
neurologic symptoms resolve. 
 
Systemic infections 
Patients are likely to be immunocompromised as a result of prior therapies. As they typically have a 
central venous catheter in situ, they are at risk of developing systemic infection. Patients should have 
no evidence of systemic infection and any identified infection should be under control before starting 
therapy. 
 
Haematologic toxicities 
Occurrence of haematologic toxicities has been reported with Qarziba, such as erythropenia, 
thrombocytopenia or neutropenia. Grade 4 haematologic toxicities, improving to at least Grade 2 or 
baseline values by start of next treatment course, do not require dose modification. 
 
Laboratory abnormalities 
Regulatory monitoring of liver function and electrolytes is recommended. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. A risk for indirect reduction of CYP activity due to 
higher TNF-α and IL-6 levels and, therefore, interactions with concomitantly used medicinal products, 
cannot be excluded. 
 
Corticosteroids 

Due to their immunosuppressive activity, concomitant treatment with corticosteroids is not 
recommended within 2 weeks prior to the first treatment course until 1 week after the last treatment 
course with dinutuximab beta, except for life-threatening conditions. 
 
Vaccinations 

Vaccinations should be avoided during administration of dinutuximab beta until 10 weeks after the last 
treatment course, due to immune stimulation through dinutuximab beta and possible risk for rare 
neurological toxicities. 
 



 

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Intravenous immunoglobulin 

Concomitant use of intravenous immunoglobulins is not recommended as they may interfere with 
dinutuximab beta-dependent cellular cytotoxicity. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data on pregnant women. No animal data are available on teratogenicity or 
embryotoxicity. Dinutuximab beta target (GD2) is expressed on neuronal tissues, especially during 
embryofetal development, and may cross the placenta; therefore, Qarziba may cause fetal harm when 
administered to pregnant women. 
 
Qarziba should not be used during pregnancy.  
 
Breast-feeding 
There are no data on lactating women. It is unknown whether dinutuximab beta is excreted in human 
milk. Breast-feeding should be discontinued during treatment with Qarziba and for 6 months after the 
last dose. 
 
Fertility 
The effects of dinutuximab beta on fertility in humans are unknown. In animals, dedicated fertility 
studies have not been conducted, but no adverse effects on reproductive organs were observed in 
toxicity studies performed in Guinea pig and cynomolgous monkey. 
 
Qarziba should not be used in women of childbearing potential not using contraception. It is 
recommended that women of childbearing potential use contraception for 6 months after 
discontinuation of treatment with dinutuximab beta. 
 
4.7 Effects on ability to drive and use machines 
 
Dinutuximab beta has major influence on the ability to drive and use machines. Patients should not use 
or drive machines during treatment with dinutuximab beta. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of dinutuximab beta has been evaluated in 514 patients with high-risk and 
relapsed/refractory neuroblastoma, who received it as a continuous infusion (98) or as repeated daily 
infusions (416). It was combined with 13-cis retinoic in most patients and with IL-2 in 307 patients. 
 
The most common adverse reactions were pyrexia (88%) and pain (77%) that occurred despite 
analgesic treatment. Other frequent adverse reactions were hypersensitivity (63%), vomiting (57%), 
diarrhoea (51%), capillary leak syndrome (40%) and hypotension (39%).  
 
Tabulated list of adverse reactions 
Adverse reactions are summarised in the table below. These adverse reactions are presented by 
MedDRA system organ class and frequency. Frequency categories are defined as: very common 
(≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 



 

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System organ class Very common Common Uncommon 

Infections and 
infestations 

infection (including 
pneumonia, skin 
infection, herpes virus 
infection, myelitis, 
encephalomyelitis), 
device related infection 

sepsis 
 

Blood and lymphatic 
system disorders 

anaemia,leukopenia,  
neutropenia, 
thrombocytopenia  

lymphopenia  disseminated 
intravascular 
coagulation, 
eosinophilia 

Immune system 
disorders 

hypersensitivity , 
cytokine release 
syndrome 

anaphylactic reaction  serum sickness  

Metabolism and 
nutrition disorders 

fluid retention decreased appetite, 
hypoalbuminaemia, 
hyponatraemia, 
hypokalaemia, 
hypophosphataemia, 
hypomagnesaemia, 
hypocalcaemia, 
dehydration 

 

