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

Central neurotoxicity

Interrupt infusion immediately, rule out other influencing factors and treat appropriately.

There is limited data available on resuming treatment and no recommendations can be made

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)

• severe central neurotoxicity that includes grade 3 or 4 with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity, and permanent neurological deficit

• all grades of posterior reversible encephalopathy syndrome and transverse myelitis

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.

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.

Central neurotoxicity

Central neurotoxicity has been reported following treatment with Qarziba. If central neurotoxicity occurs the infusion should be interrupted immediately and the patient treated symptomatically, other influencing factors such as active infection, metastatic spread of neuroblastoma to CNS, neurotoxic concomitant medications should be ruled out.

Treatment with dinutuximab beta should be permanently discontinued following the occurrence of severe neurotoxicity that includes grade 3 or 4 central neurotoxicity with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity and/or permanent neurological deficit and all grades of posterior reversible encephalopathy syndrome and transverse myelitis.

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

Regular monitoring of liver function and electrolytes is recommended.

Atypical haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) has been reported in patients who received dinutuximab beta, in some cases with fatal outcome. Signs and symptoms of aHUS should be monitored for. If aHUS is diagnosed, prompt treatment is required and dinutuximab beta should be permanently discontinued.

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 791 patients with high-risk and relapsed/refractory neuroblastoma, who received it as a continuous infusion (212) 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 (86%) and pain (57%) that occurred despite analgesic treatment. Other frequent adverse reactions were hypersensitivity (74.1%), vomiting (55%), diarrhoea (52%), capillary leak syndrome (36%), Anaemia (49%), neutropenia (46%), thrombocytopenia (42%) and hypotension (41%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials and post-marketing are listed by system organ class and by frequency and 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), uncommon (≥ 1/1,000 to < 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Very common

Common

Uncommon

Not known

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

Atypical haemolytic uraemic syndrome

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, oropharyngeal pain, and Back pain reported in >10% of patients. In addition, other common pain types reported were arthralgia, injection site pain, musculoskeletal pain, bone pain, chest pain, and neck pain.

Description of selected adverse reactions

Hypersensitivity

The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (7%) and bronchospasm (1%). 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 (2%), periorbital oedema and eyelid oedema (3%), 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.

Central Neurotoxicity

Reports of central neurotoxicity and severe neurotoxicity have been received including posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%).

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 (94% vs. 80%), CLS (45% vs. 20%), pain related to dinutuximab beta (70% vs. 62%), hypotension (44% vs. 27%), and peripheral neuropathy (9% vs. 5%), 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 the 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.