GAZYVARO Concentrate for solution for infusion Ref.[8946] Active ingredients: Obinutuzumab

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 × 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)

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 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 IRRs in patients with CLL and FL (see section 4.4):

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 Gazyvaro, the corticosteroid can be administered as an oral medicinal product if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil 1)

For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2.

Cycle 1

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

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

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 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.

Follicular lymphoma

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

Patients with previously untreated follicular lymphoma

Induction (in combination with chemotherapy²):

Gazyvaro should be administered with chemotherapy as follows:

• Six 28-day cycles in combination with bendamustine 2 or,
• Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro 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 Gazyvaro in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyvaro 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):

Gazyvaro 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 Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 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 Gazyvaro to be administered during induction treatment, followed by maintenance treatment:

² See section 5.1 for information on bendamustine dose.

Duration of treatment

Induction treatment of approximately six months (six treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyvaro, 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 Gazyvaro 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 Gazyvaro 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 Gazyvaro 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 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 Tables 4-5.

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

Table 5. Follicular lymphoma: Standard infusion rate in the absence of IRRs/hypersensitivity and recommendations in case an IRR occurred with previous infusion:

Management of IRRs (all indications)

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 Tables 4 and 5). 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 and 5). 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.

No experience with overdose is available from human clinical studies. In clinical studies with Gazyvaro, doses ranging from 50 mg up to and including 2,000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose dependent.

Patients who experience overdose should have immediate interruption or reduction of their infusion and be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B-cell depleted.

Unopened vial: 3 years.

After dilution: After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL (0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C followed by 48 hours (including infusion time) at ≤30°C.

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

40 mL concentrate in a 50 mL vial (clear Type I glass) with stopper (butyl rubber). Pack size of 1 vial.

Instructions for dilution

Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the vial.

For CLL cycles 2–6 and all FL cycles

Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for injection.

CLL only – Cycle 1

To ensure differentiation of the two infusion bags for the initial 1,000 mg dose, it is recommended to utilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the 900 mg dose for Cycle 1 Day 1 (continued) or Day 2. To prepare the 2 infusion bags, withdraw 40 mL of concentrate from the vial and dilute 4 mL into a 100 mL PVC or non-PVC polyolefin infusion bag and the remaining 36 mL in a 250 mL PVC or non-PVC polyolefin infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection. Clearly label each infusion bag. For storage conditions of the infusion bags see section 6.3.

Do not use other diluents such as glucose (5%) solution (see section 6.2).

The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted solution should not be shaken or frozen.

Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration.

No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyvaro with sodium chloride 9 mg/mL (0.9%) solution for injection, and:

• PVC, polyethylene (PE), polypropylene or polyolefin bags
• PVC, polyurethane (PUR) or PE infusion sets
• optional inline filters with product contact surfaces of polyethersulfone (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU).

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.