Psychiatric disorders  agitation, anxiety  
Nervous system 
disorders 

headache peripheral neuropathy, 
seizure, paraesthesia, 
dizziness, tremor 

intracranial pressure 
increased, posterior 
reversible 
encephalopathy 
syndrome 

Eye disorders mydriasis, pupillotonia, 
eye oedema (eyelid, 
periorbital) 

ophthalmoplegia, 
papilloedema, 
accommodation disorder, 
blurred vision, 
photophobia 

 

Cardiac disorders tachycardia cardiac failure, left 
ventricular dysfunction, 
pericardial effusion  

 

Vascular disorders hypotension, capillary 
leak syndrome 

hypertension hypovolaemic shock, 
veno-occlusive disease 

Respiratory, thoracic 
and mediastinal 
disorders 

hypoxia, cough  bronchospasm , 
dyspnoea, respiratory 
failure, lung infiltration, 
pulmonary oedema, 
pleural effusion, 
tachypnoea, 
laryngospasm  

 

Gastrointestinal 
disorders 

vomiting , diarrhoea, 
constipation, stomatitis  

nausea, lip oedema, 
ascites, abdominal 
distension, ileus, dry lips 

enterocolitis 

Hepatobiliary 
disorders 

 
 

hepatocellular injury 

Skin and 
subcutaneous tissue 
disorders 

pruritus , rash, urticaria  dermatitis (including 
exfoliative) , erythema, 
dry skin, hyperhidrosis, 
petechiae, 
photosensitivity reaction 

 



 

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System organ class Very common Common Uncommon 

Musculoskeletal and 
connective tissue 
disorders 

 muscle spasms   

Renal and urinary 
disorders 

 oliguria, urinary 
retention, 
hyperphosphaturia, 
haematuria, proteinuria 

renal failure  

General disorders and 
administration site 
conditions 

pyrexia, chills, pain*, 
peripheral oedema, 
face oedema 

injection site reaction  
 

Investigations increased weight , 
increased 
transaminases, 
increased gamma 
glutamyltransferase, 
increased blood 
bilirubin increased 
blood creatinine  
   

decreased weight, 
decreased glomerular 
filtration rate, 
hypertriglyceridaemia, 
prolonged activated 
partial thromboplastin 
time, prolonged 
prothrombin time, 
prolonged thrombin time 

 

*includes abdominal pain, pain in extremity, musculoskeletal pain, chest pain, arthralgia  
 
Description of selected adverse reactions 
Hypersensitivity 

The most frequent hypersensitivity reactions included hypotension (39%), urticaria (18%) and 
bronchospasm (4%). Cytokine release syndrome was also reported in 32% of the patients. Serious 
anaphylactic reactions occurred in 3.5% of the patients. 
 
Pain 

Pain typically occurs during the first infusion of dinutuximab beta and decreases over the treatment 
courses. Most commonly, patients reported abdominal pain, pain in the extremities, back pain, chest 
pain, or arthralgia.  
 
Capillary leak syndrome (CLS) 

Overall, 10% of CLS were severe (grade 3-4) and their frequency decreased over the treatment 
courses. 
 
Eye problems 

These included impaired visual accommodation that is correctable with eye glasses, as well as 
mydriasis (13%), blurred vision (3%) or photophobia (3%), which were usually reversible after 
treatment discontinuation. Severe eye disorders were also reported including ophthalmoplegia (2%) 
and optic atrophy. 
 
Peripheral neuropathy 

Both motor and sensory peripheral neuropathies have been reported, overall in 9% of the patients. 
Most events were of grade 1-2 and resolved.  
 

Safety profile with and without IL-2 
The combination of Qarziba with IL-2 increases the risk of adverse drug reactions compared to 
Qarziba without IL-2, especially for pyrexia (92% vs. 79%), CLS (50% vs. 25%), pain related to 
dinutuximab beta (75% vs. 63%), hypotension (43% vs. 26%), and peripheral neuropathy (14% vs. 
7%), respectively. 
 



 

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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 cases of dinutuximab beta overdose have been reported. 
In the case of overdose, patients should be carefully observed for signs or symptoms of adverse 
reactions and supportive care administered, as appropriate. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC 
 
Mechanism of action 
Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the 
carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.  
 
