QARZIBA 4.5mg / ml concentrate for solution for infusion medication leaflet

Qarziba 4.5 mg/mL concentrate for solution for infusion

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 mammaliancell line (CHO) by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion

Colourless to slightly yellow liquid

Qarziba is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months andabove, 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 ofrelapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment ofrelapsed neuroblastoma, any actively progressing disease should be stabilised by other suitablemeasures.

In patients with a history of relapsed/refractory disease and in patients who have not achieved acomplete response after first line therapy, Qarziba should be combined with interleukin-2 (IL-2).

Qarziba is restricted to hospital-use only and must be administered under the supervision of aphysician experienced in the use of oncological therapies. It must be administered by a healthcareprofessional prepared to manage severe allergic reactions including anaphylaxis in an environmentwhere full resuscitation services are immediately available.

Treatment with Qarziba consists of 5 consecutive courses, each course comprising 35 days. Theindividual dose is determined based on the body surface area and should be a total of 100 mg/m2 percourse.

Two modes of administration are possible:

* a continuous infusion over the first 10 days of each course (a total of 240 hours) at the dailydose 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 of6×106 IU/m2/day, for 2 periods of 5 consecutive days, resulting in an overall dose of 60×106 IU/m2 percourse. The first 5-day course should start 7 days prior to the first infusion of dinutuximab beta and thesecond 5-day course should start concurrently with dinutuximab beta infusion (days 1 to 5 of eachdinutuximab beta course).

Prior to starting each treatment course, the following clinical parameters should be evaluated andtreatment 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 aconsequence, either the infusion period is prolonged or, if tolerated by the patient, the infusion ratemay 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 atoriginal rate

Hypersensitivity e.g. hypotension Interrupt infusion and administerreaction supportive measures,

After resolution, resume infusion atoriginal rate

Dilated pupils with sluggish light reflex +/- photophobia Interrupt infusion,

After resolution, resume infusion at50% rate

Any Grade ≥ 3 Interrupt infusion and administersupportive measures,

Resume infusion at 50% rate if ADRresolves or improves to Grade 1 - 2,

After resolution, increase to originalrate

Recurrent Discontinue infusion,

Resume next day if ADR resolves

Hypersensitivity e.g. bronchospasm, angioedema Interrupt infusion immediately andreaction treat appropriately (see section 4.4),

Resume treatment for subsequentcourses

Capillary leak Interrupt infusion and administersyndrome supportive measures,

Resume at 50% rate if ADR resolvesor improves to Grade 1 - 2

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)

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

The safety and efficacy of Qarziba in children aged less than 12 months have not yet been established.

No data are available.

Qarziba is for intravenous infusion. The solution should be administered via a peripheral or centralintravenous line. Other intravenously co-administered agents should be delivered via a separateinfusion line (see section 6.6).

For continuous infusions, the solution is administered at a rate of 2 mL per hour (48 mL per day) usingan 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.

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)

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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, isrecommended 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.

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 to3×10 mg/kg/day orally, the day before the onset of dinutuximab beta infusion and thereafter. Themaximum single dose of gabapentin is 300 mg. This dosing schedule should be maintained for as longas required by the patient.

Oral gabapentin should be tapered off after weaning off intravenous morphine infusion, at the latestafter dinutuximab beta infusion therapy has stopped.

Opioids

Treatment with opioids is standard with dinutuximab beta. The first infusion day and course usuallyrequires a higher dose than subsequent days and courses.

* Before initiation of a continuous intravenous morphine infusion, a bolus infusion of 0.02 to0.05 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 withdinutuximab beta infusion.

* With daily infusions of dinutuximab beta, morphine infusion should be continued at a decreasedrate (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 towean off morphine over 5 days by progressively decreasing its dosing rate (e.g. to0.02 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 graduallyreduced 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.

Severe infusion-related reactions, including cytokine release syndrome (CRS), anaphylactic andhypersensitivity reactions, may occur despite the use of premedication. Occurrence of a severeinfusion related reaction (including CRS) requires immediate discontinuation of dinutuximab betatherapy and may necessitate emergency treatment.

Cytokine release syndrome frequently manifests itself within minutes to hours of initiating the firstinfusion 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 withdinutuximab beta and are commonly associated with bronchospasm and urticaria.

Premedication

Antihistamine premedication (e.g. diphenhydramine) should be administered by intravenous injectionapproximately 20 minutes before starting each dinutuximab beta infusion. It is recommended thatantihistamine 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 thefirst and second treatment course.

Treatment of hypersensitivity reactions

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

Capillary leak syndrome (CLS)

CLS is characterised by a loss of vascular tone and extravasation of plasma proteins and fluid into theextravascular space. CLS usually develops within hours after initiation of treatment, while clinicalsymptoms (i.e. hypotension, tachycardia) are reported to occur after 2 to 12 hours. Careful monitoringof 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 isnecessary in the case of an impaired visual accommodation that is correctable with eye glasses, as longas this is judged to be tolerable.

