Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Based on a subgroup analysis in previously untreated follicular lymphoma, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation.
The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1,000 mg. IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion related symptoms decreased substantially after the first 1,000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyvaro (see section 4.8).
In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL [>25 × 109/L] may be at increased risk of severe IRRs. Patients with renal impairment (CrCl <50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) >6 and CrCl <70 mL/min are more at risk of IRRs, including severe IRRs (see section 4.8). For management of IRRs see section 4.2 Posology and method of administration.
Patients must not receive further Gazyvaro infusions if they experience:
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 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 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 (see section 4.3).
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 × 109/L] and/or renal impairment [CrCl <70 mL/min]) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase) starting 12-24 hours prior to the infusion of Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). 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 (see section 4.8).
Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renal impairment (CrCl <50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.
In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.
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 (see section 4.8). 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 virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro (see section 4.8). HBVscreening should be performed in all patients before initiation of treatment with Gazyvaro. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B 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) has been reported in patients treated with Gazyvaro (see section 4.8). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. 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.
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.
Due to the potential depletion of B-cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).
No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP, fludarabine and cyclophosphamide (FC), and chlorambucil.
A risk for interactions with other concomitantly used medicinal products cannot be excluded.
Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with medicinal products 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.
Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab (see section 4.4).
The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4).
Women of childbearing potential must use effective contraception during and for 18 months after treatment with Gazyvaro.
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 (see section 5.3). There are no data from the use of obinutuzumab in pregnant women. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
In case of exposure during pregnancy, depletion of B-cells may be expected in infants due to the pharmacological properties of the product. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyvaro during pregnancy until the infant’s B-cell levels are within normal ranges (see section 4.4).
Animal studies have shown secretion of obinutuzumab in breast milk (see section 5.3).
Since human immunoglobulin G (IgG) is secreted in human milk and the potential for absorption 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.
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 (see section 5.3).
Gazyvaro has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Gazyvaro, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate.
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 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:
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.
Table 6. Summary of ADRs reported with a higher incidence (difference of ≥2% versus the comparator arm) in patients # receiving Gazyvaro + chemotherapy*:
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro 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† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster
Uncommon: Nasopharyngitis, rhinitis, influenza, oral herpes
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Squamous cell carcinoma of skin, Basal cell carcinoma
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Squamous cell carcinoma of skin, Basal cell carcinoma
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Neutropenia§, thrombocytopenia, anaemia, leukopenia
Common: Febrile neutropenia
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Neutropenia, thrombocytopenia
Common: Anaemia, leukopenia, febrile neutropenia
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Tumour lysis syndrome, hyperuricaemia, hypokalaemia
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Tumour lysis syndrome, hypokalaemia
Uncommon: Hyperuricaemia
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Insomnia
Common: Depression, anxiety
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Uncommon: Insomnia, depression, anxiety
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Headache
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Uncommon: Headache
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Atrial fibrillation
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Atrial fibrillation
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Hypertension
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Hypertension
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Cough§
Common: Nasal congestion, rhinorrhoea, oropharyngeal pain
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Uncommon: Cough, oropharyngeal pain
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Diarrhoea, constipation§
Common: Dyspepsia, haemorrhoids
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Diarrhoea
Uncommon: Constipation, haemorrhoids
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Alopecia, pruritus
Common: Eczema
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Uncommon: Pruritus
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Arthralgia§, back pain, pain in extremity
Common: Musculoskeletal chest pain, bone pain
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Pain in extremity
Uncommon: Arthralgia, back pain, musculoskeletal chest pain, bone pain
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Dysuria, urinary incontinence
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Uncommon: Dysuria, urinary incontinence
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: Pyrexia, asthenia, fatigue
Common: Chest pain
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: Pyrexia, asthenia, fatigue
Uncommon: Chest pain
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: White blood cell count decreased, neutrophil count decreased, weight increased
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Common: White blood cell count decreased, neutrophil count decreased
All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL):
Very common: IRRs
Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro 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 Gazyvaro 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 Gazyvaro plus bendamustine arm continued with Gazyvaro 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 (see section 4.4).
The incidence of IRRs was higher in the Gazyvaro 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 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.
In patients who received the recommended measures for prevention of IRRs as described in section 4.2, 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 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, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro.
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 (see section 4.4).
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 8%, 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 (see section 4.4).
The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm (16% vs. 7%) 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) (see section 4.4). 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. 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 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 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 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.
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 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 (see section 4.2, 4.4 and 5.2). Patients with a CrCl <30 mL/min were excluded from the study (see section 5.1).
In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 7% (14 out of 204) of patients treated with Gazyvaro, respectively, had moderate 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 (see section 4.2 and 5.2). Patients with a CrCl <40 mL/min were excluded from the studies (see section 5.1).
PML has been reported in patients treated with Gazyvaro (see section 4.4).
Cases of hepatitis B reactivation have been reported in patients treated with Gazyvaro (see section 4.4).
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.
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 (see section 4.4). These events may occur as part of an IRR and can be fatal.
Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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