Pharmacodynamic effects 
Dinutuximab beta has been shown in vitro to bind to neuroblastoma cell lines known to express GD2 
and to induce both complement dependent cytoxicity (CDC) and antibody dependent cell-mediated 
cytoxicity (ADCC). In the presence of human effector cells, including peripheral blood nuclear cells 
and granulocytes from normal human donors, dinutuximab beta was found to mediate the lysis of 
human neuroblastoma and melanoma cell lines in a dose-dependent manner. Additionally, in vivo 
studies demonstrated that dinutuximab beta could suppress liver metastasis in a syngeneic liver 
metastasis mouse model. 
 
Neurotoxicity associated to dinutuximab beta is likely due to the induction of mechanical allodynia 
that may be mediated by the reactivity of dinutuximab beta with the GD2 antigen located on the 
surface of peripheral nerve fibres and myelin. 
 
Clinical efficacy 
The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing the 
administration of dinutuximab beta with or without IL-2 in the first-line treatment of patients with 
high-risk neuroblastoma and in two single-arm studies in the relapsed/refractory setting. 
 
Relapsed and refractory patients  

In a compassionate use programme (study 1), 54 patients received 10 mg/m2/day dinutuximab beta 
given by continuous 10-day intravenous infusion in a 5-week treatment course, concurrently with 
subcutaneous IL-2 (6×106 IU/m²/day given on days 1-5 and 8-12 of each course) and followed by oral 
13-cis-RA treatment (160 mg/m2/day for 14 days per course). The same treatment regimen was used in 
a Phase II study (study 2), which enrolled 44 patients. 
 
Overall, these 98 patients had primary refractory neuroblastoma (40) or relapsed neuroblastoma (49) 
with an additional 9 patients enrolled after first-line therapy. These were 61 boys and 37 girls, aged 1 
to 26 years (median 5 years). Most had an initial diagnosis of INSS stage 4 disease without MYCN 
amplification (16% of the subjects had MYCN amplified tumours and in 14% this information was 
missing). Most patients with relapsed disease were enrolled after their first relapse and the median 
time from diagnosis to first relapse was about 14 months. Treatment of disease before immunotherapy 
included intensive chemotherapy regimen followed by autologous stem cell transplantation (ASCT), 
radiotherapy, and surgery. At baseline, 72 patients had measurable disease and 26 patients had no 
detectable disease.  

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


 

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Survival rates (event-free survival, overall survival) are presented by type of disease in Table 1. The 
overall response rate (complete response plus partial response) in patients with evidence of disease at 
baseline was 36% (95% confidence interval [25; 48]) and was more favourable in patients with 
refractory disease (41% [23; 57]) than in patients with relapsed disease (29% [15; 46]). 
 
Table 1: Event-free survival (EFS) and overall survival (OS) rates in relapsed and refractory patients 

 
Study 1 
N=29 

Study 2 
N=19 

Study 1 
N=15 

Study 2 
N=25 

Relapsed patients Refractory patients 

EFS 
1 year 45% 42% 58% 60% 

2 years 31% 37% 29% 56% 

OS 
1 year 90% 74% 93% 100% 

2 years 69% 42% 70% 78% 
 
First-line patients who received autologous stem cell transplantation 

In study 3, patients with high-risk neuroblastoma were enrolled after they had received induction 
chemotherapy and achieved at least a partial response, then myeloablative therapy and stem cell 
transplantation. Patients with progressive disease were excluded. Dinutuximab beta was administered 
at a dose of 20 mg/m2/day on 5 consecutive days, given by 8-hour intravenous infusion in a 5-week 
treatment course, and was combined with 13-cis-RA and with or without additional subcutaneous IL-2 
at the same posologies as in the previous studies. 
 
A total of 370 patients were randomised and received treatment. These included 64% male and 36% 
female patients with a median age of 3 years (0.6 to 20); 89% had a tumour INSS stage 4 and MYCN 
amplification was reported in 44% of the cases. The primary efficacy endpoint was 3-year EFS and 
secondary endpoint was OS. EFS and OS rates are presented in Tables 2 and 3 according to the 
evidence of disease at baseline. 
 
For patients without evidence of disease at baseline, addition of IL-2 did not improve EFS and OS. 
 
