4.1. Therapeutic indications

Chronic lymphocytic leukaemia (CLL)

Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1).

Follicular lymphoma (FL)

Gazyvaro in combination with chemotherapy followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced FL (see section 5.1)

Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Lupus nephritis (LN)

Gazyvaro in combination with mycophenolate mofetil (MMF) is indicated for the treatment of adult patients with active Class III or IV, with or without concomitant Class V, lupus nephritis (LN).

4.2. Posology and method of administration

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)

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 and for patients with LN (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 (see section 4.4)

Indication/Day of treatment/ Cycle

Patients requiring premedication

Premedication

Administration

Cycle 1:

Day 1 for CLL and FL

All patients

Intravenous corticosteroid1,4 (mandatory for CLL, recommended for FL)

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 for CLL only

All patients

Intravenous corticosteroid1 (mandatory)

Completed at least 1 hour prior to Gazyvaro infusion

Oral analgesic/anti-pyretic2

At least 30 minutes before Gazyvaro infusion

Anti-histaminic medicine3

All subsequent infusions for CLL and FL

Patients with no IRR during the previous infusion

Oral analgesic/anti-pyretic2

At least 30 minutes before Gazyvaro infusion

Patients with an IRR (Grade 1 or 2) with the previous infusion

Oral analgesic/anti-pyretic2

Anti-histaminic medicine3

Patients with a Grade 3 IRR with the previous infusion OR Patients with lymphocyte counts >25 x 109/L prior to next treatment

Intravenous corticosteroid1,4

Completed at least 1 hour prior to Gazyvaro infusion

Oral analgesic/anti-pyretic2

Anti-histaminic medicine3

At least 30 minutes before Gazyvaro infusion

LN

All patients

Intravenous corticosteroid5

Completed between 30 and 60 minutes prior to Gazyvaro 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 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

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.

5 80 mg IV methylprednisolone

6 650-1,000 mg acetaminophen/paracetamol

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1)

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

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

1See 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 bendamustine2 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

Cycle

Day of treatment

Dose of Gazyvaro

Cycle 1

Day 1

1,000 mg

Day 8

1,000 mg

Day 15

1,000 mg

Cycles 2–6 or 2–8

Day 1

1,000 mg

Maintenance

Every 2 months for 2 years or until disease progression (whichever occurs first)

1,000 mg

2See 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.

Lupus nephritis

The recommended dosage of Gazyvaro is 1 000 mg administered intravenously (see Table 4).

Gazyvaro should be used in combination with mycophenolate mofetil.

Table 4 Dose of Gazyvaro for patients with Lupus Nephritis

Dose number

Timing of treatment

Dose

1

Initial infusion

1,000 mg

2

Week 2

(two weeks after Dose 1)

1,000 mg

3

Week 24

1,000 mg

4

Week 26

(two weeks after Dose 3)

1,000 mg

5*

and thereafter

Every 6 months

1,000 mg

*Dose 5 should be administered six months after Dose 4

The patient's condition and response should be evaluated at Week 76 and beyond, and an appropriate risk-benefit analysis should be made for continuation of therapy.

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 schedule of administration should be adjusted to maintain the appropriate interval between 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). The safety and efficacy of Gazyvaro in patients with LN above 65 years of age have not been established.

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 have 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 have 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 have 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 5-8.

Chronic lymphocytic leukaemia (CLL)

Table 5 Chronic lymphocytic leukaemia: Standard infusion rate in the absence of IRRs/hypersensitivity 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.

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)

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 a maximum rate of 400 mg/hr.

If the patient experienced an IRR during the 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, when the final infusion rate was 100 mg/hr or 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.

If the patient experienced an IRR 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 a maximum rate of 400 mg/hr.

Day 15

(1,000 mg)

Cycles 2‑6

Day 1

(1,000 mg)

Follicular lymphoma (FL)

Gazyvaro should be administered at the standard infusion rate in Cycle 1 (see Table 6). In patients who do not experience Grade ≥ 3 infusion related reactions (IRRs) during Cycle 1, Gazyvaro may be administered as a short (approximately 90 minutes) duration infusion (SDI) from Cycle 2 onwards (see Table 7).

Table 6 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.

