GAZYVARO 1000mg concentrate for solution for infusion medication leaflet

Gazyvaro 1,000 mg concentrate for solution for infusion.

One vial of 40 mL concentrate contains 1,000 mg obinutuzumab, corresponding to a concentrationbefore dilution of 25 mg/mL.

Obinutuzumab is a Type II humanised anti-CD20 monoclonal antibody of the IgG1 subclass derivedby humanisation of the parental B-Ly1 mouse antibody and produced in the Chinese Hamster Ovarycell line by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colourless to slightly brownish liquid.

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

Follicular lymphoma (FL)

Gazyvaro in combination with chemotherapy, followed by Gazyvaro maintenance therapy in patientsachieving 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 thetreatment of patients with FL who did not respond or who progressed during or up to 6 months aftertreatment with rituximab or a rituximab-containing regimen.

Gazyvaro should be administered under the close supervision of an experienced physician and in anenvironment where full resuscitation facilities are immediately available.

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/orrenal 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 tostart of Gazyvaro infusion as per standard practice (see section 4.4). Patients should continue toreceive 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). Corticosteroidpremedication 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 administeredas 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 throughouteach 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)

Day oftreatment Patients requiringpremedication Premedication Administrationcycle

Intravenouscorticosteroid1,4 Completed at least

Cycle 1: (mandatory for CLL, 1 hour prior to Gazyvaro

Day 1 for recommended for FL) infusion

CLL and All patients

FL Oral analgesic/anti-pyretic2 At least 30 minutesbefore Gazyvaro

Anti-histaminic medicine3 infusion

Intravenous corticosteroid1 Completed at least1 hour prior to Gazyvaro

Cycle 1: (mandatory) infusion

Day 2 for All patients

CLL only Oral analgesic/anti-pyretic2 At least 30 minutesbefore Gazyvaro

Anti-histaminic medicine3 infusion

Patients with no IRRduring the previous Oral analgesic/anti-pyretic2infusion At least 30 minutes

All Patients with an IRR before Gazyvarosubsequent (Grade 1 or 2) with the Oral analgesic/anti-pyretic2 infusioninfusions for previous infusion Anti-histaminic medicine

CLL and Patients with a Grade 3 Intravenous Completed at least

FL IRR with the previous corticosteroid1,4 1 hour prior to Gazyvaroinfusion OR infusion

Patients withlymphocyte counts Oral analgesic/anti-pyretic2 At least 30 minutes>25 x 109/L prior to Anti-histaminic medicine3 before Gazyvaronext treatment infusion1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be usedas it has not been effective in reducing rates of IRR.2 e.g. 1,000 mg acetaminophen/paracetamol3 e.g. 50 mg diphenhydramine4.If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid canbe administered as an oral medicinal product if given at least 60 minutes prior to Gazyvaro, in which case additional IVcorticosteroid as premedication is not required.

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1)

For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shownin 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 mgfor Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, thesecond bag may be administered on the same day (no dose delay necessary, no repetition ofpremedication), provided that appropriate time, conditions and medical supervision are availablethroughout the infusion. If there are any modifications of the infusion rate or interruptions during thefirst 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 daysduration for patients with CLL

Cycle Day of treatment Dose of Gazyvaro

Day 1 100 mg

Day 2

Cycle 1 (or Day 1 continued) 900 mg

Day 8 1,000 mg

Day 15 1,000 mg

Cycles 2-6 Day 1 1,000 mg1See section 5.1 for information on chlorambucil dose

Six treatment cycles, each of 28 day duration.

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not waituntil the next planned dose. The planned treatment interval for Gazyvaro should be maintainedbetween doses.

For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shownin 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, andprednisone/prednisolone/methylprednisolone(CVP).

Maintenance

Patients who achieve a complete or partial response to induction treatment with Gazyvaro incombination 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 untildisease progression (whichever occurs first).

Patients with follicular lymphoma who did not respond or who progressed during or up to 6 monthsafter 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 treatmentcycles) with Gazyvaro in combination with bendamustine or have stable disease should continue toreceive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years oruntil disease progression (whichever occurs first).

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

Cycle Day of treatment Dose of Gazyvaro

Day 1 1,000 mg

Cycle 1

Day 8 1,000 mg

Day 15 1,000 mg

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

Every 2 months for 2 years

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

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

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not omit itor wait until the next planned dose.

If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these dosesshould 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 (Managementof IRRs or section 4.4).

No dose adjustment is required in elderly patients (see section 5.2).

No dose adjustment is required in patients with mild to moderate renal impairment (creatinineclearance [CrCl] 30-89 mL/min) (see section 5.2). The safety and efficacy of Gazyvaro has not beenestablished in patients with severe renal impairment (CrCl < 30 mL/min) (see sections 4.8 and 5.2).

The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not beenestablished. No specific dose recommendations can be made.

The safety and efficacy of Gazyvaro in children and adolescents aged below 18 years has not beenestablished. No data are available.

Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated lineafter dilution (see section 6.6). Gazyvaro infusions should not be administered as an intravenous pushor bolus.

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

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

Table 4 Chronic lymphocytic leukaemia: Standard infusion rate in the absence of

IRRs/hypersensitivity and recommendations in case an IRR occurred with previousinfusion

Rate of infusion

The infusion rate may be escalated provided that

Cycle Day of treatment the patient can tolerate it. For 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 inincrements of 50 mg/hr every 30 minutes to a

Day 2 maximum rate of 400 mg/hr.(or Day 1 continued)

Cycle 1 (900 mg) If the patient experienced an IRR during theprevious infusion, start with administration at 25mg/hr. The rate of infusion can be escalated inincrements up to 50 mg/hr every 30 minutes to amaximum rate of 400 mg/hr.

Day 8 If no IRR occurred during the previous infusion,(1,000 mg) when the final infusion rate was 100 mg/hr or

Day 15 faster, infusions can be started at a rate of(1,000 mg) 100 mg/hr and increased by 100 mg/hrincrements every 30 minutes to a maximum of400 mg/hr.

If the patient experienced an IRR during the

Cycles 2-6 Day 1 previous infusion administer at 50 mg/hr. The(1,000 mg) rate of the infusion can be escalated inincrements of 50 mg/hr every 30 minutes to amaximum rate of 400 mg/hr.

Follicular lymphoma (FL)

Gazyvaro should be administered at the standard infusion rate in Cycle 1 (see Table 5). In patientswho do not experience Grade ≥3 infusion related reactions (IRRs) during Cycle 1, Gazyvaro may beadministered 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 IRRoccurred with previous infusion

Cycle Day of treatment Rate of infusion

The infusion rate may be escalated providedthat the patient can tolerate it. Formanagement of IRRs that occur during theinfusion, refer to “Management of IRRs”.

Day 1 Administer at 50 mg/hr. The rate of infusion(1,000 mg) can be escalated in 50 mg/hr increments every30 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 finalinfusion 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 every30 minutes to a maximum of 400 mg/hr.