Table 2: Event-free survival (EFS) and overall survival (OS) rates [95% confidence interval] in 
patients without evidence of disease at baseline (complete response to initial treatment) 

Efficacy 

without IL-2 
N=104 

with IL-2 
N=107 

1 year 2 year 3 year 1 year 2 year 3 year 

EFS 77% [67; 84] 
67% 

[57; 75] 
62% 

[51; 71] 
73% 

[63; 80] 
70% 

[60; 77] 
66% 

[56; 75] 

OS 89% [81; 94] 
78% 

[68; 85] 
71% 

[60; 80] 
89% 

[81; 93] 
78% 

[68; 85] 
72% 

[61; 80] 
 
Table 3: Event-free survival (EFS) and overall survival (OS) rates [95% confidence interval] in 
patients with evidence of disease at baseline (no complete response to initial treatment) 

Efficacy 

without IL-2 
N=73 

with IL-2 
N=76 

1 year 2 year 3 year 1 year 2 year 3 year 

EFS 67% [55; 76] 
58% 

[45; 69] 
46% 

[33; 58] 
72% 

[60; 81] 
62% 

[49; 72] 
54% 

[41; 65] 

OS 83% [72; 90] 
73% 

[61; 82] 
54% 

[40; 66] 
86% 

[75; 92] 
71% 

[58; 80] 
63% 

[50; 74] 
 



 

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Immunogenicity 
The development of anti-drug antibodies is a class effect of monoclonal chimeric antibodies. Overall, 
measurable ADA titres were detected in 65 (62%) of the 105 patients examined.  
 
Given the limitation of the bioanalytical methods, data are currently insufficient to properly evaluate 
the impact of the formation of anti-drug antibodies on pharmacokinetic and pharmacodynamic 
parameters, as well as on the efficacy and safety of dinutuximab beta. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Qarziba in one or more subsets of the paediatric population in neuroblastoma (see section 4.2 for 
information on paediatric use). 
 
This medicinal product has been authorised under ‘exceptional circumstances’. 
This means that for ethical reasons it has not been possible to obtain complete information on this 
medicinal product. The European Medicines Agency will review any new information which may 
become available every year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
Distribution 
Calculations of pharmacokinetic parameters for dinutuximab beta are based upon measurements using 
non-validated bioanalytical methods. This has to be taken into consideration when interpreting PK 
parameters (Cmax, exposure, half-life) listed below. 
 
The pharmacokinetics of dinutuximab beta, based on 10-day continuous intravenous infusion of 
10 mg/m2/day (equal to a total dose of 100 mg/m2/course) were evaluated in studies 1 and 2. Mean 
plasma Cmax levels (around 12 micrograms/mL) were reached on the last day of infusion. Mean plasma 
Cmax levels, observed during 8-hour infusions (20 mg/m2/day on five consecutive days), were 
determined in another study (n=15). The observed Cmax levels were slightly higher 
(16.5 micrograms/mL) and were reached on the fifth infusion. 
 
Biotransformation 
Dinutuximab beta is a protein for which the expected metabolic pathway is degradation to small 
peptides and individual amino acids by ubiquitous proteolytic enzmes. Classical biotransformation 
studies have not been performed. 
 
Elimination 
The half-life observed in studies 1 and 2 was in the range of 190 hours, i.e. 8 days. 
 
Special population 
A population pharmacokinetic modelling approach was used to investigate the influence of covariates. 
The population pharmacokinetic model included allometric scaling (reference weight of 18.1 kg) on 
clearance and volume of distribution with exponents of 0.75 and 1, respectively. 
 
The exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion) is predicted to be 
similar in subjects with ages less than or equal to 12 years and decreases slightly for older, heavier 
subjects. Effects of gender and age were not found to influence the pharmacokinetics of dinutuximab 
beta but data in children less than 2 years of age are very limited and insufficient to support dosing. 
 
An effect of ADA formation on the volume of distribution was found (increase of 37% in volume). 
Therefore, ADA formation would be predicted to have a slight impact (less than 10% decrease) on 
exposure within 24 hours after administration, under non-steady state conditions. After reaching 
steady state, no difference in exposure is predicted, with and without ADA formation. 
 
Markers for renal (eGFR) and hepatic (bilirubin) function did not show a relationship with exposure 
(Cmax and AUC24h on day 1 and day 10 during a 10-day infusion). 



 

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5.3 Preclinical safety data 
 
General toxicology 
Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male and 
female young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinical 
dose. Findings of note included changes (decrease) in thymus weight as well as bone marrow changes 
(atrophy affecting myeloid and erythroid precursor cell lines). The bone marrow changes were slight 
to severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, blood 
pressure) were observed in monkeys. 
 
