Presentation and Status in Health Basket
1 X 20 mg / 4.5 ml
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.
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 6×10^6 IU/m²/day, for 2 periods of 5 consecutive days, resulting in an overall dose of 60×10^6 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.
For Recommended dose modifications for dinutuximab beta pleaes refer to table 1 at the attached doctor’s leaflet.
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.
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.
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.
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).
Hypersensitivity to the active substance or to any of the excipients.
Acute grade 3 or 4, or extensive chronic graft-versus-host disease (GvHD).
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.
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%).
See prescribing information for full details.
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 and Lactation
Pregnancy: There are no data on pregnant women. Qarziba should not be used during pregnancy.
Lactation: 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
See prescribing information for full details.
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.
Shelf life: Diluted solution (solution for infusion): Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 mL syringe) and for up to 7 days at 37 ºC (250 mL infusion bag). 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.
Storage: Store in a refrigerator (2 °C – 8 °C). Protect from light. Do not freeze.