This information is intended for use by health professionals

 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.

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

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

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.

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.

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.

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.

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

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.

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:

Ireland:

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

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]

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).

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 °C (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.

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

Date of first authorisation: 08 May 2017

10. Date of revision of the text

10/2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.