Other 
No non-clinical studies to evaluate the potential of dinutuximab beta to cause carcinogenicity, 
genotoxicity or developmental and reproductive toxicity have been conducted. In the repeat-dose 
toxicity studies in Guinea pigs and cynomolgus monkeys, no adverse effects of dinutuximab beta were 
observed on reproductive organs at exposure levels above clinical levels.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 

Histidine 
Sucrose 
Polysorbate 20 
Water for injections 
Hydrochloric acid (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
3 years 
 
Diluted solution (solution for infusion) 
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 mL 
syringe) and for up to 7 days at 37 ºC (250 mL infusion bag), after cumulative storage in a refrigerator 
(2 °C – 8 °C) for 72 hours (see section 6.6). 
 
From a microbiological point of view, the 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 
would not normally be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled 
and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 



 

14 

6.5 Nature and contents of container 
 
Clear Type I glass vial (6 mL) with a halobutyl rubber stopper and aluminium flip-off cap, containing 
a minimum extractable volume of 4.5 mL concentrate for solution for infusion.  
 
Each carton contains 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for infusion must be prepared under aseptic conditions. The solution must not be exposed 
to direct sunlight or heat. 
 
The patient specific daily dose of Qarziba is calculated based on body surface area (see section 4.2). 
Qarziba should be diluted aseptically to the patient specific concentration/dose with sodium chloride 
9 mg/mL (0.9%) solution for infusion containing 1% human albumin (e.g. 5 mL of human albumin 
20% per 100 mL sodium chloride solution). 
 
For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, or 
sufficient for up to 5 days of continuous infusion. The daily dose is 10 mg/m2. The amount of solution 
to be infused per day (within a treatment course of 10 consecutive days) should be 48 mL; with 
240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL syringe, or 250 mL 
in an infusion bag suitable for the employed infusion pump, i.e. an overfill of 2 mL (syringe) or 10 mL 
(infusion bag) to allow for dead volumes of the infusion systems. 
 
For repeated daily 8-hour infusions, the daily dose is 20 mg/m2 and the calculated dose should be 
diluted in 100 mL sodium chloride 9 mg/mL (0.9%) containing 1% human albumin. 
 
The solution for infusion should be administered via a peripheral or central intravenous line. Other 
intravenously co-administered agents should be delivered via a separate infusion line. The container 
should be inspected visually for particulates prior to administration. It is recommended that a 
0.22 micrometre in-line filter is used during infusion. 
 
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can be 
used, e.g. syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note that 
elastomeric pumps are not considered suitable in combination with in-line filters. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
EUSA Pharma  
(Netherlands) B.V. 
Johannes Vermeerplein 11 
1071 DV   
Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1191/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 



 

15 

Date of first authorisation: 08 May 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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


 

16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 MARKETING 
AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 



 

17 

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) 
 
Rentschler Biotechnologie GmbH 
Erwin-Rentschler-Strasse 21 
Laupheim, Baden-Wuerttemberg 
88471 
Germany  
 
Name and address of the manufacturer(s) responsible for batch release 
 
Millmount Healthcare Ltd 
Block 7, City North Business Campus 
Stamullen, Co. Meath 
K32 YD60 
Ιreland 
 
 
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 (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. 

 
 



 

18 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 
This being a marketing authorisation under exceptional circumstances and pursuant to Article 14(8) of 
Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following 
measures: 
 
Description Due date 
Non-interventional post-authorisation safety study (PASS): In order to collect 
data on pain and its management, effect on peripheral and central nervous 
system, including visual impairment, long-term safety and long-term 
effectiveness, the MAH should submit the results of a study based on data 
deriving from a registry of patients with high risk neuroblastoma. 

Annual reports to 
be submitted 

In order to better define the posology in children over the entire age range and 
the impact of HACAs on PD, efficacy and safety, the MAH will submit the 
results of an evaluation of plasma samples collected from patients in studies 
APN311-202v1-2-3 and APN311-304 according to an agreed protocol. 

31 December 2020 

In order to evaluate the add-on effect of IL-2 in patients with relapsed 
refractory neuroblastoma, the MAH will submit the results of study APN311-
202v3. 

31 December 2021 

In order to evaluate the long-term survival effect of dinutuximab, the MAH 
will submit at least 5-year survival data for patients included in studies 
APN311-202 and APN311-302. 