Cycle 1

Day 1

(1,000 mg)

Administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Day 8

(1,000 mg)

If no IRR or if an IRR Grade 1 occurred during the previous infusion when the final infusion rate was 100 mg/hr or 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.

If the patient experienced an IRR of Grade 2 or higher during the previous infusion administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Day 15

(1,000 mg)

Cycles 2–6 or 2–8

Day 1

(1,000 mg)

Maintenance

Every 2 months for 2 years or until disease progression (whichever occurs first)

Table 7 Follicular lymphoma: Short duration infusion (SDI) 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 2–8

Day 1

(1,000 mg)

If no IRR of Grade ≥3 occurred during

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 symptoms or a Grade 3 IRR occurred during the previous SDI, administer the next obinutuzumab infusion at the standard rate (see Table 6).

Maintenance

Every 2 months for 2 years or until disease progression (whichever occurs first)

Lupus nephritis

The initial Gazyvaro infusion should be administered at the standard infusion rate (see Table 8). Patients who do not experience Grade ≥ 3 infusion related reactions during the previous infusion may receive Gazyvaro as a short (approximately 90 minutes) duration infusion from Dose 2 onwards (see Table 9), with continued premedication.

Table 8 Lupus nephritis: Standard infusion rate

Dose number

Timing of treatment

Rate of infusion

1

Initial infusion

(1,000 mg)

Administer at a rate of 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. For management of IRRs that occur during infusion, refer to Management of IRRs.

2

Week 2 - two weeks after Dose 1

(1,000 mg)

Administer at a rate of 100 mg/hr. The rate of infusion can be escalated at a rate of 100 mg/hr every 30 minutes to a maximum of 400 mg/hr.

3

Week 24

(1,000 mg)

4

Week 26 - two weeks after Dose 3

(1,000 mg)

5* and thereafter

Every 6 months

(1,000 mg)

*Dose 5 should be administered six months after Dose 4

Table 9 Lupus nephritis: Short duration infusion (SDI) rate and recommendations in case an IRR occurred with previous infusion

Dose number

Rate of infusion

1

See Table 8

2 and thereafter

If no IRR of Grade ≥3 occurred during the previous infusion: 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes.

If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurred during the previous SDI, administer Gazyvaro at the standard infusion rate (see Table 8).

Management of IRRs

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).

Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL)

• 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 5-7). 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 5-7). 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.

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 6-7).

Lupus nephritis (LN)

• 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 further IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Table 8).

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 to half the rate that was used at the time of the reaction and symptoms treated. Infusion can be continued upon resolution of symptoms at the reduced rate for an additional 30 minutes. If the patient does not experience any further IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 8 and 9).

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 (See Table 8).

• 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 8-9). If the patient experiences ongoing symptoms or a Grade 3 or higher IRR occurred during the previous 90-minute infusion, administer all subsequent Gazyvaro infusions at the standard infusion rate (see Table 8).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Special warnings and precautions are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications.

Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL)

Based on a subgroup analysis in previously untreated FL, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation.

Infusion related reactions

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. IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, 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 IRRs of all Grades 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, irrespective of indication, 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 and/or high circulating 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). For management of IRRs see section 4.2 Posology and method of administration.

Patients must not receive further Gazyvaro infusions if they experience:

• acute life-threatening respiratory symptoms,

• a Grade 4 (i.e. life threatening) IRR or,

• a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion).

Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension 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. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine.

Hypersensitivity reactions

Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to clinically distinguish from IRRs. Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity to obinutuzumab must not be treated (see section 4.3).

Tumour lysis syndrome (TLS)

TLS has been reported with Gazyvaro. Patients who are considered to be at risk of TLS (e.g. 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]) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase) starting 12‑24 hours prior to the infusion of Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Neutropenia

Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). Late onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia (see section 4.8).

Thrombocytopenia

Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.

Coagulation abnormalities including disseminated intravascular coagulation (DIC)

DIC including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyvaro. The majority of cases involved non-overt DIC, with subclinical (asymptomatic) changes in platelets and laboratory coagulation parameters occurring within 1-2 days after the first infusion with spontaneous resolution usually occurring within one to two weeks, not requiring drug discontinuation or specific intervention. In some cases, the events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC were identified. Patients suspected to have non-overt DIC should be monitored closely with coagulation parameters including platelets and clinical observation for signs or symptoms of overt DIC. Gazyvaro should be discontinued at first onset of suspected overt DIC and appropriate treatment initiated.