Cycles 2-6 or Day 12-8 (1,000 mg) If the patient experienced an IRR of Grade 2or 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 casean IRR occurred with previous infusion

Cycle Day of treatment Rate of infusion

For management of IRRs that occur duringthe infusion, refer to “Management of IRRs”.

Cycles 2-6 or Day 1 If no IRR of Grade ≥3 occurred during2-8 (1,000 mg) Cycle 1:

100 mg/hr for 30 minutes, then 900 mg/hr forapproximately 60 minutes.

Every 2 months for 2 years or If an IRR of Grade 1-2 with ongoing

Maintenance until disease progression symptoms or a Grade 3 IRR occurred during(whichever occurs first) the previous SDI infusion, administer the nextobinutuzumab 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, ortreatment discontinuations of Gazyvaro as outlined below (see also section 4.4).

* Grade 4 (life threatening): Infusion must be stopped and therapy must be permanentlydiscontinued.

* Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolutionof symptoms, the infusion can be restarted at no more than half the previous rate (the rate beingused at the time that the IRR occurred) and, if the patient does not experience any IRRsymptoms, the infusion rate escalation can resume at the increments and intervals as appropriatefor the treatment dose (see Tables 4 -6). For CLL patients receiving the Day 1 (Cycle 1) dosesplit 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 asecond 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 experienceany IRR symptoms, the infusion rate escalation can resume at the increments and intervals asappropriate 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 to25 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 permanentlydiscontinued.

* Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolutionof symptoms, the infusion can be restarted at no more than half the previous rate (the rate beingused 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 mustbe stopped and therapy must be permanently discontinued. If the patient is able to complete theinfusion without further Grade 3 IRRs, the next infusion should be given at a rate not higherthan 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 notexperience any IRR symptoms, the infusion rate escalation can resume at the increments andintervals as appropriate for the treatment dose (see Tables 5-6).

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

In order to improve the traceability of biological medicinal products, the trade name and batch numberof the administered product should be clearly recorded (or stated) in the patient file.

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

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 tocytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patientswho received the combined measures for prevention of IRRs (adequate corticosteroid, oralanalgesic/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 decreasedincidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on arelatively small number of patients) were similar before and after mitigation measures wereimplemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidenceand 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 bemanaged by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRsrequiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishablefrom immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a hightumour burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increasedrisk 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, includingsevere IRRs (see section 4.8). For management of IRRs see section 4.2 Posology and method ofadministration.

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 orduring a subsequent infusion).

Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefullythroughout the infusion and the post-infusion period. Hypotension may occur during Gazyvarointravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for12 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 ofwithholding their anti-hypertensive medicine.

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 clinicallydistinguish from IRRs. Hypersensitivity symptoms can occur after previous exposure and very rarelywith the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, theinfusion must be stopped and treatment permanently discontinued. Patients with knownhypersensitivity to obinutuzumab must not be treated (see section 4.3).

TLS has been reported with Gazyvaro. Patients who are considered to be at risk of TLS (e.g. patientswith a high tumour burden and/or a high circulating lymphocyte count [> 25 x 109/L] and/or renalimpairment [CrCl < 70 mL/min]) should receive prophylaxis. Prophylaxis should consist of adequatehydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urateoxidate (e.g. rasburicase) starting 12-24 hours prior to the infusion of Gazyvaro as per standardpractice (see section 4.2). All patients considered at risk should be carefully monitored during theinitial days of treatment with a special focus on renal function, potassium, and uric acid values. Anyadditional guidelines according to standard practice should be followed. For treatment of TLS, correctelectrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care,including dialysis as indicated.

Severe and life-threatening neutropenia including febrile neutropenia has been reported duringtreatment with Gazyvaro. Patients who experience neutropenia should be closely monitored withregular laboratory tests until resolution. If treatment is necessary it should be administered inaccordance 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 stronglyrecommended that patients with severe neutropenia lasting more than 1 week receive antimicrobialprophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungalprophylaxis should also be considered (see section 4.2). Late onset neutropenia (occurring >28 daysafter the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment hasbeen completed/stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more atrisk of neutropenia (see section 4.8).

Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renalimpairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatalhaemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clearrelationship between thrombocytopenia and haemorrhagic events has not been established.

Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regularlaboratory tests should be performed until the event resolves, and dose delays should be considered incase of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelettransfusion) according to institutional practice is at the discretion of the treating physician. Use of anyconcomitant therapies which could possibly worsen thrombocytopenia-related events, such as plateletinhibitors 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 inpatients receiving Gazyvaro. The majority of cases involved non-overt DIC, with subclinical(asymptomatic) changes in platelets and laboratory coagulation parameters occurring within 1-2 daysafter the first infusion with spontaneous resolution usually occurring within one to two weeks, notrequiring 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 havenon-overt DIC should be monitored closely with coagulation parameters including platelets andclinical observation for signs or symptoms of overt DIC. Gazyvaro should be discontinued at firstonset 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 andtachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failurehave occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRRand can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. Inaddition these patients should be hydrated with caution in order to prevent a potential fluid overload.

Gazyvaro should not be administered in the presence of an active infection and caution should beexercised when considering the use of Gazyvaro in patients with a history of recurring or chronicinfections. Serious bacterial, fungal, and new or reactivated viral infections can occur during andfollowing 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, includingsevere infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infectionswas observed in all phases of the studies, including follow-up, with the highest incidence seen in themaintenance phase. During the follow-up phase, Grade 3-5 infections are observed more in patientswho received Gazyvaro plus bendamustine in the induction phase.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failureand death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro (see section4.8). HBVscreening 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 coreantibody (HBcAb) status. These can be complemented with other appropriate markers as per localguidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients withpositive hepatitis B serology should consult liver disease experts before start of treatment and shouldbe monitored and managed following local medical standards to prevent hepatitis reactivation.

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 withnew-onset or changes to pre-existing neurologic manifestations. The symptoms of PML arenonspecific and can vary depending on the affected region of the brain. Motor symptoms withcorticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensoryabnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptomsregarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PMLincludes, 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). Therapywith Gazyvaro should be withheld during the investigation of potential PML and permanentlydiscontinued in case of confirmed PML. Discontinuation or reduction of any concomitantchemotherapy or immunosuppressive therapy should also be considered. The patient should bereferred to a neurologist for the evaluation and treatment of PML.

The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has notbeen 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 Gazyvaroduring pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virusvaccines should be postponed until the infant’s B-cell count has recovered. The safety and timing ofvaccination should be discussed with the infant’s physician (see section 4.6).

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

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

Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridinediphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore,no pharmacokinetic interaction is expected with medicinal products known to be metabolised by theseenzyme 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 ofbendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyvaro.

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

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

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

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

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

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 andharm 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.

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 toxicitystudies in cynomolgus monkeys (see section 5.3).