31 December 2021 



 

19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 

20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

21 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Qarziba 4.5 mg/mL concentrate for solution for infusion 
dinutuximab beta 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
1 mL of concentrate contains 4.5 mg dinutuximab beta. 
Each 4.5 mL vial contains 20 mg dinutuximab beta. 
 
 
3. LIST OF EXCIPIENTS 
 
Histidine, sucrose, polysorbate 20, water for injections, hydrochloric acid. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
20 mg/4.5 mL 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Read the package leaflet before use. 
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 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Keep the vial in the outer carton in order to protect from light. 
 
 



 

22 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
EUSA Pharma  
(Netherlands) B.V. 
Johannes Vermeerplein 11 
1071 DV   
Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1191/001 
 
 
13. BATCH NUMBER 
 

Lot 
 

 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 

Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Qarziba 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



 

23 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Qarziba 4.5 mg/mL concentrate for solution for infusion 
dinutuximab beta 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
20 mg/4.5 mL 
 
 
6. OTHER 
 
 



 

24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

25 

 
Package leaflet: Information for the user 

 
Qarziba 4.5 mg/mL concentrate for solution for infusion 

dinutuximab beta 
 

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 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. 
• If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Qarziba is and what it is used for 
2. What you need to know before you use Qarziba 
3. How to use Qarziba 
4. Possible side effects 
5. How to store Qarziba 
6. Contents of the pack and other information 
 
 
1. What Qarziba is and what it is used for 
 
Qarziba contains dinutuximab beta, which belongs to a group of medicines called ‘monoclonal 
antibodies’. These are proteins, which specifically recognise and bind to other unique proteins in the 
body. Dinutuximab beta binds to the molecule known as disialoganglioside 2 (GD2), which is present 
on cancer cells, and this activates the body’s immune system, causing it to attack the cancer cells. 
 
Qarziba is used to treat neuroblastoma that has a high risk of coming back after a series of 
treatments, which include a stem cell transplantation for rebuilding the immune system. It is also used 
to treat neuroblastoma that has come back (relapsed) or could not be completely treated with previous 
therapies. 
 
Prior to the treatment of relapsed neuroblastoma, your treating physician will stabilise any actively 
progressing disease by other suitable measures. 
 
Your doctor will further decide whether the co-administration of a second medicine, interleukin-2, is 
necessary for the treatment of your cancer. 
 
Neuroblastoma is a type of cancer that grows from abnormal nerve cells in the body, in particular in 
the glands above the kidneys. It is one of the most common cancers in infancy. 
 
It is used for patients aged 12 months and above. 
 
 

http://en.wikipedia.org/wiki/Cancer
http://en.wikipedia.org/wiki/Cancer


 

26 

2. What you need to know before you use Qarziba 
 
Do not use Qarziba if you 
 
• are allergic to dinutuximab beta or any of the other ingredients of this medicine (listed in 

section 6) 
• have acute grade 3 or 4, or extensive long-lasting graft-versus-host disease 

This disease is a reaction in which cells of transplanted tissue attack cells of the recipient. 
 
Warnings and precautions 
 
Before receiving Qarziba, you will have blood tests to check your liver, lung, renal and bone marrow 
functions. 
 
You might notice the following when you first receive Qarziba and during the course of treatment: 
• pain 

Pain is one of the most common side effects of Qarziba. It usually occurs at the beginning of 
infusion. Therefore, your doctor will give you an appropriate pain treatment starting 3 days 
before and continuing during use of Qarziba. 

• allergic reactions or other infusion-related reactions 
Tell your doctor or nurse if you have any kind of reaction during or after the infusion, such as: 
- fever, shivering and/or low blood pressure 
- difficulties in breathing 
- skin rash, hives 
You will receive appropriate treatment to prevent these reactions and be closely monitored for 
these symptoms during infusion of Qarziba. 

• leakage from small blood vessels (capillary leak syndrome) 
Leakage of blood components from small blood vessels may cause rapid swelling in arms, legs 
and other parts of the body. Rapid drop in blood pressure, light-headedness and breathing 
difficulties are further signs. 

• eye problems 
You may notice changes to your vision. 

• problems with your nerves 
You may notice numbness, tingling or burning in your hands, feet, legs or arms, reduced 
sensation or weakness with movement. 

 
Tell your doctor immediately if you notice any of these problems. 
 
Your doctor will do blood tests and may do eye tests while you are taking this medicine. 
 
