GAZYVA

Corticosteroid premedication is recommended for patients with FL. Corticosteroid premedication is mandatory for patients with CLL during the first infusion, and for patients with LN through at least infusion #5. Premedication for subsequent infusions and other premedication should be administered as described below.

Hypotension, as a symptom of IRR, 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 7 Warnings and Precautions).

Table 11 Premedication to be administered before GAZYVA Infusion to reduce the risk of Infusion Related Reactions Day of Treatment Cycle Patients requiring premedication Premedication Administration Cycle 1: CLL Day 1 Day 2 FL Day 1 All patients Intravenous corticosteroid1, 2 Completed at least 1 hour prior to GAZYVA infusion.

Oral analgesic/anti-pyretic3 At least 30 minutes before GAZYVA infusion. Anti-histaminic drug4 All subsequent Patients with no IR during the previous infusion Oral analgesic/anti-pyretic3 At least 30 minutes before GAZYVA infusion. GAZYVA® (obinutuzumab) Page 8 of 96 Day of Treatment Cycle Patients requiring premedication Premedication Administration infusions: CLL and FL Patients with an IR (Grade 1 or 2) with the previous infusion Oral analgesic/anti-pyretic3 At least 30 minutes before GAZYVA infusion.

Anti-histaminic drug4 Patients with a Grade 3 IR 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 GAZYVA infusion. Oral analgesic/anti-pyretic3 At least 30 minutes before GAZYVA infusion.

Anti-histaminic drug3 Lupus nephritis All patients Intravenous corticosteroid5 Completed between 30 and 60 minutes prior to GAZYVA infusion. Starting from Dose 6, intravenous corticosteroid should only be administered to patients who have experienced an IRR in the prior infusion.

Oral analgesic/anti-pyretic6 Anti-histaminic drug4 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 IR. 2 If a corticosteroid-containing chemotherapy regimen is administered on the same day as GAZYVA, the corticosteroid can be administered as an oral medication if given at least 1 hour prior to GAZYVA, in which case additional IV corticosteroid as premedication is not required.

g. g. 50 mg diphenhydramine 5 80 mg IV methylprednisolone 6 650 – 1000 mg acetaminophen/paracetamol Premedication for anti-microbial prophylaxis CLL and FL patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period.

Antiviral and antifungal […]

Table 77 Infusion Rate Modification Guidelines for Infusion Related Reactions for the LN indication Grade 4 (life- threatening) • Stop infusion and permanently discontinue therapy. GAZYVA® (obinutuzumab) Page 13 of 96 Grade 3 (severe) • Temporarily interrupt infusion and treat symptoms.

o For patients who experience Grade 3 IRRs during standard infusion upon resolution of symptoms, restart infusion at no more than half the previous rate (the rate being used at the time that the IRR occurred). o If the patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose (Table 5).

o If the patient experiences a second occurrence of a Grade 3 IRR, stop infusion and permanently discontinue therapy. Grade 1-2 (mild and moderate) • Reduce infusion rate to half the infusion rate that was used at the time of the reaction and treat symptoms.

• Upon resolution of symptoms, the infusion should be kept at the reduced rate for an additional 30 minutes. • If patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose (Table 5).

(See 7 Warnings and Precautions: Infusion Related Reactions) Pediatrics The safety and efficacy of GAZYVA in children below 18 years of age have not been established. Health Canada has not authorized an indication for pediatric use.

1 Special Populations). 3 Pharmacokinetics). Renal impairment No dose adjustment is required in patients with mild or moderate (creatinine clearance [CrCl] 30-89 mL/min) renal impairment. 3 Pharmacokinetics). Hepatic Impairment The safety and efficacy of GAZYVA in patients with hepatic impairment have not been established.

3.

Reconstitution Parenteral Products:

Instructions for dilution GAZYVA should be prepared by a health professional using aseptic technique. Use a sterile needle and syringe to prepare GAZYVA. 9% aqueous sodium chloride solution. For administration of 1000 mg GAZYVA, use 250 mL infusion bags.

For preparation of infusion bags for CLL only Cycle 1, Day 1 dose administered over 2 days To ensure differentiation of the two infusion bags for the initial 1000 mg dose, the recommendation is to use 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 (see Table 8 below).

9% aqueous sodium chloride solution. Clearly label each infusion bag. Table 88 Reconstitution Dose of GAZYVA to be Administered Required Amount of GAZYVA Liquid Concentrate Size of PVC or non-PVC polyolefin infusion bag 100 mg 4 mL 100 mL 900 mg 36 mL 250 mL 1000 mg 40 mL 250 mL Vial size: 50 mL Available volume: 40 mL Concentration: 25 mg/mL Do not use other diluents such as Dextrose (5%) solution (see Incompatibilities).

The bag should be gently inverted to mix the solution in order to avoid excessive foaming. Parenteral drug products should be inspected visually for particulates and discolouration prior to administration. Incompatibilities There are no incompatibilities […]