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

The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenanceand 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 patientshad FL)

* GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had noresponse to or who progressed during or up to 6 months after treatment with rituximab or arituximab-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 ADRspresented in the following has been performed on the entire study population (i.e. iNHL).

Table 7 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 orrituximab 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 torituximab plus chemotherapy followed by rituximab maintenance in patients achieving aresponse (study BO21223/GALLIUM)

* Patients with iNHL who had no response to or who progressed during or up to 6 months aftertreatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plusbendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustinealone (study GAO4753g/GADOLIN)

The incidences presented in Table 7 (all grades and Grades 3-5) are the highest incidence of that ADRreported from any of the three studies.

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

Table 7 Summary of ADRs reported in patients# receiving Gazyvaro + chemotherapy*

System organ class All Grades Grades 3-5†

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

Gazyvaro maintenance (iNHL) Gazyvaro maintenance (iNHL)

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

Common Oral herpes, rhinitis, pharyngitis, Urinary tract infection,lung infection, influenza pneumonia, lung infection, upperrespiratory 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, Squamous cell carcinoma of skin,

Basal cell carcinoma Basal cell carcinoma

Very common Neutropenia§, thrombocytopenia, Neutropenia, thrombocytopeniaanaemia, leukopenia

Common Febrile neutropenia Anaemia, leukopenia, febrileneutropenia

Uncommon Disseminated intravascularcoagulation##

Common Tumour lysis syndrome, Tumour lysis syndrome,hyperuricaemia, hypokalaemia hypokalaemia

Uncommon Hyperuricaemia

Very common Insomnia

Common Depression, anxiety

Uncommon Insomnia, depression, anxiety

Very common Headache

Uncommon Headache

Not known Progressive multifocalleukoencephalopathy

Common Atrial fibrillation Atrial fibrillation

Common Hypertension Hypertension

Very common Cough§

Common Nasal congestion, rhinorrhoea,oropharyngeal pain

Uncommon Cough, oropharyngeal pain

Very common Diarrhoea, constipation§

System organ class All Grades Grades 3-5†

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

Gazyvaro maintenance (iNHL) Gazyvaro maintenance (iNHL)

Common Dyspepsia, haemorrhoids Diarrhoeagastrointestinal perforation

Uncommon Constipation, haemorrhoids

Very common Alopecia, pruritus

Common Eczema

Uncommon Pruritus

Very common Arthralgia§, back pain, pain inextremity

Common Musculoskeletal chest pain, bone Pain in extremitypain

Uncommon Arthralgia, back pain,musculoskeletal chest pain, bonepain

Renal and Urinary Disorders

Common Dysuria, urinary incontinence

Uncommon Dysuria, urinary incontinence

Very common Pyrexia, Asthenia, fatigue

Common Chest pain Pyrexia, asthenia, fatigue

Uncommon Chest pain

Rare Cytokine release syndrome**

Common White blood cell count decreased, White blood cell count decreased,neutrophil count decreased, neutrophil count decreasedweight increased

Uncommon Hypogammaglobulinemia

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 inpostmarketing 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 populationin both studies.

The incidences presented in the following sections if referring to iNHL are the highest incidence ofthat 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).

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 throatirritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also beenreported (see section 4.4).

Chronic Lymphocytic Leukaemia

The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximabplus 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 first1,000 mg infusions of Cycle 1.

In patients who received the recommended measures for prevention of IRRs as described in section4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (whichoccurred in relatively few patients) were similar before and after mitigation measures wereimplemented.

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 inpatients receiving Gazyvaro plus chemotherapy compared to patients in the comparator arm. Inpatients receiving Gazyvaro plus chemotherapy, the incidence of IRRs was highest on Day 1 andgradually decreased with subsequent infusions. This decreasing trend continued during maintenancetherapy with Gazyvaro alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions wascomparable between the Gazyvaro and the relevant comparator arms. Overall, 4% of patientsexperienced 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 2in study BO21223 (10/99 [10.1%] vs. 23/529 [4.3%] respectively; IRRs attributed by the investigatorto 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 symptomsand signs were similar in both studies.

Infusion related reactions observed in Study MO40597/GAZELLE are summarized in Table 8.

Table 8 Study MO40597/GAZELLE Short-Duration Infusion: Infusion Related Reactionsaby Cycle (Safety-Evaluable Population)

CTCAE C1 C1b by day C2C C3 C4 C5 C6 C7 Over all

Grade Overall induction(standard cyclesinfusion) Day 1 Day 2d Day 8 Day 15

All 65/113 57/113 4/51 6/112 5/111 13/110 9/108 7/108 6/107 5/105 2/55 71/113

Grade (57.5%) (50.4%) (7.8%) (5.4%) (4.5%) (11.8%) (8.3%) (6.5%) (5.6%) (4.8%) (3.6%) (62.8%)

Grade 6/113 5/113 1/51 0 0 0 0 0 1/107 0 0 7/113≥3 (5.3%) (4.4%) (2.0%) (0.9%) (6.2%)

C=cycle; CTCAE = Common Terminology Criteria for Adverse Events; IRR=infusion related reactiona Infusion related reaction defined as any event that occurred during or within 24 hours from the end of studytreatment 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 intervalsc Patients received short-duration infusion from C2 onward. The denominator at C2 and subsequent cyclesrepresents 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 tothe rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use ofgranulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro pluschlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3-5 events reported in12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases ofprolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab pluschlorambucil 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 higherrelative to the comparator arm with an increased risk during the induction period. The incidence ofprolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence ofinfection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% ofpatients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had alower 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 ahigher proportion of patients compared to study BO21223 in which patients receiving standardduration infusion 69/113 [61.1%] vs 247/595 [41.5%], respectively, throughout induction). Themedian and range of neutrophil count values were similar in both studies at each time point. Febrileneutropenia 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 tothe rituximab plus chlorambucil arm (16% vs. 7%) especially during the first cycle. Four percent ofpatients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurringwithin 24 hours after the Gazyvaro infusion) (see section 4.4). The overall incidence of haemorrhagicevents was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatalhaemorrhagic events was balanced between the treatment arms; however, all of the events in patientstreated with Gazyvaro were reported in Cycle 1. No Grade 5 events of thrombocytopenia werereported. A clear relationship between thrombocytopenia and haemorrhagic events has not beenestablished.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

The incidence of thrombocytopenia was 15%. Thrombocytopenia occurred more frequently in Cycle 1in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end ofinfusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro pluschemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similaracross 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 ina higher proportion of patients compared to study BO21223 in which patients received standardduration infusion (21/113 [28.6%] vs 63/595 [10.6%], respectively, throughout induction). The medianand range of platelet count values were similar in both studies at each time point. Nothrombocytopenia events reported in MO40597 were associated with bleeding.