Children 
 
This medicine should not be given to children under 12 months because there is insufficient 
experience in this age group. 
 
Other medicines and Qarziba 
 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Do not use medicines that suppress the immune system from 2 weeks before the first dose of 
Qarziba until 1 week after the last treatment course, unless prescribed by your doctor. Examples of 
medicines that suppress the immune system are corticosteroids used to reduce inflammation or prevent 
organ transplant rejection. 
 
Avoid vaccinations during treatment with Qarziba and for 10 weeks afterwards.  
 



 

27 

Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.  
 
Talk to your doctor before you receive Qarziba if you are of childbearing age. It is recommended to 
use contraception for 6 months after discontinuation of treatment with Qarziba. You may only use 
Qarziba if your doctor assesses that benefits outweigh risks for a foetus. 
 
Tell your doctor if you are breast-feeding. Do not breast-feed during treatment with Qarziba and for 
6 months after the last dose. It is not known if the medicine can pass into breast-milk. 
 
Driving and using machines 
 
Qarziba has several side effects that may affect your ability to drive and use machines. Do not perform 
these activities if your ability to concentrate and react is affected. 
 
 
3. How to use Qarziba 
 
A doctor experienced in the use of medicines to treat cancer will supervise your treatment. It will be 
given to you by a doctor or nurse while you are in hospital. It is given into one of your veins 
(intravenous infusion) usually by using special tubes (catheters) and a pump. During and after the 
infusion, you will be checked regularly for infusion-related side effects. 
 
Qarziba will be given to you in five treatment courses of 35 days and the infusion will last 5 or 10 days 
in the beginning of each course. The recommended dose is 100 mg dinutuximab beta per square 
metre of body surface per treatment course. The doctor will calculate your body surface area from 
your height and weight. 
 
If your doctor considers co-administration of interleukin-2, it will be given twice, by injection under 
the skin, each time for 5 consecutive days (before and during treatment with Qarziba). 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or nurse immediately if you have any of the following: 
Very common (may affect more than 1 in 10 people): 
• rapid swelling of arms, legs and other body parts, rapid drop in blood pressure, light-headedness 

and breathing difficulties (capillary leak syndrome) 
• pain in the stomach, throat, chest, face, hands, feet, legs, arms, back, neck, joint, or muscles 
• allergic reactions and cytokine release syndrome with symptoms such as face or throat swelling, 

breathing difficulties, dizziness, hives, rapid or noticeable heartbeat, low blood pressure, hives, 
rash, fever, or nausea 

 
Other side effects and their frequencies include: 
Very common (may affect more than 1 in 10 people): 
• fever, chills 
• vomiting, diarrhoea, constipation 
• inflammation of the mouth and lips (stomatitis) 
• cough 
• itching, rash 
• low blood pressure, increased heartbeat 
• oxygen deficiency 



 

28 

• tissue swelling (in the face, lip, around the eye, in the lower limbs) 
• increased weight 
• infection, in particular infection associated with the catheter that delivers the medicine 
• headache 
• dilated pupils or abnormal pupil reactions 
• abnormal blood or urine tests (blood cells and other components, liver function, renal function) 
 
Common (may affect up to 1 in 10 people): 
• life-threatening infection (sepsis) 
• fits 
• agitation, anxiety 
• nerve disorder in the arms and/or legs (with abnormal sensations or weakness), light-

headedness, trembling, muscle spasms 
• paralysis of eye muscles, blurred vision, light sensitivity, swelling in the retina 
• high blood pressure 
• cardiac failure, fluid around the heart 
• respiratory failure, fluid in the lungs 
• sudden constriction of the airways (bronchospasm, laryngospasm), rapid breathing 
• decreased appetite, nausea, abdominal distension, accumulation of fluid in the abdominal cavity 
• injection-site reactions, skin problems such as reddening, dry skin, eczema, excessive sweating, 

reaction to light 
• unable to pass urine or passing reduced urine volume 
• decreased weight, loss of fluids (dehydration) 
 
Uncommon (may affect up to 1 in 100 people): 
• shock due to decreased body fluid volume 
• formation of blood clots in the small blood vessels (disseminated intravascular coagulation) 
• a type of allergy (serum sickness) with fever, rash, joint inflammation 
• a brain disorder characterised by headache, confusion, seizures and loss of vision (posterior 

reversible encephalopathy syndrome) 
• inflammation of the intestine, injury to the liver 
• kidney failure 
• a condition in which some of the small veins in the liver are obstructed (veno-occlusive disease) 
 
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 Qarziba 
 
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 label and the carton after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer carton in order to protect from light. 
 