Treatment must be interrupted in patients who experience Grade 3 vision toxicity (i.e. subtotal visionloss per toxicity scale). In case of any eye problems, patients should be referred promptly to anophtalmology specialist.

Occasional occurrences of peripheral neuropathy have been reported with Qarziba. Cases of motor orsensory neuropathy lasting more than 4 days must be evaluated and non-inflammatory causes, such asdisease progression, infections, metabolic syndromes and concomitant medication, should beexcluded.

Treatment should be permanently discontinued in patients experiencing any objective prolongedweakness 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 afterneurologic symptoms resolve.

Systemic infections

Patients are likely to be immunocompromised as a result of prior therapies. As they typically have acentral venous catheter in situ, they are at risk of developing systemic infection. Patients should haveno evidence of systemic infection and any identified infection should be under control before startingtherapy.

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 orbaseline values by start of next treatment course, do not require dose modification.

Regulatory monitoring of liver function and electrolytes is recommended.

No interaction studies have been performed. A risk for indirect reduction of CYP activity due tohigher TNF-α and IL-6 levels and, therefore, interactions with concomitantly used medicinal products,cannot be excluded.

Due to their immunosuppressive activity, concomitant treatment with corticosteroids is notrecommended within 2 weeks prior to the first treatment course until 1 week after the last treatmentcourse with dinutuximab beta, except for life-threatening conditions.

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

Intravenous immunoglobulin

Concomitant use of intravenous immunoglobulins is not recommended as they may interfere withdinutuximab beta-dependent cellular cytotoxicity.

There are no data on pregnant women. No animal data are available on teratogenicity orembryotoxicity. Dinutuximab beta target (GD2) is expressed on neuronal tissues, especially duringembryofetal development, and may cross the placenta; therefore, Qarziba may cause fetal harm whenadministered to pregnant women.

Qarziba should not be used during pregnancy.

There are no data on lactating women. It is unknown whether dinutuximab beta is excreted in humanmilk. Breast-feeding should be discontinued during treatment with Qarziba and for 6 months after thelast dose.

The effects of dinutuximab beta on fertility in humans are unknown. In animals, dedicated fertilitystudies have not been conducted, but no adverse effects on reproductive organs were observed intoxicity studies performed in Guinea pig and cynomolgous monkey.

Qarziba should not be used in women of childbearing potential not using contraception. It isrecommended that women of childbearing potential use contraception for 6 months afterdiscontinuation of treatment with dinutuximab beta.

Dinutuximab beta has major influence on the ability to drive and use machines. Patients should not useor drive machines during treatment with dinutuximab beta.

The safety of dinutuximab beta has been evaluated in 628 patients with high-risk andrelapsed/refractory neuroblastoma, who received it as a continuous infusion (212) or as repeated dailyinfusions (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 despiteanalgesic treatment. Other frequent adverse reactions were hypersensitivity (74.1%), vomiting (57%),diarrhoea (51%), capillary leak syndrome (40%), Anaemia (72.3%), neutropenia (52%),thrombocytopenia (49.6%)and hypotension (42.2%).

Adverse reactions reported in clinical trials are listed by system organ class and by frequency andsummarised in the table below. These adverse reactions are presented by MedDRA system organ classand 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 arepresented in order of decreasing seriousness. The type of adverse reactions seen in the post-marketingsetting is consistent with the reactions seen in clinical trials.

System organ class Very common Common Uncommon

Infections and infection (including sepsisinfestations pneumonia, skininfection, herpes virusinfection, myelitis,encephalomyelitis),device related infection

Blood and lymphatic Anaemia leukopenia, lymphopenia disseminatedsystem disorders neutropenia, intravascularthrombocytopenia coagulation,eosinophilia

Immune system hypersensitivity , anaphylactic reaction serum sicknessdisorders cytokine releasesyndrome

Metabolism and fluid retention decreased appetite,nutrition disorders hypoalbuminaemia,hyponatraemia,hypokalaemia,hypophosphataemia,hypomagnesaemia,hypocalcaemia,dehydration

Psychiatric disorders agitation, anxiety

Nervous system headache peripheral neuropathy, intracranial pressuredisorders seizure, paraesthesia, increased, posteriordizziness, tremor reversibleencephalopathysyndrome

Eye disorders mydriasis, ophthalmoplegia,pupillotonia, eye papilloedema,oedema (eyelid, accommodation disorder,periorbital) blurred vision,photophobia

Cardiac disorders tachycardia cardiac failure, leftventricular dysfunction,pericardial effusion

Vascular disorders hypotension, capillary hypertension hypovolaemic shock,leak syndrome veno-occlusived isease

