Posology : מינונים

4.2   Posology and method of administration

Gazyva 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 Gazyva 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)

Premedication to reduce the risk of IRRs is outlined in Table 1 (see also section 4.4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

Hypotension, as a symptom of IRRs, may occur during Gazyva intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyva infusion and for the first hour after administration (see section 4.4).

Table 1      Premedication to be administered before Gazyva infusion to reduce the risk of IRRs in patients with CLL and FL(see section 4.4)

Day of
Patients requiring treatment                                     Premedication                 Administration premedication cycle
Intravenous corticosteroid1,4             Completed at least 1 hour
(mandatory for CLL,           prior to Gazyva infusion
Cycle 1:                                      recommended for FL)
Day 1 for CLL      All patients               Oral analgesic/anti- and FL pyretic2                      At least 30 minutes before
3
Gazyva infusion
Anti-histaminic medicine
Intravenous
Completed at least 1 hour corticosteroid1 prior to Gazyva infusion
Cycle 1:                                      (mandatory)
Day 2 for CLL      All patients               Oral analgesic/anti- only                                          pyretic2                      At least 30 minutes before Gazyva infusion
Anti-histaminic medicine3



Day of
Patients requiring treatment                                         Premedication                      Administration premedication cycle
Patients with no IRR
Oral analgesic/anti- during the previous pyretic2 infusion                                                          At least 30 minutes before Patients with an IRR           Oral analgesic/anti-               Gazyva infusion All subsequent     (Grade 1 or 2) with the        pyretic2 infusions for      previous infusion              Anti-histaminic medicine3 CLL and FL         Patients with a Grade 3        Intravenous
Completed at least 1 hour
IRR with the previous          corticosteroid1,4 prior to Gazyva infusion infusion OR
Patients with
Oral analgesic/anti- lymphocyte counts                                                 At least 30 minutes before pyretic2
>25 x 109/L prior to                                              Gazyva infusion Anti-histaminic medicine3 next treatment
1
100 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
4.
If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyva, the corticosteroid can be administered as an oral medicinal product if given at least 60 minutes prior to Gazyva, in which case additional IV corticosteroid as premedication is not required.

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1) 
For patients with CLL the recommended dose of Gazyva in combination with chlorambucil is shown in Table 2.

Cycle 1

The recommended dose of Gazyva in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2, (or Day 1 continued), 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 – 6

The recommended dose of Gazyva in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle.



Table 2          Dose of Gazyva to be administered during 6 treatment cycles each of 28 days duration for patients with CLL


Cycle                       Day of treatment               Dose of Gazyva 
Day 1                         100 mg
Day 2
900 mg
Cycle 1                    (or Day 1 continued)
Day 8                        1,000 mg
Day 15                      1,000 mg
Cycles 2-6                            Day 1                      1,000 mg 1
See section 5.1 for information on chlorambucil dose

Duration of treatment
Six treatment cycles, each of 28 day duration.

Delayed or missed doses
If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyva should be maintained between doses.

Follicular lymphoma

For patients with FL, the recommended dose of Gazyva in combination with chemotherapy is shown in Table 3.

Patients with previously untreated follicular lymphoma

Induction (in combination with chemotherapy2)
Gazyva should be administered with chemotherapy as follows:

•         Six 28-day cycles in combination with bendamustine2 or,
•         Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyva alone or,
•         Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone(CVP).

Maintenance
Patients who achieve a complete or partial response to induction treatment with Gazyva in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyva 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).

Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen

Induction (in combination with bendamustine2)
Gazyva should be administered in six 28-day cycles in combination with bendamustine2.

Maintenance
Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyva in combination with bendamustine or have stable disease should continue to 
receive Gazyva 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).

Table 3           Follicular lymphoma: Dose of Gazyva to be administered during induction treatment, followed by maintenance treatment

Cycle                 Day of treatment                 Dose of Gazyva 
Day 1                         1,000 mg

Cycle 1
Day 8                         1,000 mg
Day 15                         1,000 mg

Cycles 2–6
Day 1                         1,000 mg or 2–8

Every 2 months for 2 years
Maintenance         or until disease progression               1,000 mg (whichever occurs first)
2
See section 5.1 for information on bendamustine dose

Duration of treatment
Induction treatment of approximately six months (six treatment cycles of Gazyva, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyva, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first).

Delayed or missed doses
If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose.
If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.

During maintenance, maintain the original dosing schedule for subsequent doses.

Dose modifications during treatment (all indications)
No dose reductions of Gazyva are recommended.

For management of symptomatic adverse events (including IRRs), see paragraph below (Management of IRRs or section 4.4).

