Gazyva

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.

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.

Follicular Lymphoma (FL)

Gazyvaro in combination with chemotherapy, followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma.

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. Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.

Prophylaxis and premedication for infusion related reactions (IRRs)

). 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.

Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of IRRs in patients with CLL and FL

¹100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR.

² e.g. 1,000 mg acetaminophen/paracetamol

³ e.g. 50 mg diphenhydramine

^4.If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medication if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil¹)

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

Cycle 1

The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2, (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle.

Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day.

Cycles 2 - 6

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

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

¹

Duration of treatment

Six treatment cycles, each of 28 day duration.

Delayed or missed doses

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

Follicular lymphoma

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

Patients with previously untreated follicular lymphoma

Induction (in combination with chemotherapy²)

Gazyvaro should be administered with chemotherapy as follows:

- Six 28-day cycles in combination with bendamustine² or,

- Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or,

- Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone(CVP).

Maintenance

Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).

Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen

Induction (in combination with bendamustine²)

Gazyvaro should be administered in six 28-day cycles in combination with bendamustine².

Maintenance

Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).

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

²

Duration of treatment

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

Delayed or missed doses

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

If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.

During maintenance, maintain the original dosing schedule for subsequent doses.

Dose modifications during treatment (all indications)

No dose reductions of Gazyvaro are recommended.

).

Special populations

Elderly

No dose adjustment is required in elderly patients.

Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min). 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. Gazyvaro infusions should not be administered as an intravenous push or bolus.

Instructions on the rate of infusion are shown in Tables 4-5.

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

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

Management of IRRs (all indications)

).

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

- Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.

- Grade 1-2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

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.

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

Infusion Related Reactions

The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1,000 mg. 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. 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.

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.

Patients must not receive further Gazyvaro infusions if they experience:

- acute life-threatening respiratory symptoms,

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

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

Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine.

Hypersensitivity reactions

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

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. 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. Late onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) may occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia.

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. 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. These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.

Infections

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

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

Hepatitis B reactivation

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

Progressive multifocal leukoencephalopathy (PML)

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

Immunisation

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

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

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

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

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

Pharmacokinetic interactions

Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with 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.

The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia.

Women of childbearing potential

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

Pregnancy

A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta. 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.

Breast-feeding

Animal studies have shown secretion of obinutuzumab in breast milk.

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

Fertility

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

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.

Summary of the safety profile

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

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

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

- GAO4753g/GADOLIN (N=392): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

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

Table 6 summarises the ADRs of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of > 2%) compared to the relevant comparator arm in at least one pivotal study in:

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

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

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

The incidences presented in Table 6 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.

Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Tabulated list of adverse reactions

Table 6 Summary of ADRs reported with a higher incidence (difference of >2% versus the comparator arm) in patients^# receiving Gazyvaro + chemotherapy*

In study GAO4753g/GADOLIN, patients in the bendamustine arm received 6 months of induction treatment only, whereas after the induction period, patients in the Gazyvaro plus bendamustine arm continued with Gazyvaro maintenance treatment.

During the maintenance period in study GAO4753g/GADOLIN, the most common adverse reactions were cough (15%), upper respiratory infections (12%), neutropenia (11%), sinusitis (10%), diarrhoea (8%), IRRs (8%), nausea (8%), fatigue (8%), bronchitis (7%), arthralgia (7%), pyrexia (6%), nasopharyngitis (6%), and urinary tract infections (6%). The most common Grade 3-5 adverse reactions were neutropenia (10%), and anaemia, febrile neutropenia, thrombocytopenia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1%).

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

Description of selected adverse reactions

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

Infusion related reactions

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

Chronic Lymphocytic Leukaemia

The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 65% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3-4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3-5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.

The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

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

Neutropenia and infections

Chronic Lymphocytic Leukaemia

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

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the Gazyvaro plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 7%, respectively. The incidence of infection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections.

Thrombocytopenia and haemorrhagic events

Chronic Lymphocytic Leukaemia

The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm (15%) compared to the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported in Cycle 1. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

The incidence of thrombocytopenia was 14%. Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 5% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1.