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 patientsexperienced 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 orolder experienced more serious adverse events and adverse events leading to withdrawal or death thanpatients < 65 years of age.

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients treated with Gazyvaro pluschlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced moreserious adverse events and adverse events leading to death than patients with a CrCl ≥ 50 mL/min(see section 4.2, pct. 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 renalimpairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, G rade 3 to5 adverse events and adverse events leading to treatment withdrawal (patients in BO21223 only) thanpatients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min wereexcluded from the studies (see section 5.1).

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 coronarysyndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (seesection 4.4). These events may occur as part of an IRR and can be fatal.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 beenadministered. The incidence and intensity of adverse reactions reported in these studies did not appearto be dose dependent.

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

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies,

ATC code: L01FA03

Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembraneantigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not onhaematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineeringof the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune effectorcells such as natural killer (NK) cells, macrophages and monocytes as compared tonon-glycoengineered antibodies.

In nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependentcellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) throughrecruitment of FcɣRIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates alow degree of complement dependent cytotoxicity (CDC). Compared to Type I antibodies,obinutuzumab, a Type II antibody, is characterised by an enhanced direct cell death induction with aconcomitant reduction in CDC at an equivalent dose. Obinutuzumab, as a glycoengineered antibody, ischaracterised by enhanced ADCC and ADCP compared to non-glycoengineered antibodies at anequivalent dose. In animal models obinutuzumab mediates potent B-cell depletion and antitumourefficacy.

In the pivotal clinical study in patients with CLL (BO21004/CLL11), 91% (40 out of 44) of evaluablepatients treated with Gazyvaro were B-cell depleted (defined as CD19+ B-cell counts < 0.07 x 109/L)at the end of treatment period and remained depleted during the first 6 months of follow up. Recoveryof B-cells was observed within 12-18 months of follow up in 35% (14 out of 40) of patients withoutprogressive disease and 13% (5 out of 40) with progressive disease.

In the pivotal clinical study in patients with iNHL (GAO4753/GADOLIN), 97% (171 out of 176) ofevaluable patients treated with Gazyvaro were B-cell depleted at the end of the treatment period, and97% (61 out of 63) remained depleted for more than 6 months from the last dose. Recovery of B-cellswas observed within 12-18 months of follow-up in 11% (5 out of 46) of evaluable patients.

Chronic Lymphocytic Leukaemia

A Phase III international, multicentre, open label, randomised, two-stage, three-arm clinical study(BO21004/CLL11) investigating the efficacy and safety of Gazyvaro plus chlorambucil (GClb)compared to rituximab plus chlorambucil (RClb) or chlorambucil (Clb) alone was conducted inpatients with previously untreated CLL with comorbidities.

Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the followingmeasures of coexisting medical conditions: comorbidity score (CIRS) of greater than 6 or reducedrenal function as measured by CrCl < 70 mL/min. Patients with inadequate liver function (National

Cancer Institute - Common Terminology Criteria for Adverse Events Grade 3 liver function tests(AST, ALT > 5 x ULN for > 2 weeks; bilirubin > 3 x ULN) and renal function (CrCl < 30 mL/min)were excluded. Patients with one or more individual organ/system impairment score of 4 as assessedby the CIRS definition, excluding eyes, ears, nose, throat and larynx organ system, were excluded.

A total of 781 patients were randomised 2:2:1 to receive Gazyvaro plus chlorambucil, rituximab pluschlorambucil or chlorambucil alone. Stage 1a compared Gazyvaro plus chlorambucil to chlorambucilalone in 356 patients and Stage 2 compared Gazyvaro plus chlorambucil to rituximab pluschlorambucil in 663 patients.

In the majority of patients, Gazyvaro was given intravenously as a 1,000 mg initial dose administeredon Day 1, Day 8 and Day 15 of the first treatment cycle. In order to reduce the rate of infusion relatedreactions in patients, an amendment was implemented and 140 patients received the first Gazyvarodose administered over 2 days (Day 1 [100 mg] and Day 2 [900 mg]) (see section 4.2 and 4.4). Foreach subsequent treatment cycle (Cycles 2 to 6), patients received Gazyvaro 1,000 mg on Day 1 only.

Chlorambucil was given orally at 0.5 mg/kg body weight on Day 1 and Day 15 of all treatment cycles(1 to 6).

The demographics data and baseline characteristics were well balanced between the treatment arms.

The majority of patients were Caucasian (95%) and male (61%). The median age was 73 years, with44% being 75 years or older. At baseline, 22% of patients had Binet Stage A, 42% had Binet Stage Band 36% had Binet Stage C.

The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity scoreabove 6. The median estimated CrCl was 62 mL/min and 66% of all patients had a CrCl < 70 mL/min.

Forty-two percent of patients enrolled had both a CrCl < 70 mL/min and a comorbidity score of > 6.

Thirty-four percent of patients were enrolled on comorbidity score alone, and 23% of patients wereenrolled with only impaired renal function.

The most frequently reported coexisting medical conditions (using a cut off of 30% or higher), in the

MedDRA body systems are: Vascular disorders (73%), Cardiac disorders (46%), Gastrointestinaldisorders (38%), Metabolism and nutrition disorders (40%), Renal and urinary disorders (38%),

Musculoskeletal and connective tissue disorders (33%).

Efficacy results for patients with previously untreated CLL are summarised in Table 9. Kaplan-Meiercurves for progression-free survival (PFS) and Overall Survival (OS) are shown in Figures 1-4.

Table 9 Summary of efficacy from BO21004/CLL11 study

Stage 1a Stage 2

Gazyvaro + Rituximab + Gazyvaro +

Chlorambucil chlorambucil chlorambucil chlorambucil

N=118 N= 238 N= 330 N= 33322.8 months median observation 18.7 months median observationtime g time g

Primary endpoint

Investigator-assessed PFS (PFS-INV)a

Number (%) of patients with event 96 (81.4%) 93 (39.1%) 199 (60.3%) 104 (31.2%)

Median time to event (months) 11.1 26.7 15.2 26.7

Hazard ratio (95% CI) 0.18 [0.13; 0.24] 0.39 [0.31; 0.49]p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001

Key secondary endpoints

IRC-assessed PFS (PFS-IRC)a

Number (%) of patients with event 90 (76.3%) 89 (37.4%) 183 (55.5%) 103 (30.9%)

Median time to event (months) 11.2 27.2 14.9 26.7

Hazard ratio (95% CI) 0.19 [0.14; 0.27] 0.42 [0.33; 0.54]p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001

End of treatment response rate

No. of patients included in the analysis 118 238 329 333

Responders (%) 37 (31.4%) 184 (77.3%) 214 (65.0%) 261 (78.4%)

Non-responders (%) 81 (68.6%) 54 (22.7%) 115 (35.0%) 72 (21.6%)

Difference in response rate, (95% CI) 45.95 [35.6; 56.3] 13.33 [6.4; 20.3]p-value (Chi-squared Test) < 0.0001 0.0001