Worsening of pre-existing cardiac conditions

In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.

Infections

Gazyvaro should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyvaro in patients with a history of recurring or chronic infections. Serious bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyvaro therapy. Fatal infections have been reported.

Patients (CLL) with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in the maintenance phase. During the follow-up phase, Grade 3-5 infections are observed more in patients who received Gazyvaro plus bendamustine in the induction phase.

Hepatitis B reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti‑CD20 antibodies including Gazyvaro (see section 4.8). HBV screening should be performed in all patients before initiation of treatment with Gazyvaro. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody (HBcAb) status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation.

Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyvaro (see section 4.8). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.

Immunisation

The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery.

Exposure in utero to obinutuzumab and vaccination of infants with live virus vaccines

Due to the potential depletion of B-cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant's physician (see section 4.6).

Lupus nephritis (LN)

Infections

Gazyvaro should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyvaro in patients with a history of recurring or chronic infections. Serious bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyvaro therapy. Fatal infections have been reported.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Gazyvaro. At minimum, this should include HBsAg status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients with positive hepatitis B serology should be monitored and managed following local medical standards to prevent hepatitis reactivation.

Neutropenia

Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary, it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate.

Infusion related reactions

In patients with LN, infusion related reactions (IRRs) occurred predominantly during infusion of the first 1 000 mg. IRRs were generally mild (Grade 1) to moderate (Grade 2) and could be managed by slowing or temporarily halting the infusion (see Management of IRRs). However, severe (Grade 3) and life-threatening (Grade 4) IRRs requiring symptomatic treatment were also reported. See section 4.2 for information on prophylaxis.

Patients must not receive further Gazyvaro infusions if they experience:

• acute life-threatening respiratory symptoms,

• a Grade 4 (i.e. life threatening) IRR or,

• a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion).

Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension 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. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine.

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in patients treated with Gazyvaro for CLL and/or FL (see section 4.8), and has not been reported in patients treated with Gazyvaro during the LN placebo-controlled studies. The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.

Immunisation

The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied, and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery.

Exposure in utero to obinutuzumab and vaccination of infants with live virus vaccines

Due to the potential depletion of B-cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant's physician (see section 4.6).

Elderly

The safety and efficacy of Gazyvaro in patients with LN above 65 years of age have not been established.

Renal impairment

The safety and efficacy of Gazyvaro have not been established in patients with severe renal impairment (CrCl < 30 mL/min).

4.5. Interaction with other medicinal products and other forms of interaction

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP, fludarabine and cyclophosphamide (FC), and chlorambucil.

A risk for interactions with other concomitantly used medicinal products cannot be excluded.

Pharmacokinetic interactions

Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with medicinal products known to be metabolised by these enzyme systems.

Co-administration with Gazyvaro had no effect on the pharmacokinetics of bendamustine, FC, chlorambucil or the individual components of CHOP. In addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyvaro.

Pharmacodynamic interactions

Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab (see section 4.4).

The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must use effective contraception during and for 18 months after treatment with Gazyvaro.

Pregnancy

A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta (see section 5.3). There are no data from the use of obinutuzumab in pregnant women. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

In case of exposure during pregnancy, depletion of B-cells may be expected in infants due to the pharmacological properties of the product. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyvaro during pregnancy until the infant's B-cell levels are within normal ranges (see section 4.4).

Breast-feeding

Animal studies have shown secretion of obinutuzumab in breast milk (see section 5.3).

Since human immunoglobulin G (IgG) is secreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during Gazyvaro therapy and for 18 months after the last dose of Gazyvaro.

Fertility

No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies in cynomolgus monkeys (see section 5.3).

4.7. Effects on ability to drive and use machines

Gazyvaro has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Gazyvaro, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate.

4.8. Undesirable effects

Undesirable effects are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications.

Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL)

Summary of the safety profile

The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies:

• BO21004/CLL11 (N=781): Patients with previously untreated CLL

• BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL)

• GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

These trials investigated Gazyvaro in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL. Therefore, in order to provide the most comprehensive safety information, the analysis of ADRs presented in the following has been performed on the entire study population (i.e. iNHL).

Table 10 summarises all ADRs including those of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in:

• Patients with CLL receiving Gazyvaro plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11)

• Patients with previously untreated iNHL receiving Gazyvaro plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyvaro maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM)

• Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plus bendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN)

The incidences presented in Table 10 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Tabulated list of adverse reactions

Table 10 Summary of ADRs reported in patients# receiving Gazyvaro + chemotherapy*

System organ class

Frequency

All Grades

Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL)

Grades 3-5†

Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL)

Infections and infestations

Very common

Upper respiratory tract infection, sinusitis§, urinary tract infection, pneumonia§, herpes zoster§, nasopharyngitis

Common

Oral herpes, rhinitis, pharyngitis, lung infection, influenza

Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster

Uncommon

Hepatitis B reactivation

Nasopharyngitis, rhinitis, influenza, oral herpes

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common

Squamous cell carcinoma of skin, Basal cell carcinoma

Squamous cell carcinoma of skin, Basal cell carcinoma

Blood and lymphatic system disorders

Very common

Neutropenia§, thrombocytopenia, anaemia, leukopenia

Neutropenia, thrombocytopenia

Common

Febrile neutropenia

Anaemia, leukopenia, febrile neutropenia

Uncommon

Disseminated intravascular coagulation##

Metabolism and nutrition disorders

Common

Tumour lysis syndrome, hyperuricaemia, hypokalaemia

Tumour lysis syndrome, hypokalaemia

Uncommon

Hyperuricaemia

Psychiatric disorders

Very common

Insomnia

Common

Depression, anxiety

Uncommon

Insomnia, depression, anxiety

Nervous system disorders

Very common

Headache

Uncommon

Headache

Not known

Progressive multifocal leukoencephalopathy

Cardiac disorders

Common

Atrial fibrillation

Atrial fibrillation

Vascular disorders

Common

Hypertension

Hypertension

Respiratory, thoracic and mediastinal disorders

Very common

Cough§

Common

Nasal congestion, rhinorrhoea, oropharyngeal pain

Uncommon

Cough, oropharyngeal pain

Gastrointestinal disorders

Very common

Diarrhoea, constipation§

Common

Dyspepsia, haemorrhoids gastrointestinal perforation

Diarrhoea

Uncommon

Constipation, haemorrhoids

Skin and subcutaneous tissue disorders

Very common

Alopecia, pruritus

Common

Eczema

Uncommon

Pruritus

Musculoskeletal and connective tissue disorders

Very common

Arthralgia§, back pain, pain in extremity

Common

Musculoskeletal chest pain, bone pain

Pain in extremity

Uncommon

Arthralgia, back pain, musculoskeletal chest pain, bone pain

Immune system disorders

Rare

Cytokine release syndrome**

Renal and Urinary Disorders

Common

Dysuria, urinary incontinence

Uncommon

Dysuria, urinary incontinence

General disorders and administration site conditions

Very common

Pyrexia, Asthenia, fatigue

Common

Chest pain

Pyrexia, asthenia, fatigue

Uncommon

Chest pain

Investigations

Common

White blood cell count decreased, neutrophil count decreased, weight increased

White blood cell count decreased, neutrophil count decreased

Uncommon

Hypogammaglobulinemia

Injury, poisoning and procedural complications

Very common

IRRs

IRRs

# Only the highest frequency observed in the trials is reported (based on studies BO21004/previously untreated CLL, BO21223/previously untreated advanced iNHL and GAO4753g/rituximab refractory iNHL)

## Disseminated intravascular coagulation (DIC) including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyvaro (see section 4.4)

† No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms

* Chemotherapy: Chlorambucil in CLL; bendamustine, CHOP, CVP in iNHL including FL

§ observed also during maintenance treatment with at least 2% higher incidence in Gazyvaro arm (BO21223)

**Based on clinical trial exposures in FL and CLL

The profile of adverse reactions in patients with FL was consistent with the overall iNHL population in both studies.

Description of selected adverse reactions

The incidences presented in the following sections if referring to iNHL are the highest incidence of that ADR reported from either pivotal study (BO21223/GALLIUM, GAO4753g/GADOLIN).

The study MO40597 was designed to characterize the safety profile of short duration infusions (approximately 90 minutes) from Cycle 2, in patients with previously untreated FL (see section 5.1 Pharmacodynamic properties).

Infusion related reactions

Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see section 4.4).

Chronic Lymphocytic Leukaemia

The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 66% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3‑4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3‑5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.

In patients who received the recommended measures for prevention of IRRs as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

Grade 3-4 IRRs occurred in 12% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyvaro plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyvaro plus chemotherapy, the incidence of IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyvaro alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the Gazyvaro and the relevant comparator arms. Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro.

Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597 assessing the safety of SDI, a greater proportion of patients experienced any grade IRRs at Cycle 2 compared to the proportion who experienced IRRs after standard infusion at Cycle 2 in study BO21223 (10/99 [10.1%] vs. 23/529 [4.3%] respectively; IRRs attributed by the investigator to any component of study therapy). No patients experienced Grade ≥3 IRRs after SDI at Cycle 2 in MO40597; 3/529 (0.6%) experienced Grade ≥3 IRRs at Cycle 2 in study BO21223. IRR symptoms and signs were similar in both studies.

Infusion related reactions observed in Study MO40597/GAZELLE are summarized in Table 11.

Table 11 Study MO40597/GAZELLE Short-Duration Infusion: Infusion Related Reactionsa by Cycle (Safety-Evaluable Population)

CTCAE Grade

C1 Overall

(standard infusion)

C1b by day

C2C

C3

C4

C5

C6

C7

Over all induction cycles

Day 1

Day 2d

Day 8

Day 15

All Grade

65/113 (57.5%)

57/113 (50.4%)

4/51 (7.8%)

6/112 (5.4%)

5/111 (4.5%)

13/110 (11.8%)

9/108 (8.3%)

7/108 (6.5%)

6/107 (5.6%)

5/105 (4.8%)

2/55 (3.6%)

71/113 (62.8%)

Grade ≥3

6/113 (5.3%)

5/113 (4.4%)

1/51 (2.0%)

0

0

0

0

0

1/107 (0.9%)

0

0

7/113 (6.2%)

C=cycle; CTCAE = Common Terminology Criteria for Adverse Events; IRR=infusion related reaction

a Infusion related reaction defined as any event that occurred during or within 24 hours from the end of study treatment infusion that were judged by the investigator to be related to any components of therapy.

b C1 comprised three infusions at the standard infusion rate, administered at weekly intervals

c Patients received short-duration infusion from C2 onward. The denominator at C2 and subsequent cycles represents the number of patients who received SDI at that cycle.

d Patients treated with bendamustine on Cycle 1 Day 2.

Neutropenia and infections

Chronic Lymphocytic Leukaemia

The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm (41%) compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3‑5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see section 4.4).

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the Gazyvaro plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence of infection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see section 4.4).

Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597, assessing the safety of SDI, neutropenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients receiving standard duration infusion 69/113 [61.1%] vs 247/595 [41.5%], respectively, throughout induction). The median and range of neutrophil count values were similar in both studies at each time point. Febrile neutropenia was reported in a similar proportion of patients in MO40597 and BO21223 (6/113 [5.3%] vs 31/595 [5.2%], respectively). Infection was reported less frequently in MO40597 than in BO21223 (45/113 [39.8%] vs 284/595 [47.7%], respectively).

Thrombocytopenia and haemorrhagic events

Chronic Lymphocytic Leukaemia

The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm (16% vs. 7%) especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion) (see section 4.4). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported in Cycle 1. No Grade 5 events of thrombocytopenia were reported. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

The incidence of thrombocytopenia was 15%. Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 4% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1.

Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597, assessing the safety of SDI, thrombocytopenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients received standard duration infusion (21/113 [28.6%] vs 63/595 [10.6%], respectively, throughout induction). The median and range of platelet count values were similar in both studies at each time point. No thrombocytopenia events reported in MO40597 were associated with bleeding.

