Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available.
Posology
Prophylaxis and premedication for tumour lysis syndrome (TLS)
Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl <70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12-24 hours prior to start of Gazyvaro infusion as per standard practice (see section 4.4). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.
Prophylaxis and premedication for infusion related reactions (IRRs)
Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration (see section 4.4).
Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of infusion related reactions (see section 4.4)
|
Day of treatment cycle
|
Patients requiring premedication
|
Premedication
|
Administration
|
|
Cycle 1:
Day 1
|
All patients
|
Intravenous corticosteroid1
|
Completed at least 1 hour prior to Gazyvaro infusion
|
|
Oral analgesic/anti-pyretic2
|
At least 30 minutes before Gazyvaro infusion
|
|
Anti-histaminic medicine3
|
|
Cycle 1:
Day 2
|
All patients
|
Intravenous corticosteroid1
|
Completed at least 1 hour prior to Gazyvaro infusion
|
|
Oral analgesic/anti-pyretic2
|
At least 30 minutes before Gazyvaro infusion
|
|
Anti-histaminic medicine3
|
|
Cycle 1:
Day 8, Day 15
Cycles 2-6:
Day 1
|
Patients with a Grade 3 IRR with the previous infusion OR
Patients with lymphocyte counts >25 x 109/L prior to next treatment
|
Intravenous corticosteroid1
|
Completed at least 1 hour prior to Gazyvaro infusion
|
|
All patients
|
Oral analgesic/anti-pyretic2
|
At least 30 minutes before Gazyvaro infusion
|
|
Patients with an IRR (Grade 1 or more) with the previous infusion
|
Anti-histaminic medicine3
|
1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone.
Hydrocortisone should not be used as it has not been effective in reducing rates of IRR.
2 e.g. 1,000 mg acetaminophen/paracetamol
3 e.g. 50 mg diphenhydramine
Dose
The recommended dose of Gazyvaro is shown in Table 2.
Cycle 1
The recommended dose of Gazyvaro is 1,000 mg administered over Day 1 and Day 2, and on Day 8 and Day 15 of the first 28 day treatment cycle. Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day.
Cycles 2 to 6
The recommended dose of Gazyvaro is 1,000 mg administered on Day 1.
Table 2 Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration
|
Cycle
|
Day of treatment
|
Dose of Gazyvaro
|
|
Cycle 1
|
Day 1
|
100 mg
|
|
Day 2
(or Day 1 continued)
|
900 mg
|
|
Day 8
|
1,000 mg
|
|
Day 15
|
1,000 mg
|
|
Cycles 2-6
|
Day 1
|
1,000 mg
|
Duration of treatment
Six treatment cycles, each of 28 day duration.
Delayed or missed doses
If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyvaro should be maintained between doses.
Dose modifications during treatment
No dose reductions of Gazyvaro are recommended.
Special populations
Elderly
No dose adjustment is required in elderly patients (see section 5.2).
Renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min) (see section 5.2). The safety and efficacy of Gazyvaro has not been established in patients with severe renal impairment (CrCl < 30 mL/min).
Hepatic impairment
The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not been established. No specific dose recommendations can be made.
Paediatric population
The safety and efficacy of Gazyvaro in children and adolescents aged below 18 years has not been established. No data are available.
Method of administration
Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution (see section 6.6). Gazyvaro infusions should not be administered as an intravenous push or bolus.
For instructions on dilution of Gazyvaro before administration, see section 6.6.
Instructions on the rate of infusion are shown in Table 3.
Table 3 Standard infusion rate in the absence of infusion reactions/hypersensitivity
|
Cycle
|
Day of treatment
|
Rate of infusion
|
|
Cycle 1
|
Day 1
(100 mg)
|
Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate.
|
|
Day 2
(or Day 1 continued)
(900 mg)
|
Administer at 50 mg/hr.
The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
|
|
Day 8
|
Infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
|
|
Day 15
|
|
Cycles 2-6
|
Day 1
|
Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4).
• Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.
• Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Table 3). The Day 1 (Cycle 1) infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.
• Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Table 3). The Day 1 (Cycle 1) infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.
In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Infusion Related Reactions (IRRs)
The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1,000 mg. In patients who received the combined measures for prevention of IRRs (adequate glucocorticoid, oral analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, a decreased incidence of all Grade IRRs was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion-related symptoms decreased substantially after the first 1,000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyvaro (see section 4.8).
In the majority of patients, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden (i.e. high peripheral lymphocyte count in CLL [> 25 x 109/L] may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs (see section 4.8).