No. of complete respondersc (%) 0 (0.0%) 53 (22.3%) 23 (7.0%) 69 (20.7%)

Stage 1a Stage 2

Gazyvaro + Rituximab + Gazyvaro +

Chlorambucil chlorambucil chlorambucil chlorambucil

N=118 N= 238 N= 330 N= 33322.8 months median observation 18.7 months median observationtime g time g

Molecular remission at end of treatmentd

No. of patients included in the analysis 90 168 244 239

MRD negativee (%) 0 (0%) 45 (26.8%) 6 (2.5%) 61 (25.5%)

MRD positivef (%) 90 (100%) 123 (73.2%) 238 (97.5%) 178 (74.5%)

Difference in MRD rates, (95% CI) 26.79 [19.5; 34.1] 23.06 [17.0; 29.1]

Event free survival

No. (%) of patients with event 103 (87.3%) 104 (43.7%) 208 (63.0 %) 118 (35.4 %)

Median time to event (months) 10.8 26.1 14.3 26.1

Hazard ratio (95% CI) 0.19 [0.14; 0.25] 0.43 [0.34; 0.54]p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0001

Time to new anti-leukaemic therapy

No. (%) of patients with event 65 (55.1%) 51 (21.4%) 86 (26.1%) 55 (16.5%)

Median time to event (months) 14.8 NR 30.8 NR

Hazard ratio (95% CI) 0.24 [0.16; 0.35] 0.59 [0.42; 0.82]p-value (Log-Rank test, stratifiedb) < 0.0001 < 0.0018

Overall survival

No. (%) of patients with event 57 (48.3%) 93 (39.1%) 147 (44.5%) 121 (36.3%)

Median time to event (months) 66.7 NR 73.1 NR

Hazard ratio (95% CI) 0.68 [0.49; 0.94] 0.76 [0.60; 0.97]p-value (Log-Rank test, stratifiedb) 0.0196 0.0245

IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Intervals, MRD:

Minimal Residual Disease, NR = Not reacheda Defined as the time from randomisation to the first occurrence of progression, relapse or death from any cause as assessedby the investigatorb stratified by Binet stage at baselinec Includes 11 patients in the GClb arm with a complete response with incomplete marrow recoveryd Blood and bone marrow combinede MRD negativity is defined as a result below 0.0001f Includes MRD positive patients and patients who progressed or died before the end of treatmentg Median observation time for overall survival (OS) data corresponds to 62.5 months median observation time in Stage 1aand to 59.4 months median observation time in Stage 2.

Results of subgroup analyses

Results of the progression free survival (PFS) subgroup analysis (i.e. sex, age, Binet stages, CrCl,

CIRS score, beta2-microglobulin, IGVH status, chromosomal abnormalities, lymphocyte count atbaseline) were consistent with the results seen in the overall Intent-to-Treat population. The risk ofdisease progression or death was reduced in the GClb arm compared to the RClb arm and Clb arm inall subgroups except in the subgroup of patients with deletion 17p. In the small subgroup of patientswith deletion 17p, only a positive trend was observed compared to Clb (HR=0.42, p=0.0892); nobenefit was observed compared to RClb. For subgroups, reduction of the risk of disease progression ordeath ranged from 92% to 58% for GClb versus Clb and 72% to 29% for GClb versus RClb.

Figure 1 Kaplan-Meier curve of Investigator assessed PFS from Stage 1a in patients with CLL(Study BO21004/CLL11)

Figure 2 Kaplan-Meier curve of OS from Stage 1a in patients with CLL (Study

BO21004/CLL11)

Figure 3 Kaplan-Meier curve of investigator assessed PFS from Stage 2 in patients with CLL(Study BO21004/CLL11)

Figure 4 Kaplan-Meier curve of OS from Stage 2 in patients with CLL (Study BO21004/CLL11)

In the QLQC30 and QLQ-CLL-16 questionnaires conducted during the treatment period, nosubstantial difference in any of the subscales was observed. Data during follow up, especially for thechlorambucil alone arm, is limited. However, no notable differences in quality of life during follow uphave been identified to date.

Health-related quality of life assessments, specific to fatigue through treatment period, show nostatistically significant difference suggesting that the addition of Gazyvaro to a chlorambucil regimendoes not increase the experience of fatigue for patients.

Previously untreated follicular lymphoma (study BO21223/GALLIUM)

In a phase III, open label, multicentre, randomised clinical study (BO21223/GALLIUM),1202 patients with previously untreated Grade 1-3a advanced (stage II bulky disease, stage III/IV) FLwere evaluated. Patients with FL Grade 3b were excluded from the study. Patients were randomised to1:1 to receive either Gazyvaro (n=601 patients) or rituximab (n=601 patients) in combination withchemotherapy (bendamustine, CHOP or CVP), followed by Gazyvaro or rituximab maintenance inpatients achieving a complete or partial response.

Gazyvaro was given by intravenous infusion as a dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on

Day 1 of subsequent cycles. In total, six cycles of Gazyvaro (every 28 days) were given incombination with six cycles of bendamustine, and a total of eight cycles of Gazyvaro (every 21 days)were given in combination with six cycles of CHOP or eight cycles of CVP. Gazyvaro wasadministered prior to chemotherapy. Bendamustine was given intravenously on Days 1 and 2 for alltreatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyvaro. Standarddosing of CHOP and CVP was given. Following Cycles 6-8, in combination with chemotherapy,responding patients received Gazyvaro maintenance therapy every 2 months until disease progressionor for up to 2 years.

The demographic data and baseline characteristics of the patient population were well balancedbetween the treatment arms; median age was 59 years, 81% were Caucasian, 53% were female, 79%had a FLIPI score of ≥ 2 and 7% had Stage II (bulky), 35% had Stage III and 57% had Stage IVdisease, 44% had bulky disease (> 7 cm), 34% had at least one B-symptom at baseline and 97% had an

ECOG performance status of 0-1 at baseline. Fifty-seven percent received bendamustine, 33%received CHOP, and 10% received CVP chemotherapy.

Efficacy results for patients with previously untreated FL are summarised in Table 10. Kaplan-Meiercurves for progression-free survival (PFS) are shown in Figure 5.