Lupus nephritis

Summary of the safety profile

In pooled data from placebo-controlled studies in 200 patients with lupus nephritis treated with Gazyvaro, the most frequently observed adverse drug reactions were upper respiratory tract infection (29%), COVID‑19 (22.5%) and urinary tract infection (21%).

Tabulated list of adverse reactions

The ADRs listed in Table 12 are based on pooled safety data from two clinical studies in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis, up to week 76:

● REGENCY (CA41705): a Phase III study which included 136 patients treated with Gazyvaro plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids.

● NOBILITY (WA29748): a Phase II study which included 64 patients treated with Gazyvaro plus standard therapy with MMF/mycophenolic acid and corticosteroids.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 12 ADRs reported in patients receiving Gazyvaro + standard therapy* in LN

System Organ Class

Frequency

All Grades

Grades 3-5

Infections and infestations

Very common

Upper respiratory tract infection, COVID-19, urinary tract infection, bronchitis,

Common

Pneumonia, herpes simplex

COVID-19, urinary tract infection, pneumonia

Injury, Poisoning and Procedural Complications

Very common

IRR

Common

IRR

Blood and Lymphatic System Disorders

Very common

Neutropenia

Common

Neutropenia

Investigations

Very common

Blood immunoglobulin M decreased**

*mycophenolate mofetil (MMF) and corticosteroids

**Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials.

Description of selected adverse reactions

Infections

Infections were reported in 72.0% of patients in the Gazyvaro arm vs. 61.7% of patients in the placebo arm. The most frequently reported infections were upper and lower respiratory tract infections. Grade 3-5 infections events were reported in 11.5% of patients in the Gazyvaro arm vs 9.8% of patients in the placebo arm. Fatal infection events were reported in 1% of patients in the Gazyvaro arm vs 0.5% of patients in the placebo arm (see section 4.4).

Neutropenia

Neutropenia and related events were reported in 14.0% of patients in the Gazyvaro arm vs 6.2% of patients in the placebo arm. Grade 3-4 neutropenia was reported in 7% of patients treated with Gazyvaro vs 0.5% of patients in the placebo arm. The majority of neutropenia and related events resolved/improved spontaneously or with use of granulocyte colony-stimulating factors (see section 4.4).

Infusion-related reactions

IRRs were reported in 13.5% of patients in the Gazyvaro arm vs 10.4% of patients in the placebo arm. IRRs in both arms were predominantly Grade 1-2 and occurred during/after the first infusion. Grade 3‑4 IRRs were reported in 1.5% of patients in the Gazyvaro arm vs 0.5% of patients in the placebo arm. All Grade 3-4 events occurred during/after either the first or second infusion. The incidence and severity of IRRs decreased with subsequent infusions (see section 4.4).

In the REGENCY study, most common IRR signs/symptoms included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia.

Special populations

Elderly

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with Gazyvaro plus chlorambucil were 75 years or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than those patients < 75 years of age.

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, patients 65 years or older experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age.

Renal impairment

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients treated with Gazyvaro plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than patients with a CrCl ≥ 50 mL/min (see section 4.2, 4.4 and 5.2). Patients with a CrCl < 30 mL/min were excluded from the study (see section 5.1).

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 7% (14 out of 204) of patients treated with Gazyvaro, respectively, had moderate renal impairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, Grade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in BO21223 only) than patients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min were excluded from the studies (see section 5.1).

Lupus Nephritis

The population pharmacokinetic analysis (n = 196) of Gazyvaro showed that creatinine clearance does not affect the pharmacokinetics of obinutuzumab in patients with LN. The pharmacokinetics of obinutuzumab in patients with mild (CrCl 60 - <90 mL/min, n=45) or moderate (CrCl 30 - <60 mL/min, n=17) renal impairment were similar to those in patients with normal kidney function. The safety and efficacy of Gazyvaro in patients with severe renal impairment has not been formally studied.

Additional safety information from clinical studies experience

Worsening of pre-existing cardiac conditions

Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro in CLL and NHL (see section 4.4). These events may occur as part of an IRR and can be fatal.

Laboratory abnormalities

Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed in CLL shortly after the first infusion of Gazyvaro.

Obinutuzumab treatment resulted in a decrease in total immunoglobulins in pooled LN data from placebo-controlled studies, mainly driven by reduction in IgM.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.