Once opened, Qarziba is intended for immediate use. 
 
 

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


 

29 

6. Contents of the pack and other information 
 
What Qarziba contains 
 
• The active substance is dinutuximab beta. 

1 mL concentrate contains 4.5 mg dinutuximab beta. Each vial contains 20 mg dinutuximab 
beta in 4.5 mL. 

• The other ingredients are histidine, sucrose, polysorbate 20, water for injections, hydrochloric 
acid (for pH adjustment). 

 
What Qarziba looks like and contents of the pack 
 
Qarziba is a clear, colourless liquid, provided in a clear glass vial with a rubber stopper and aluminium 
seal. 
Each carton contains 1 vial. 
 
• Marketing Authorisation Holder 

EUSA Pharma  
(Netherlands) B.V. 
Johannes Vermeerplein 11 
1071 DV   
Amsterdam 
Netherlands 

 
• Manufacturer 

Millmount Healthcare Ltd 
Block 7, City North Business Campus 
Stamullen, Co. Meath 
K32 YD60 
Ιreland 

 
This leaflet was last revised in {MM/YYYY}. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Qarziba is restricted to hospital-use only and must be administered under the supervision of a 
physician experienced in the use of oncological therapies. It must be administered by a healthcare 
professional prepared to manage severe allergic reactions including anaphylaxis in an environment 
where full resuscitation services are immediately available. 
 
Posology 
Treatment with dinutuximab beta consists of 5 consecutive courses, each course comprising 35 days. 
The individual dose is determined based on the body surface area and should be a total of 100 mg/m2 
per course. 
 
Two modes of administration are possible: 
• a continuous infusion over the first 10 days of each course (a total of 240 hours) at the daily 

dose of 10 mg/m2 
• or five daily infusions of 20 mg/m2 administered over 8 hours, on the first 5 days of each course 
 

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


 

30 

If IL-2 is combined with dinutuximab beta, it should be given as subcutaneous injections for 
5 consecutive days twice during each course. First 5-day treatment should start 7 days prior to first 
dinutuximab beta infusion. Second 5-day treatment with IL-2 should start concurrently with 
dinutuximab beta infusion (days 1 to 5 of each course). IL-2 is administered as 6×106 IU/m2/day, 
resulting in an overall dose of 60×106 IU/m2/course. 
 
Preparation of the infusion 
The solution for infusion must be prepared under aseptic conditions. The solution must not be exposed 
to direct sunlight or heat. 
 
The patient-specific daily dose of Qarziba is calculated based on body surface area. Qarziba should be 
diluted aseptically to the patient-specific concentration/dose with sodium chloride 9 mg/mL (0.9%) 
solution for infusion, containing 1% human albumin (e.g. 5 mL of human albumin 20% per 100 mL 
sodium chloride solution). 
 
• For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, or 

sufficient for up to 5 days of continuous infusion. The daily dose is 10 mg/m2. The amount of 
solution to be infused per day (within a treatment course of 10 consecutive days) should be 
48 mL; with 240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL 
syringe, or 250 mL in an infusion bag suitable for the employed infusion pump, i.e. an overfill 
of 2 mL (syringe) or 10 mL (infusion bag) to allow for dead volumes of the infusion systems. 

 
• For repeated daily infusions, the daily dose is 20 mg/m2 and the calculated dose should be 

diluted in 100 mL sodium chloride 9 mg/mL (0.9%) containing 1% human albumin. 
 
Administration of the infusion 
The solution for infusion should be administered via a peripheral or central intravenous line. Other 
intravenously co-administered agents should be delivered via a separate infusion line. The container 
should be inspected visually for particulates prior to administration. It is recommended that a 
0.22 micrometre in-line filter is used during infusion. 
 
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can be 
applied, e.g. syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note that 
elastomeric pumps are not considered suitable in combination with in-line filters. 
 
Storage of the diluted solution 
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 mL 
syringe) and for up to 7 days at 37 ºC (250 mL infusion bag), after cumulative storage in a refrigerator 
(2 °C – 8 °C) for 72 hours. 
 
From a microbiological point of view, the 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 
would not normally be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled 
and validated aseptic conditions. 
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	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 MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET