Gazyvaro 1,000 mg concentrate for solution for infusion.

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

Obinutuzumab is a Type II humanised anti-CD20 monoclonal antibody of the IgG1 subclass derived by humanisation of the parental B-Ly1 mouse antibody and produced in the Chinese Hamster Ovary cell 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.

 

Chronic Lymphocytic Leukaemia (CLL)

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

Follicular Lymphoma (FL)

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

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 infusion related reactions is outlined in Table 1 and 2 (see also section 4.4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

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

Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of infusion related reactions in patients with CLL (see section 4.4)

Day of treatment cycle	Patients requiring premedication	Premedication	Administration
Cycle 1: Day 1	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
Cycle 1: Day 2	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	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	Completed at least 1 hour prior to Gazyvaro infusion
		Oral analgesic/anti-pyretic2 Anti-histaminic medicine3	At least 30 minutes before Gazyvaro infusion

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

Table 2 Premedication to be administered before Gazyvaro infusion to reduce the risk of infusion related reactions in patients with FL (see section 4.4)

Day of treatment cycle	Patients requiring premedication	Premedication	Administration
Cycle 1: Day 1	All patients	Intravenous corticosteroid1 (recommended)	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	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	Completed at least 1 hour prior to Gazyvaro infusion
		Oral analgesic/anti-pyretic2 Anti-histaminic medicine3	At least 30 minutes before Gazyvaro infusion

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

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 3.

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 3 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 (FL)

For patients with FL, the recommended dose of Gazyvaro in combination with bendamustine is shown in Table 4.

Induction (in combination with bendamustine²)

Cycle 1

The recommended dose of Gazyvaro in combination with bendamustine is 1,000 mg administered on Day 1, Day 8 and Day 15 of the first 28 day treatment cycle.

Cycles 2-6

The recommended dose of Gazyvaro in combination with bendamustine is 1,000 mg administered on Day 1 of each 28 day treatment cycle.

Maintenance

Patients who respond 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 two years or until disease progression (whichever occurs first).

Table 4 Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration, followed by Gazyvaro maintenance for patients with FL

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	Day 1	1,000 mg
Maintenance	Every two months for two years or until disease progression (whichever occurs first)	1,000 mg

² See section 5.1 for information on bendamustine dose

Duration of treatment

Six treatment cycles, each of 28 day duration, followed by maintenance once every two months for two 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 wait until the next planned dose. During induction, the planned treatment interval for Gazyvaro should be maintained between doses. During maintenance, maintain the original dosing schedule for subsequent doses.

Dose modifications during treatment (all indications)

No dose reductions of Gazyvaro are recommended.

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

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

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

Method of administration

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

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

Instructions on the rate of infusion are shown in Tables 5-6.

Table 5 Standard infusion rate in the absence of infusion related reactions/hypersensitivity in patients with CLL (in case of infusion related reactions, see “Management of IRRs”)

Cycle	Day of treatment	Rate of infusion
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 infusion related reaction 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.
	Day 8 (1,000 mg)	If no infusion related reaction occurred during the prior 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.
	Day 15 (1,000 mg)
Cycles 2-6	Day 1 (1,000 mg)

Table 6 Standard infusion rates in the absence of infusion related reactions/hypersensitivity in patients with FL (in case of infusion related reactions, see “Management of IRRs”)

Cycle	Day of treatment	Rate of infusion
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 infusion related reaction occurred during the prior 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.
	Day 15 (1,000 mg)
Cycles 2–6	Day 1 (1,000 mg)
Maintenance	Every two months for two years or until disease progression (whichever occurs first)

Management of IRRs (all indications)

Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4).

• Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.

• Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 5 and 6). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further. The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.

• Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 5 and 6). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

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 number of the administered product should be clearly recorded (or stated) in the patient file.

Infusion Related Reactions (IRRs)

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).

If the patient experiences an IRR, the infusion should be managed according to the grade of the reaction. For Grade 4 IRRs, the infusion must be stopped and therapy permanently discontinued. For Grade 3 IRRs, the infusion must be temporarily interrupted and appropriate medicine administered to treat the symptoms. For Grade 1-2 IRRs, the infusion must be slowed down and symptoms treated as appropriate. Upon resolution of symptoms, the infusion can be restarted, except following Grade 4 IRRs, at no more than half the previous rate and, if the patient does not experience the same adverse event with the same severity, the infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose. In CLL patients, if the previous infusion rate was not well tolerated, instructions for the Cycle 1, Day 1 and Day 2 infusion rate should be used for subsequent cycles (see Table 5 in section 4.2).

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 eva luated for the benefits and risks of withholding their anti-hypertensive medicine.

Hypersensitivity reactions including anaphylaxis

Anaphylaxis has been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to distinguish from IRRs. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion must be stopped and treatment permanently discontinued. Patients with known IgE mediated hypersensitivity to obinutuzumab must not be treated (see section 4.3).

Tumour lysis syndrome (TLS)

Tumour lysis syndrome (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). Cases of 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) have also been reported. 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.

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 with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8).

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). Hepatitis B virus 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. eva luation 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 eva luation 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).

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC (fludarabine, cyclophosphamide) 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 drugs 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 or bendamustine may increase neutropenia (see section 4.4).

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. 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).

Because 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 eva luate 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).

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.