Table 10 Summary of efficacy in patients with previously untreated FL from BO21223/

GALLIUM study

Rituximab + Chemotherapy Gazyvaro +Chemotherapyfollowed by rituximab followed by Gazyvaromaintenance maintenance

N=601 N=601

Primary Endpoint

Investigator-assessed PFS§ (PFS-INV)primary analysis

Number (%) of patients with event 144 (24.0%) 101 (16.8%)

HR [95% CI] 0.66 [0.51, 0.85]p-value (Log-Rank test, stratified*) 0.00123 year PFS estimate [%] 73.3 80.0[95% CI] [68.8, 77.2] [75.9, 83.6]

Rituximab + Chemotherapy Gazyvaro +Chemotherapyfollowed by rituximab followed by Gazyvaromaintenance maintenance

N=601 N=601

PFS-INV final analysis§§

Number (%) of patients with event 244 (40.6%) 206 (34.3%)

HR [95% CI] 0.77 [0.64, 0.93]p-value (Log-Rank test, stratified*) 0.00553 year PFS estimate [%] 75.5 82.4[95% CI] [71.8, 78.9] [79.0, 85.3]7 year PFS estimate [%] 55.7 63.4[95% CI] [51.3, 59.9] [59.0, 67.4]

Key Endpoints

IRC-assessed PFS (PFS-IRC)primary analysis

Number (%) of patients with event 125 (20.8%) 93 (15.5%)

HR [95% CI] 0.71 [0.54, 0.93]p-value (Log-Rank test, stratified*) 0.0138

Time to next anti-lymphoma therapy#primary analysis

Number (%) of patients with event 111 (18.5%) 80 (13.3%)

HR [95% CI] 0.68 [0.51, 0.91]p-value (Log-Rank test, stratified*) 0.0094

Overall Survival# primary analysis

No. (%) of patients with event 46 (7.7%) 35 (5.8%)

HR [95% CI] 0.75 [0.49, 1.17] ¶p-value (Log-Rank test, stratified*) 0.21¶

Overall Survival final analysis§§

No. (%) of patients with event 86 (14.3%) 76 (12.6%)

HR [95% CI] 0.86 [0.63, 1.18]p-value (Log-Rank test, stratified*) 0.36

Rituximab + Chemotherapy Gazyvaro +Chemotherapyfollowed by rituximab followed by Gazyvaromaintenance maintenance

N=601 N=601

Overall Response Rate** at End of

Induction‡ (INV-assessed, CT) #primary analysis

Responders (%) (CR, PR) 522 (86.9%) 532 (88.5%)

Difference in response rate (%) [95%

CI] 1.7% [-2.1%, 5.5%]p-value (Cochran-Mantel-Haenszeltest) 0.33

Complete Response (CR) 143 (23.8%) 117 (19.5%)

Partial Response (PR) 379 (63.1%) 415 (69.1%)

IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Interval

* Stratification factors were chemotherapy regimen, FLIPI risk group for follicular lymphoma, geographic region§ Significance level at this efficacy interim analysis/primary analysis: 0.012, data cut-off 31 January 2016, medianobservation time 34/35 months§§ Final analysis, data cut-off 30 July 2021, median observation time 94 months¶ Data Not Yet Mature. Median was not reached at time of analysis# not adjusted for multiplicity

**Assessed as per modified Cheson 2007 criteria‡ End of Induction = end of induction phase, does not include monotherapy maintenance

Figure 5 Kaplan-Meier curve of INV-assessed progression-free survival in patients withpreviously untreated FL (Study BO21223/GALLIUM), final analysis*

R-Chemo: Rituximab plus chemotherapy, G-Chemo: Gazyvaro plus chemotherapy, HR: hazard ratio, CI: confidence interval

*Final analysis, data cut-off 30 July 2021, median observation time 94 months

Results of subgroup analyses

Results of subgroup analyses (not adjusted for multiplicity) were, in general, consistent with theresults seen in the FL population, supporting the robustness of the overall result (primary analysis,data cut-off 31 January 2016). The subgroups evaluated included IPI, FLIPI, Bulky Disease, B

Symptoms at baseline, Ann Arbor Stage and ECOG at baseline. In patients with FLIPI score 0-1 (lowrisk), no difference between Gazyvaro plus chemotherapy and rituximab plus chemotherapy wasobserved (INV-assessed PFS HR 1.17 (95%CI 0.63;2.19, 40 PFS events). This subgroupcomprised21% (253/1202) of the FL ITT population and experienced 16.3% (40/245) of the PFS events. Inaddition, exploratory subgroup analyses of PFS across chemotherapy regimens (bendamustine, CHOPand CVP) were consistent with the results seen in the Gazyvaro plus chemotherapy population. Theobserved HRs by chemotherapy subgroup were as follows; CHOP (n = 398): HR 0.77 (95% CI: 0.50,1.20), CVP (n = 118): HR 0.63 (95% CI: 0.32, 1.21), and bendamustine (n = 686): HR 0.61 (95% CI:0.43, 0.86).

Patient Reported Outcomes

Based on the FACT-Lym questionnaire collected during treatment and follow-up phases, patients inboth treatment arms experienced clinically meaningful improvements in lymphoma-related symptomsas defined by a ≥ 3 point increase from baseline in the Lymphoma subscale, a ≥ 6 point increase frombaseline in the FACT Lym TOI and a ≥ 7 point increase from baseline in the FACT Lym Total score.

EQ-5D utility scores were similar at baseline, during treatment and follow-up. No meaningfuldifferences were seen between the arms in HRQOL or health status measures.

Due to the open label design the patient reported outcomes should be interpreted with caution.

Patients with follicular lymphoma who did not respond or who progressed during or up to 6 monthsafter treatment with rituximab or a rituximab-containing regimen (study GAO4753g/GADOLIN).

In a phase III, open label, multicentre, randomised clinical study (GAO4753g/GADOLIN),396 patients with iNHL who had no response during treatment or who progressed within 6 monthsfollowing the last dose of rituximab or a rituximab-containing regimen (including rituximabmonotherapy as part of induction or maintenance treatment) were evaluated. Patients were randomised1:1 to receive either bendamustine (B) alone (n = 202) or Gazyvaro in combination with bendamustine(G+B) (n = 194) for 6 cycles, each of 28 days duration. Patients in the G+B arm who did not havedisease progression (i.e. patients with a complete response (CR), partial response (PR) or stabledisease (SD)) at the end of induction continued receiving Gazyvaro maintenance once every twomonths for two years or until disease progression (whichever occurred first). Patients were stratifiedaccording to region, iNHL subtype (follicular versus non-follicular), rituximab-refractory type(whether refractory to prior rituximab monotherapy or rituximab in combination with chemotherapy)and the number of prior therapies (≤ 2 versus > 2).

The demographic data and baseline characteristics were well balanced between the treatment arms(median age 63 years, the majority were Caucasian [88%] and male [58%]). The majority of patientshad follicular lymphoma (81%). The median time from initial diagnosis was 3 years and the mediannumber of prior therapies was 2 (range 1 to 10); 44% of patients had received 1 prior therapy and 34%of patients had received 2 prior therapies.

Gazyvaro was given by intravenous infusion as a dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on

Day 1 of Cycles 2-6, and in patients who did not have disease progression, once every two months fortwo years or until disease progression (whichever occurs first). Bendamustine was given intravenouslyon Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with

Gazyvaro or 120 mg/m2/day when given alone. In patients treated with G+ B, 79.4% received all sixtreatment cycles compared to 66.7% of patients in the B arm.

