QARZIBA Concentrate for solution for infusion Ref.[27962] Active ingredients: Dinutuximab

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.

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.

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.

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.

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.

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.

^* 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 (Northern Ireland): Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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