Obinutuzumab

The safety of immunisation with live or attenuated viral vaccines following obinutuzumab 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 obinutuzumab 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.

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

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

The combination of obinutuzumab with chlorambucil, bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CVP (cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone) may increase the risk of neutropenia.

Obinutuzumab should not be administered in the presence of an active infection and caution should be exercised when considering the use of obinutuzumab 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 obinutuzumab therapy. Fatal infections have been reported.

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 obinutuzumab. 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.

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. Obinutuzumab 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 obinutuzumab during pregnancy until the infant's B-cell levels are within normal ranges.

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 obinutuzumab therapy and for 18 months after the last dose of obinutuzumab.

Women of childbearing potential

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

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.

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

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

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

Summary of the safety profile

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

• BO21004/CLL11 (N=781): Patients with previously untreated CLL
• BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL)
• GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

These trials investigated obinutuzumab in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by obinutuzumab 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). T able 9 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 obinutuzumab plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11)
• Patients with previously untreated iNHL receiving obinutuzumab plus chemotherapy (bendamustine, CHOP, CVP) followed by obinutuzumab 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 obinutuzumab plus bendamustine, followed by obinutuzumab maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN)

The incidences presented in Table 1 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.

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

Tabulated list of adverse reactions

Table 1. Summary of ADRs reported in patients# receiving obinutuzumab + chemotherapy*:

^# Only the highest frequency observed in the trials is reported (based on studies BO21004/previously untreated CLL, BO21223/previously untreated advanced iNHL and GAO4753g/rituximab refractory iNHL)
^## Disseminated intravascular coagulation (DIC) including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving obinutuzumab
^† 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 obinutuzumab arm (BO21223)
^** Based on clinical trial exposures in FL and CLL

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

Description of selected adverse reactions

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

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

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

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

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma:

Grade 3-4 IRRs occurred in 12% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients receiving obinutuzumab plus chemotherapy compared to patients in the comparator arm. In patients receiving obinutuzumab 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 obinutuzumab alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the obinutuzumab and the relevant comparator arms. Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of obinutuzumab.

Short Duration Infusion in patients with Follicular Lymphoma:

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

Table 2. Study MO40597/GAZELLE Short-Duration Infusion: Infusion Related Reactions^a by Cycle (Safety-Evaluable Population):

C = cycle; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion related reaction
^a Infusion related reaction defined as any event that occurred during or within 24 hours from the end of study treatment infusion that were judged by the investigator to be related to any components of therapy.
^b C1 comprised three infusions at the standard infusion rate, administered at weekly intervals
^c Patients received short-duration infusion from C2 onward. The denominator at C2 and subsequent cycles represents the number of patients who received SDI at that cycle.
^d Patients treated with bendamustine on Cycle 1 Day 2.

Neutropenia and infections

Chronic Lymphocytic Leukaemia:

The incidence of neutropenia was higher in the obinutuzumab 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 obinutuzumab 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 obinutuzumab plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the obinutuzumab plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma:

In the obinutuzumab plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence of infection was 81% in the obinutuzumab 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.

Short Duration Infusion in patients with Follicular Lymphoma:

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

Thrombocytopenia and haemorrhagic events

Chronic Lymphocytic Leukaemia:

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

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma:

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

Short Duration Infusion in patients with Follicular Lymphoma:

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

Lupus nephritis

Summary of the safety profile

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

Tabulated list of adverse reactions

The ADRs listed in Table 3 are based on pooled safety data from two clinical studies in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis, up to week 76:

• REGENCY (CA41705): a Phase III study which included 136 patients treated with obinutuzumab plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids.
• NOBILITY (WA29748): a Phase II study which included 64 patients treated with obinutuzumab plus standard therapy with MMF/mycophenolic acid and corticosteroids.

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

Table 3. ADRs reported in patients receiving obinutuzumab + standard therapy* in LN:

^* mycophenolate mofetil (MMF) and corticosteroids
^** Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials.

Description of selected adverse reactions

Infections

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

Neutropenia

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

Infusion-related reactions

IRRs were reported in 13.5% of patients in the obinutuzumab arm vs 10.4% of patients in the placebo arm. IRRs in both arms were predominantly Grade 1-2 and occurred during/after the first infusion. Grade 3-4 IRRs were reported in 1.5% of patients in the obinutuzumab arm vs 0.5% of patients in the placebo arm. All Grade 3-4 events occurred during/after either the first or second infusion. The incidence and severity of IRRs decreased with subsequent infusions. In the REGENCY study, most common IRR signs/symptoms included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia.

Special populations

Elderly

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with obinutuzumab 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 obinutuzumab 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 7% (14 out of 204) of patients treated with obinutuzumab, respectively, had moderate renal impairment (CrCL <50 mL/min). These patients experienced more serious adverse events, Grade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in BO21223 only) than patients with a CrCl ≥50 mL/min. Patients with a CrCl <40 mL/min were excluded from the studies.

Lupus Nephritis

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

Additional safety information from clinical studies experience

Worsening of pre-existing cardiac conditions

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

Laboratory abnormalities

Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed in CLL shortly after the first infusion of obinutuzumab. Obinutuzumab treatment resulted in a decrease in total immunoglobulins in pooled LN data from placebo-controlled studies, mainly driven by reduction in IgM.