Special populations

Elderly

Chronic Lymphocytic Leukaemia

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

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

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

Renal impairment

Chronic Lymphocytic Leukaemia

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

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 8% (15 out of 194) of patients treated with Gazyvaro, respectively, had moderate renal impairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, adverse events leading to death and adverse events leading to treatment withdrawal than patients with a CrCl > 50 mL/min. Patients with a CrCl < 40 mL/min were excluded from the studies.

Additional safety information from clinical studies experience

Progressive multifocal leukoencephalopathy

PML has been reported in patients treated with Gazyvaro.

Hepatitis B reactivation

Cases of hepatitis B reactivation have been reported in patients treated with Gazyvaro.

Gastro-Intestinal Perforation

Cases of gastro-intestinal perforation have been reported in patients receiving Gazyvaro, mainly in iNHL. In the pivotal studies in iNHL up to 1% of patients experienced gastrointestinal perforation.

Worsening of pre-existing cardiac conditions

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

Laboratory abnormalities

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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

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

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC15

Mechanism of action

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

In nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) through recruitment of FcɣRIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates a low 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 a concomitant reduction in CDC at an equivalent dose. Obinutuzumab, as a glycoengineered antibody, is characterised by enhanced ADCC and ADCP compared to non-glycoengineered antibodies at an equivalent dose. In animal models obinutuzumab mediates potent B-cell depletion and antitumour efficacy.

In the pivotal clinical study BO21004/CLL11, 91% (40 out of 44) of evaluable patients 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. Recovery of B-cells was observed within 12-18 months of follow up in 35% (14 out of 40) of patients without progressive disease and 13% (5 out of 40) with progressive disease.

Clinical efficacy and safety

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 in patients with previously untreated chronic lymphocytic leukaemia with comorbidities.

Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the following measures of coexisting medical conditions: comorbidity score (CIRS) of greater than 6 or reduced renal 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 assessed by 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 plus chlorambucil or chlorambucil alone. Stage 1a compared Gazyvaro plus chlorambucil to chlorambucil alone in 356 patients and Stage 2 compared Gazyvaro plus chlorambucil to rituximab plus chlorambucil in 663 patients. Efficacy results are summarised in Table 7 and in Figures 1-3.

In the majority of patients, Gazyvaro was given intravenously as a 1,000 mg initial dose administered on Day 1, Day 8 and Day 15 of the first treatment cycle. In order to reduce the rate of infusion related reactions in patients, an amendment was implemented and 140 patients received the first Gazyvaro dose administered over 2 days (Day 1 [100 mg] and Day 2 [900 mg]). For each 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, with 44% being 75 years or older. At baseline, 22% of patients had Binet Stage A, 42% had Binet Stage B and 36% had Binet Stage C.

The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity score above 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 were enrolled 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%), Gastrointestinal disorders (38%), Metabolism and nutrition disorders (40%), Renal and urinary disorders (38%), Musculoskeletal and connective tissue disorders (33%).

Table 7 Summary of efficacy from BO21004/CLL11 study

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

^a Defined as the time from randomisation to the first occurrence of progression, relapse or death from any cause as assessed by the investigator

^b stratified by Binet stage at baseline

^c Includes 11 patients in the GClb arm with a complete response with incomplete marrow recovery

^d Blood and bone marrow combined

^e MRD negativity is defined as a result below 0.0001

^f Includes MRD positive patients and patients who progressed or died before the end of treatment

NR = Not reached

** Data not yet mature

Overall survival (OS) for Stage 1a is presented in Figure 2. OS for Stage 2 will continue to be followed and is not yet mature. 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 at baseline) were consistent with the results seen in the overall Intent-to-Treat population. The risk of disease progression or death was reduced in the GClb arm compared to the RClb arm and Clb arm in all subgroups except in the subgroup of patients with deletion 17p. In the small subgroup of patients with deletion 17p, only a positive trend was observed compared to Clb (HR=0.42, p=0.0892); no benefit was observed compared to RClb. For subgroups, reduction of the risk of disease progression or death 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)

Quality of life

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

Health-related quality of life assessments, specific to fatigue through treatment period, show no statistically significant difference suggesting that the addition of Gazyvaro to a chlorambucil regimen does not increase the experience of fatigue for patients.

