Chemical formula: C₆₅₁₂H₁₀₀₆₀N₁₇₁₂O₂₀₂₀S₄₄
Obinutuzumab interacts in the following cases:
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 (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CVP (cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone) may increase the risk of neutropenia.
Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with obinutuzumab. 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 obinutuzumab. 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.
Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with obinutuzumab. 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 obinutuzumab 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.
Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with obinutuzumab. Hypersensitivity may be difficult to clinically distinguish from IRRs. Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity to obinutuzumab must not be treated.
Tumour lysis syndrome (TLS) has been reported with obinutuzumab. 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 × 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 obinutuzumab 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.
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.
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 obinutuzumab plus bendamustine in the induction phase.
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 obinutuzumab. HBVscreening should be performed in all patients before initiation of treatment with obinutuzumab. 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 obinutuzumab. 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.
Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with obinutuzumab. 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.
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 must use effective contraception during and for 18 months after treatment with obinutuzumab.
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.
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:
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).
The list below 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:
The incidences presented in the following list (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.
Summary of ADRs reported with a higher incidence (difference of ≥2% versus the comparator arm) in patients # receiving obinutuzumab + chemotherapy*:
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Upper respiratory tract infection, sinusitis§, urinary tract infection, pneumonia§,herpes zoster§, nasopharyngitis
Common: Oral herpes, rhinitis, pharyngitis, lung infection, influenza
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster
Uncommon: Nasopharyngitis, rhinitis, influenza, oral herpes
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Squamous cell carcinoma of skin, Basal cell carcinoma
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Squamous cell carcinoma of skin, Basal cell carcinoma
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Neutropenia§, thrombocytopenia, anaemia, leukopenia
Common: Febrile neutropenia
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Neutropenia, thrombocytopenia
Common: Anaemia, leukopenia, febrile neutropenia
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Tumour lysis syndrome, hyperuricaemia, hypokalaemia
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Tumour lysis syndrome, hypokalaemia
Uncommon: Hyperuricaemia
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Insomnia
Common: Depression, anxiety
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Uncommon: Insomnia, depression, anxiety
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Headache
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Uncommon: Headache
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Atrial fibrillation
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Atrial fibrillation
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Hypertension
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Hypertension
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Cough§
Common: Nasal congestion, rhinorrhoea, oropharyngeal pain
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Uncommon: Cough, oropharyngeal pain
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Diarrhoea, constipation§
Common: Dyspepsia, haemorrhoids
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Diarrhoea
Uncommon: Constipation, haemorrhoids
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Alopecia, pruritus
Common: Eczema
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Uncommon: Pruritus
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Arthralgia§, back pain, pain in extremity
Common: Musculoskeletal chest pain, bone pain
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Pain in extremity
Uncommon: Arthralgia, back pain, musculoskeletal chest pain, bone pain
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Dysuria, urinary incontinence
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Uncommon: Dysuria, urinary incontinence
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: Pyrexia, asthenia, fatigue
Common: Chest pain
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: Pyrexia, asthenia, fatigue
Uncommon: Chest pain
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: White blood cell count decreased, neutrophil count decreased, weight increased
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Common: White blood cell count decreased, neutrophil count decreased
All Grades obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: IRRs
Grades 3-5† obinutuzumab + chemotherapy* (CLL, iNHL) followed by obinutuzumab maintenance (iNHL):
Very common: IRRs
# With a higher incidence (difference of ≥2% between the treatment arms). 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).
† 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).
In study GAO4753g/GADOLIN, patients in the bendamustine arm received 6 months of induction treatment only, whereas after the induction period, patients in the obinutuzumab plus bendamustine arm continued with obinutuzumab maintenance treatment.
During the maintenance period in study GAO4753g/GADOLIN, the most common adverse reactions were cough (20%), neutropenia (13%), upper respiratory infections (12%), sinusitis (10%), diarrhoea (10%), bronchitis (10%), nausea (9%), fatigue (9%), IRRs (8%), urinary tract infections (7%), nasopharyngitis (7%), pyrexia (7%), arthralgia (6%), vomiting (6%), rash (6%), pneumonia (5%), dyspnea (5%) and pain in extremity (5%). The most common Grade 3-5 adverse reactions were neutropenia (10%), febrile neutropenia (2%) and anaemia, thrombocytopenia, pneumonia, 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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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, G rade 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.
PML has been reported in patients treated with obinutuzumab.
Cases of hepatitis B reactivation have been reported in patients treated with obinutuzumab.
Cases of gastro-intestinal perforation have been reported in patients receiving obinutuzumab, mainly in iNHL. In the pivotal studies in iNHL up to 1% of patients experienced gastrointestinal perforation.
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. These events may occur as part of an IRR and can be fatal.
Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of obinutuzumab.
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