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 Gazyva has not been established in patients with severe renal impairment (CrCl < 30 mL/min) (see sections 4.8 and 5.2).

Hepatic impairment
The safety and efficacy of Gazyva in patients with impaired hepatic function has not been established.
No specific dose recommendations can be made.

Paediatric population
The safety and efficacy of Gazyva in children and adolescents aged below 18 years has not been established. No data are available.

Method of administration
Gazyva is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution (see section 6.6). Gazyva infusions should not be administered as an intravenous push or bolus.

For instructions on dilution of Gazyva before administration, see section 6.6.

Instructions on the rate of infusion are shown in Tables 4-6.


Chronic lymphocytic leukaemia (CLL)
Table 4    Chronic lymphocytic leukaemia: Standard infusion rate in the absence of IRRs/hypersensitivity and recommendations in case an IRR occurred with previous infusion

Rate of infusion
Day of            The infusion rate may be escalated provided
Cycle                                    that the patient can tolerate it. For treatment management of IRRs that occur during the infusion, refer to “Management of IRRs”.
Day 1             Administer at 25 mg/hr over 4 hours. Do not
(100 mg)            increase the infusion rate.
If no IRR occurred during the previous infusion, administer at 50 mg/hr.
The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to
Day 2 a maximum rate of 400 mg/hr.
(or Day 1 continued)
Cycle 1                                   If the patient experienced an IRR during the (900 mg) previous infusion, start with administration at 25 mg/hr. The rate of infusion can be escalated in increments up to 50 mg/hr every
30 minutes to a maximum rate of 400 mg/hr.
Day 8
(1,000 mg)          If no IRR occurred during the previous infusion,
Day 15            when the final infusion rate was 100 mg/hr or
(1,000 mg)          faster, 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 1            If the patient experienced an IRR during the
Cycles 2-6                                 previous infusion administer at 50 mg/hr. The (1,000 mg) rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.


Follicular lymphoma (FL)

Gazyva should be administered at the standard infusion rate in Cycle 1 (see Table 5). In patients who do not experience Grade ≥3 infusion related reactions (IRRs) during Cycle 1, Gazyva may be administered as a short (approximately 90 minutes) duration infusion (SDI) from Cycle 2 onwards (see Table 6).



Table 5      Follicular lymphoma: Standard infusion rate and recommendations in case an IRR occurred with previous infusion

Cycle            Day of treatment           Rate of infusion
The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to “Management of IRRs”.

Administer at 50 mg/hr. The rate of infusion
Day 1 can be escalated in 50 mg/hr increments every
(1,000 mg)
30 minutes to a maximum of 400 mg/hr.
Cycle 1
Day 8               If no IRR or if an IRR Grade 1 occurred
(1,000 mg)             during the previous infusion when the final infusion rate was 100 mg/hr or faster,
Day 15               infusions can be started at a rate of 100 mg/hr
(1,000 mg)             and increased by 100 mg/hr increments every
30 minutes to a maximum of 400 mg/hr.
Cycles 2–6 or                  Day 1
2–8                     (1,000 mg)
If the patient experienced an IRR of Grade 2 or higher during the previous infusion
Every 2 months for 2 years or   administer at 50 mg/hr. The rate of infusion Maintenance         until disease progression     can be escalated in 50 mg/hr increments every (whichever occurs first)      30 minutes to a maximum of 400 mg/hr.


Table 6      Follicular lymphoma: Short duration infusion rate and recommendations in case an IRR occurred with previous infusion

Cycle            Day of treatment           Rate of infusion
For management of IRRs that occur during the infusion, refer to “Management of IRRs”.

Cycles 2–6 or                 Day 1                If no IRR of Grade ≥3 occurred during 2–8                    (1,000 mg)              Cycle 1:
100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes.

If an IRR of Grade 1-2 with ongoing
Every 2 months for 2 years or symptoms or a Grade 3 IRR occurred during
Maintenance        until disease progression the previous SDI infusion, administer the next
(whichever occurs first) obinutuzumab infusion at the standard rate
(see Table 5).



Management of IRRs (all indications)
Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyva 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 Tables 4-6). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 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 Tables 4-6). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

Management of IRRs occurring during SDI

•     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 not greater than 400 mg/hr.
If the patient experiences a second Grade 3 IRR after resuming the infusion, the infusion must be stopped and therapy must be permanently discontinued. If the patient is able to complete the infusion without further Grade 3 IRRs, the next infusion should be given at a rate not higher than the standard rate.
•     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 Tables 5-6).