The primary analysis, based on independent Review Committee (IRC) assessment demonstrated astatistically significant - 45% reduction in the risk of disease progression or death, in patients withiNHL receiving G+B followed by Gazyvaro maintenance, compared with patients receivingbendamustine alone. The reduction in the risk of disease progression or death seen in the iNHLpopulation is driven by the subset of patients with FL.

The majority of the patients in study GAO4753g had FL (81.1%). Efficacy results from the primaryanalysis in the FL population are shown in Table 11 and Figures 6 and 8. 11.6% of the patients hadmarginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL). In the non-FLpopulation the HR for IRC-assessed PFS was 0.94 [95% CI: 0.49, 1.90]. No definitive conclusionscould be drawn on efficacy in the MZL and SLL sub-populations.

At final analysis, the median observation time was 45.9 months (range: 0-100.9 months) for FLpatients in the B arm and 57.3 months (range: 0.4-97.6 months) for patients in the G+B arm,representing an additional 25.6 months and 35.2 months of median follow-up in B and G+B arms,respectively, since the primary analysis. Only Investigator (INV) assessed endpoints were reported atfinal analysis since IRC assessments did not continue. Overall, the investigator assessed efficacyresults were consistent with what was observed in the primary analysis. The overall survival (OS) inpatients with FL was stable with longer follow-up (see Figure 7); the HR for risk of death was 0.71(95%CI: 0.51, 0.98).

Table 11 Summary of primary efficacy analysis in patients with FL# from

GAO4753g/GADOLIN study

Gazyvaro +

Bendamustinefollowed by

Gazyvaro

Bendamustine maintenance

N=166 N=155

Median observation Median observationtime: 20 months time: 22 months

Primary Endpoint in FL population

IRC-assessed PFS (PFS-IRC)

Number (%) of patients with event 90 (54.2%) 54 (34.8%)

Median time to event (months, 95% CI) 13.8 (11.4, 16.2) NR (22.5,-)

HR (95% CI) 0.48 (0.34, 0.68)p-value (Log-Rank test, stratified*) < 0.0001

Secondary Endpoints

Investigator-assessed PFS (PFS-INV)

Number (%) of patients with event 102 (61.4%) 62 (40.0%)

Median time to event (months, 95% CI) 13.7 (11.0, 15.5) 29.2 (17.5,-)

HR (95% CI) 0.48 (0.35, 0.67)p-value (Log-Rank test, stratified*) < 0.0001

Best Overall Response (BOR) (IRC-assessed)§

No. of patients included in the analysis 161 153

Responders (%) (CR/PR) 124 (77.0%) 122 (79.7%)

Difference in response rate (95% CI) 2.72 (-6.74, 12.18)p-value (Cochran-Mantel-Haenszel test) 0.6142

Complete Responders (%) 31 (19.3%) 24 (15.7%)

Partial Responders (%) 93 (57.8%) 98 (64.1%)

Stable Disease (%) 18 (11.2%) 13 (8.5%)

Duration of response (DOR) (IRC-assessed)

No of patients included in the analysis 127 122

Gazyvaro +

Bendamustinefollowed by

Gazyvaro

Bendamustine maintenance

N=166 N=155

Median observation Median observationtime: 20 months time: 22 months

No. (%) of patients with event 74 (58.3%) 36 (29.5%)

Median duration (months) of DOR (95% CI) 11.9 (8.8, 13.6) NR (25.4,-)

HR (95% CI) 0.36 (0.24, 0.54)

Overall Survival

No. (%) of patients with event 36 (21.7%) 25 (16.1%)

Median time to event (months) NR NR

HR (95% CI) 0.71 (0.43, 1.19)p-value (Log-Rank test, stratified*) 0.1976

IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Intervals,

NR = Not Reached# Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab ora rituximab-containing regimen

*Stratification factors for analysis were refractory type (rituximab monotherapy vs. rituximab + chemotherapy) andprior therapies (≤ 2 vs > 2). Follicular versus non-follicular was also a stratification factor for the study but is notapplicable in the subgroup analysis of patients with FL.§ Best response within 12 months of start of treatment

Figure 6 Kaplan-Meier curve of IRC-assessed PFS in patients with FL # (Study

GAO4753g/GADOLIN)# Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or arituximab-containing regimen

Figure 7 Kaplan-Meier curve of Overall Survival in FL patients at Final Analysis (Study

GAO4753g/GADOLIN)

Results of subgroup analyses

Results of subgroup analyses were in general consistent with the results seen in the FL population,supporting the robustness of the overall result.

Figure 8 IRC-assessed PFS by patient subgroup in FL *# (Study GAO4753g/GADOLIN)

*pre-specified analyses performed on the intent to treat (ITT) population were repeated on the FL population; analysis ofdouble refractory (i.e. unresponsive to or disease progression during or within 6 months of the last dose of an alkylatingagent-based regimen) status was exploratory.# Patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or arituximab-containing regimen

Short Duration Infusion Study MO40597 (GAZELLE)

The safety of short (approximately 90 minutes) duration infusion (SDI) of obinutuzumab administeredin combination with CHOP, CVP or bendamustine chemotherapy was evaluated in a multicenter,open-label, single arm study in 113 patients with previously untreated advanced follicular lymphoma(Study MO40597/GAZELLE).

Patients received the first cycle of obinutuzumab at the standard infusion rate on Day 1, 8, and 15 of

Cycle 1. Patients who did not experience any Grade ≥3 IRRs during the first cycle received SDI from

Cycle 2 onwards.

The primary endpoint of the study was the proportion of patients who experienced a Grade ≥3 IRRassociated with SDI during Cycle 2, among those who had previously received 3 administrations ofobinutuzumab at the standard infusion rate during Cycle 1 without experiencing a Grade ≥3 IRR.

No Grade ≥3 IRRs were observed among patients receiving SDI at Cycle 2. After Cycle 2 only onepatient experienced a Grade 3 IRR (hypertension at Cycle 5). See section 4.8 Undesirable Effects.

Patient-reported Outcomes

Due to the open label design the patient reported outcomes should be interpreted with caution. Basedon the FACT-Lym questionnaire and EQ-5D index scale collected during the treatment and duringfollow-up periods, health-related quality of life was generally maintained in the pivotal study with nomeaningful difference between the arms. However, in patients with FL the addition of Gazyvaro tobendamustine delayed the time to worsening of health-related quality of life as measured by the

FACT-Lym TOI score by 2.2 months (median 5.6 versus 7.8 months for B and G+B respectively

HR = 0.83; 95% CI: 0.60, 1.13).

Immunogenicity assay results are highly dependent on several factors including assay sensitivity andspecificity, assay methodology, assay robustness to quantities of Gazyvaro/antibody in the circulation,sample handling, timing of sample collection, concomitant medicines and underlying disease. Forthese reasons, comparison of incidence of antibodies to Gazyvaro with the incidence of antibodies toother products may be misleading.