Respiratory, thoracic hypoxia, cough bronchospasm ,and mediastinal dyspnoea, respiratorydisorders failure, lung infiltration,pulmonary oedema,pleural effusion,tachypnoea,laryngospasm

Gastrointestinal vomiting , diarrhoea, nausea, lip oedema, enterocolitisdisorders constipation, stomatitis ascites, abdominaldistension, ileus, dry lips

Hepatobiliary hepatocellular injurydisorders

Skin and pruritus , rash, urticaria dermatitis (includingsubcutaneous tissue exfoliative) , erythema,disorders dry skin, hyperhidrosis,

System organ class Very common Common Uncommonpetechiae,photosensitivity reaction

Musculoskeletal and muscle spasmsconnective tissuedisorders

Renal and urinary oliguria, urinary renal failuredisorders retention,hyperphosphaturia,haematuria, proteinuria

General disorders pyrexia, chills, pain*, injection site reactionand administration peripheral oedema,site conditions face oedema

Investigations increased weight , decreased weight,increased decreased glomerulartransaminases, filtration rate,increased gamma hypertriglyceridaemia,glutamyltransferase, prolonged activatedincreased blood partial thromboplastinbilirubin increased time, prolongedblood creatinine prothrombin time,prolonged thrombin time

*includes abdominal pain, pain in extremity, oropharyngeal pain, and Back pain reported in >10% ofpatients. In addition, other common pain types reported were arthralgia, injection site pain,musculoskeletal pain, bone pain, chest pain, and neck pain.

The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (15%) andbronchospasm (5.3% ). Cytokine release syndrome was also reported in 32% of the patients. Seriousanaphylactic reactions occurred in 3.5% of the patients.

Pain typically occurs during the first infusion of dinutuximab beta and decreases over the treatmentcourses. Most commonly, patients reported abdominal pain, pain in the extremities, back pain, chestpain, or arthralgia.

Capillary leak syndrome (CLS)

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

Eye problems

These included impaired visual accommodation that is correctable with eye glasses, as well asmydriasis (10.7%), periorbital oedema and eyelid oedema (7.1%), blurred vision (3%) or photophobia(3%), which were usually reversible after treatment discontinuation. Severe eye disorders were alsoreported including ophthalmoplegia (2%) and optic atrophy.

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 todinutuximab beta (75% vs. 63%), hypotension (43% vs. 26%), and peripheral neuropathy (14% vs.

7%), respectively.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of dinutuximab beta overdose have been reported.

In the case of overdose, patients should be carefully observed for signs or symptoms of adversereactions and supportive care administered, as appropriate.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC16

Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against thecarbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.

Dinutuximab beta has been shown in vitro to bind to neuroblastoma cell lines known to express GD2and to induce both complement dependent cytoxicity (CDC) and antibody dependent cell-mediatedcytoxicity (ADCC). In the presence of human effector cells, including peripheral blood nuclear cellsand granulocytes from normal human donors, dinutuximab beta was found to mediate the lysis ofhuman neuroblastoma and melanoma cell lines in a dose-dependent manner. Additionally, in vivostudies demonstrated that dinutuximab beta could suppress liver metastasis in a syngeneic livermetastasis mouse model.

Neurotoxicity associated to dinutuximab beta is likely due to the induction of mechanical allodyniathat may be mediated by the reactivity of dinutuximab beta with the GD2 antigen located on thesurface of peripheral nerve fibres and myelin.

The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing theadministration of dinutuximab beta with or without IL-2 in the first-line treatment of patients withhigh-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 betagiven by continuous 10-day intravenous infusion in a 5-week treatment course, concurrently withsubcutaneous IL-2 (6×106 IU/m²/day given on days 1-5 and 8-12 of each course) and followed by oral13-cis-RA treatment (160 mg/m2/day for 14 days per course). The same treatment regimen was used ina 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 1to 26 years (median 5 years). Most had an initial diagnosis of INSS stage 4 disease without MYCNamplification (16% of the subjects had MYCN amplified tumours and in 14% this information wasmissing). Most patients with relapsed disease were enrolled after their first relapse and the mediantime from diagnosis to first relapse was about 14 months. Treatment of disease before immunotherapyincluded intensive chemotherapy regimen followed by autologous stem cell transplantation (ASCT),radiotherapy, and surgery. At baseline, 72 patients had measurable disease and 26 patients had nodetectable disease.