Follicular lymphoma

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) FL were evaluated. Patients with FL Grade 3b were excluded from the study. Patients were randomised to 1:1 to receive either Gazyvaro (n=601 patients) or rituximab (n=601 patients) in combination with chemotherapy (bendamustine, CHOP or CVP), followed by Gazyvaro or rituximab maintenance in patients 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 in combination 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 was administered prior to chemotherapy. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m²/day when given in combination with Gazyvaro. Standard dosing 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 progression or for up to 2 years.

The demographic data and baseline characteristics of the patient population were well balanced between 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 IV disease, 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 8. Kaplan-Meier curves for progression-free survival (PFS) are shown in Figure 4.

Table 8 Summary of efficacy in patients with previously untreated FL from BO21223/ GALLIUM study

Figure 4 Kaplan-Meier curve of INV-assessed progression-free survival in patients with previously untreated FL (Study BO21223/GALLIUM)

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

Results of subgroup analyses

Results of subgroup analyses (not adjusted for multiplicity) were, in general, consistent with the results seen in the FL population, supporting the robustness of the overall result. 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 (low risk), no difference between Gazyvaro plus chemotherapy and rituximab plus chemotherapy was observed (INV-assessed PFS HR 1.17 (95%CI 0.63;2.19, 40 PFS events). This subgroup comprised 21% (253/1202) of the FL ITT population and experienced 16.3% (40/245) of the PFS events. In addition, exploratory subgroup analyses of PFS across chemotherapy regimens (bendamustine, CHOP and CVP) were consistent with the results seen in the Gazyvaro plus chemotherapy population. The observed 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 in both treatment arms experienced clinically meaningful improvements in lymphoma-related symptoms as defined by a > 3 point increase from baseline in the Lymphoma subscale, a > 6 point increase from baseline 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 meaningful differences 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 months after 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 months following the last dose of rituximab or a rituximab-containing regimen (including rituximab monotherapy as part of induction or maintenance treatment) were evaluated. Patients were randomised 1:1 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 have disease progression (i.e. patients with a complete response (CR), partial response (PR) or stable disease (SD)) at the end of induction continued receiving Gazyvaro maintenance once every two months for two years or until disease progression (whichever occurred first). Patients were stratified according 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 patients had follicular lymphoma (81%). The median time from initial diagnosis was 3 years and the median number 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 for two years or until disease progression (whichever occurs first). Bendamustine was given intravenously on 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 six treatment cycles compared to 66.7% of patients in the B arm.

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

The majority of the patients in study GAO4753g had FL (81.1%). Efficacy results in the FL population are shown in Table 9. 11.6% of the patients had marginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL).