Patients in the CLL pivotal study BO21004/CLL11 were tested at multiple time-points foranti-therapeutic antibodies (ATA) to Gazyvaro. In patients treated with Gazyvaro 8 out of 140 patientsin the randomised phase and 2 out of 6 in the run in phase tested positive for ATA at 12 months offollow up. Of these patients, none experienced anaphylactic or hypersensitivity reactions that wereconsidered related to ATA, nor was clinical response affected.

No post-baseline HAHA (Human Anti-Human Antibody) were observed in patients with iNHL treatedin study GAO4753g/GADOLIN. In study BO21223/GALLIUM, 1/565 patient (0.2% of patients witha post-baseline assessment) developed HAHA at induction completion. While the clinical significanceof HAHA is not known, a potential correlation between HAHA and clinical course cannot be ruledout.

The European Medicines Agency has waived the obligation to submit the results of studies with

Gazyvaro in all subsets of the paediatric population in CLLand FL (see section 4.2 for information onpaediatric use).

A population pharmacokinetic (PK) model was developed to analyse the PK data in 469 iNHL,342 CLL and 130 diffuse large B-cell lymphoma (DLBCL) patients from Phase I, Phase II and Phase

III studies who received obinutuzumab alone or in combination with chemotherapy.

Obinutuzumab is administered intravenously, therefore absorption is not applicable. There have beenno studies performed with other routes of administration. From the population PK model, after the

Cycle 6 Day 1 infusion in CLL patients, the estimated median Cmax value was 465.7 μg/mL and

AUC(τ) value was 8961 μg*d/mL and in iNHL patients the estimated median Cmax value was539.3 μg/mL and AUC(τ) value was 10956 μg*day/mL.

Following intravenous administration, the volume of distribution of the central compartment (2.98 Lin patients with CLL and 2.97 in patients with iNHL), approximates serum volume, which indicatesdistribution is largely restricted to plasma and interstitial fluid.

The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared bycatabolism.

The clearance of obinutuzumab was approximately 0.11 L/day in CLL patients and 0.08 L/day iniNHL patients with a median elimination t½ of 26.4 days in CLL patients and 36.8 days in iNHLpatients. Obinutuzumab elimination comprises two parallel pathways which describe clearance, alinear clearance pathway and a non-linear clearance pathway which changes as a function of time.

During the initial treatment, the non-linear time-varying clearance pathway is dominant and isconsequently the major clearance pathway. As treatment continues, the impact of this pathwaydiminishes and the linear clearance pathway predominates. This is indicative of target mediated drugdisposition (TMDD), where the initial abundance of CD20 cells causes a rapid removal ofobinutuzumab from the circulation. However, once the majority of CD20 cells are bound withobinutuzumab, the impact of TMDD on PK is minimised.

In the population pharmacokinetic analysis, gender was found to be a covariate which explains someof the inter-patient variability, with a 22% greater steady state clearance (CLss) and a 19% greatervolume of distribution (V) in males. However, results from the population analysis have shown thatthe differences in exposure are not significant (with an estimated median AUC and Cmax in CLLpatients of 11282 µg*d/mL and 578.9 µg/mL in females and 8451 µg*d/mL and 432.5 µg/mL in males,respectively at Cycle 6 and AUC and Cmax in iNHL of 13172 µg*d/mL and 635.7 µg/mL in femalesand 9769 µg*d/mL and 481.3 µg/mL in males, respectively), indicating that there is no need to doseadjust based on gender.

The population pharmacokinetic analysis of obinutuzumab showed that age did not affect thepharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics ofobinutuzumab among patients < 65 years (n=375), patients between 65-75 years (n=265) and patients> 75 years (n=171).

No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in paediatricpatients.

The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does notaffect pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mildcreatinine clearance (CrCl 50-89 mL/min, n=464) or moderate (CrCl 30 to 49 mL/min, n=106) renalimpairment were similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n=383).

Pharmacokinetic data in patients with severe renal impairment (CrCl 15-29 mL/min) is limited (n=8),therefore no dose recommendations can be made.

No formal pharmacokinetic study has been conducted in patients with hepatic impairment.

No studies have been performed to establish the carcinogenic potential of obinutuzumab.

No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility.

In repeat-dose toxicity studies in cynomolgus monkeys obinutuzumab had no adverse effects on maleand female reproductive organs.

An enhanced pre and postnatal development (ePPND) toxicity study in pregnant cynomolgus monkeysshowed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitumday 20 to delivery resulted in complete depletion of B-cells in infant monkeys at weekly intravenousobinutuzumab doses of 25 and 50 mg/kg (2-5 times the clinical exposure based on Cmax and AUC).

Offspring exposure on day 28 post-partum suggests that obinutuzumab can cross the blood-placentabarrier. Concentrations in infant serum on day 28 post-partum were in the range of concentrations inmaternal serum, whereas concentrations in milk on the same day were very low (less than 0.5% of thecorresponding maternal serum levels) suggesting that exposure of infants must have occurred in utero.

The B-cell counts returned to normal levels, and immunologic function was restored within 6 monthspost-partum.

In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to theforeign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinicalexposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg).

Findings included acute anaphylactic or anaphylactoid reactions and an increased prevalence ofsystemic inflammation and infiltrates consistent with immune-complex mediated hypersensitivityreactions, such as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation.

These reactions led to unscheduled termination of 6/36 animals treated with obinutuzumab duringdosing and recovery phases; these changes were partially reversible. No renal toxicity with a causalrelationship to obinutuzumab has been observed in humans.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Poloxamer 188

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years.

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°Cfollowed by 48 hours (including infusion time) at ≤ 30°C.

From a microbiological point of view, the prepared infusion solution should be used immediately. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place incontrolled 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 1vial.

Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake thevial. Use a sterile needle and syringe to prepare Gazyvaro.

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-PVCpolyolefin 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 toutilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the900 mg dose for Cycle 1 Day 1 (continued) or Day 2. To prepare the 2 infusion bags, withdraw 40 mLof concentrate from the vial and dilute 4 mL into a 100 mL PVC or non-PVC polyolefin infusion bagand the remaining 36 mL in a 250 mL PVC or non-PVC polyolefin infusion bag containing sodiumchloride 9 mg/ml (0.9%) solution for injection. Clearly label each infusion bag. For storage conditionsof the infusion bags see section 6.3.

Dose of Gazyvaro to be Required amount of Size of PVC or non-PVCadministered Gazyvaro concentrate polyolefin infusion bag100 mg 4 mL 100 mL900 mg 36 mL 250 mL1000 mg 40 mL 250 mL

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 dilutedsolution should not be shaken or frozen.

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

No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mLto 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 stopcockinfusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU).

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

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/14/937/001

Date of first authorisation: 23 July 2014

Date of latest renewal: 02 April 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.