Posology : מינונים

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         e.g. hypotension                         Interrupt infusion and administer reaction                                                          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         e.g. bronchospasm, angioedema            Interrupt infusion immediately and reaction                                                          treat appropriately (see section 4.4), Resume treatment for subsequent courses
Capillary leak                                                    Interrupt infusion and administer syndrome                                                          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.