Table 9 Summary of efficacy in patients with FL^# from GAO4753g/GADOLIN study

	Bendamustine N=166	Gazyvaro + Bendamustine followed by Gazyvaro maintenance N=155
	Median observation time: 20 months	Median observation time: 22 months
Primary Endpoint in FL population
IRC-assessed PFS (PFS-IRC)		Pharmacokinetic properties 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. Absorption Obinutuzumab is administered intravenously, therefore absorption is not applicable. There have been no 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() value was 8961 μg-d/mL and in iNHL patients the estimated median Cmax value was 539.3 μg/mL and AUC() value was 10956 μg-day/mL. Distribution Following intravenous administration, the volume of distribution of the central compartment (2.98 L in patients with CLL and 2.97 in patients with iNHL), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid. Biotransformation The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared by catabolism. Elimination The clearance of obinutuzumab was approximately 0.11 L/day in CLL patients and 0.08 L/day in iNHL patients with a median elimination t½ of 26.4 days in CLL patients and 36.8 days in iNHL patients. Obinutuzumab elimination comprises two parallel pathways which describe clearance, a linear 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 is consequently the major clearance pathway. As treatment continues, the impact of this pathway diminishes and the linear clearance pathway predominates. This is indicative of target mediated drug disposition (TMDD), where the initial abundance of CD20 cells causes a rapid removal of obinutuzumab from the circulation. However, once the majority of CD20 cells are bound with obinutuzumab, the impact of TMDD on PK is minimised. Pharmacokinetic/pharmacodynamic relationship(s) In the population pharmacokinetic analysis, gender was found to be a covariate which explains some of the inter-patient variability, with a 22% greater steady state clearance (CLss) and a 19% greater volume of distribution (V) in males. However, results from the population analysis have shown that the differences in exposure are not significant (with an estimated median AUC and Cmax in CLL patients 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 females and 9769 µg-d/mL and 481.3 µg/mL in males, respectively), indicating that there is no need to dose adjust based on gender. Elderly The population pharmacokinetic analysis of obinutuzumab showed that age did not affect the pharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics of obinutuzumab among patients < 65 years (n=375), patients between 65-75 years (n=265) and patients > 75 years (n=171). Paediatric population No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in paediatric patients. Renal impairment The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mild creatinine clearance (CrCl 50-89 mL/min, n=464) or moderate (CrCl 30 to 49 mL/min, n=106) renal impairment 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. Hepatic impairment No formal pharmacokinetic study has been conducted in patients with hepatic impairment. Pharmacotherapeutic group Antineoplastic agents, monoclonal antibodies, ATC code: L01XC15 Preclinical safety data 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 male and female reproductive organs. An enhanced pre and postnatal development (ePPND) toxicity study in pregnant cynomolgus monkeys showed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitum day 20 to delivery resulted in complete depletion of B-cells in infant monkeys at weekly intravenous obinutuzumab 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-placenta barrier. Concentrations in infant serum on day 28 post-partum were in the range of concentrations in maternal serum, whereas concentrations in milk on the same day were very low (less than 0.5% of the corresponding 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 months post-partum. In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure 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 of systemic inflammation and infiltrates consistent with immune-complex mediated hypersensitivity reactions, such as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation. These reactions led to unscheduled termination of 6/36 animals treated with obinutuzumab during dosing and recovery phases; these changes were partially reversible. No renal toxicity with a causal relationship to obinutuzumab has been observed in humans. List of excipients L-histidine L-histidine hydrochloride monohydrate Trehalose dihydrate Poloxamer 188 Water for injections Shelf life Unopened vial 3 years. After dilution After dilution, chemical and physical stability have been demonstrated in sodium chloride 9 mg/mL (0.9%) solution for injection at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C followed by 48 hours (including infusion time) at ≤ 30°C. From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions. Special precautions for storage Store in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. Nature and contents of container 40 mL concentrate in a 50 mL vial (clear Type I glass) with stopper (butyl rubber). Pack size of 1 vial. Special precautions for disposal and other handling Instructions for dilution Gazyvaro should be prepared by a healthcare professional using aseptic technique. Do not shake the vial. For CLL cycles 2 - 6 and all FL cycles Withdraw 40 mL of concentrate from the vial and dilute in polyvinyl chloride (PVC) or non-PVC polyolefin infusion bags containing sodium chloride 9 mg/mL (0.9%) solution for injection. CLL only - Cycle 1 To ensure differentiation of the two infusion bags for the initial 1,000 mg dose, it is recommended to utilise bags of different sizes to distinguish between the 100 mg dose for Cycle 1 Day 1 and the 900 mg dose for Cycle 1 Day 1 (continued) or Day 2. Dose of Gazyvaro to be administered Required amount of Gazyvaro concentrate Size of PVC or non-PVC polyolefin infusion bag 100 mg 4 mL 100 mL 900 mg 36 mL 250 mL 1000 mg 40 mL 250 mL Do not use other diluents such as glucose (5%) solution. The bag should be gently inverted to mix the solution in order to avoid excessive foaming. The diluted solution should not be shaken or frozen. Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. No incompatibilities have been observed between Gazyvaro, in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of Gazyvaro with sodium chloride 9 mg/mL (0.9%) solution for injection, and: - PVC, polyethylene (PE), polypropylene or polyolefin bags - PVC, polyurethane (PUR) or PE infusion sets - optional inline filters with product contact surfaces of polyethersulfone (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU). Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Marketing authorisation holder Roche Registration GmbH Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen Germany Marketing authorisation number(s) EU/1/14/937/001 Date of first authorisation/renewal of the authorisation 23 July 2014 Date of revision of the text 06 April 2018 References: https://www.drugs.com/gazyva.html https://www.rxlist.com/gazyva-drug.htm Available in countries Australia Canada Chile USA Find in a country: A B C D E F G H I J K L M N O P Q R S T U V Y Z