Survival rates (event-free survival, overall survival) are presented by type of disease in Table 1. Theoverall response rate (complete response plus partial response) in patients with evidence of disease atbaseline was 36% (95% confidence interval [25; 48]) and was more favourable in patients withrefractory 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 Study 2 Study 1 Study 2

N=29 N=19 N=15 N=25

Relapsed patients Refractory patients1 year 45% 42% 58% 60%

EFS2 years 31% 37% 29% 56%1 year 90% 74% 93% 100%

OS2 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 inductionchemotherapy and achieved at least a partial response, then myeloablative therapy and stem celltransplantation. Patients with progressive disease were excluded. Dinutuximab beta was administeredat a dose of 20 mg/m2/day on 5 consecutive days, given by 8-hour intravenous infusion in a 5-weektreatment course, and was combined with 13-cis-RA and with or without additional subcutaneous IL-2at 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 MYCNamplification was reported in 44% of the cases. The primary efficacy endpoint was 3-year EFS andsecondary endpoint was OS. EFS and OS rates are presented in Tables 2 and 3 according to theevidence 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] inpatients without evidence of disease at baseline (complete response to initial treatment)without IL-2 with IL-2

N=104 N=107

Efficacy1 year 2 year 3 year 1 year 2 year 3 year77% 67% 62% 73% 70% 66%

EFS[67; 84] [57; 75] [51; 71] [63; 80] [60; 77] [56; 75]89% 78% 71% 89% 78% 72%

OS[81; 94] [68; 85] [60; 80] [81; 93] [68; 85] [61; 80]

Table 3: Event-free survival (EFS) and overall survival (OS) rates [95% confidence interval] inpatients with evidence of disease at baseline (no complete response to initial treatment)without IL-2 with IL-2

N=73 N=76

Efficacy1 year 2 year 3 year 1 year 2 year 3 year67% 58% 46% 72% 62% 54%

EFS[55; 76] [45; 69] [33; 58] [60; 81] [49; 72] [41; 65]83% 73% 54% 86% 71% 63%

OS[72; 90] [61; 82] [40; 66] [75; 92] [58; 80] [50; 74]

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 evaluatethe impact of the formation of anti-drug antibodies on pharmacokinetic and pharmacodynamicparameters, as well as on the efficacy and safety of dinutuximab beta.

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 forinformation 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 thismedicinal product. The European Medicines Agency will review any new information which maybecome available every year and this SmPC will be updated as necessary.

Calculations of pharmacokinetic parameters for dinutuximab beta are based upon measurements usingnon-validated bioanalytical methods. This has to be taken into consideration when interpreting PKparameters (Cmax, exposure, half-life) listed below.

The pharmacokinetics of dinutuximab beta, based on 10-day continuous intravenous infusion of10 mg/m2/day (equal to a total dose of 100 mg/m2/course) were evaluated in studies 1 and 2. Meanplasma 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), weredetermined in another study (n=15). The observed Cmax levels were slightly higher(16.5 micrograms/mL) and were reached on the fifth infusion.

Dinutuximab beta is a protein for which the expected metabolic pathway is degradation to smallpeptides and individual amino acids by ubiquitous proteolytic enzmes. Classical biotransformationstudies have not been performed.

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) onclearance 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 besimilar in subjects with ages less than or equal to 12 years and decreases slightly for older, heaviersubjects. Effects of gender and age were not found to influence the pharmacokinetics of dinutuximabbeta 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) onexposure within 24 hours after administration, under non-steady state conditions. After reachingsteady 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).

General toxicology

Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male andfemale young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinicaldose. 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 slightto severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, bloodpressure) were observed in monkeys.

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-dosetoxicity studies in Guinea pigs and cynomolgus monkeys, no adverse effects of dinutuximab beta wereobserved on reproductive organs at exposure levels above clinical levels.

Histidine

Sucrose

Polysorbate 20

Water for injections

Hydrochloric acid (for pH adjustment)

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

Unopened vial3 years

Diluted solution (solution for infusion)

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 mLsyringe) 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 usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould not normally be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlledand validated aseptic conditions.

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.

Clear Type I glass vial (6 mL) with a halobutyl rubber stopper and aluminium flip-off cap, containinga minimum extractable volume of 4.5 mL concentrate for solution for infusion.

Each carton contains 1 vial.

The solution for infusion must be prepared under aseptic conditions. The solution must not be exposedto 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 chloride9 mg/mL (0.9%) solution for infusion containing 1% human albumin (e.g. 5 mL of human albumin20% per 100 mL sodium chloride solution).

For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, orsufficient for up to 5 days of continuous infusion. The daily dose is 10 mg/m2. The amount of solutionto be infused per day (within a treatment course of 10 consecutive days) should be 48 mL; with240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL syringe, or 250 mLin 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 bediluted 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. Otherintravenously co-administered agents should be delivered via a separate infusion line. The containershould be inspected visually for particulates prior to administration. It is recommended that a0.22 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 beused, e.g. syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note thatelastomeric 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 localrequirements.

EUSA Pharma (Netherlands) B.V.

Beechavenue 54,1119PW, Schiphol-Rijk

Netherlands

EU/1/17/1191/001

Date of first authorisation: 08 May 2017

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

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