|Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemiaThe overall safety profile of MabThera in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy. The most frequently observed adverse drug reactions (ADRs) in patients receiving MabThera were infusion-related reactions which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1 % after eight doses of MabThera.Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trials in patients with CLL.The most frequent reported or observed serious adverse drug reactions were:• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.• Infections, see section 4.4.• Cardiovascular events, see section 4.4.Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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 < 1/1000) and very rare (< 1/10,000). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under not known.Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy |
The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the MabThera-arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.
|System Organ Class||Very Common||Common||Uncommon||Rare||Very Rare||Not known8|
|Infections and infestations||bacterial infections, viral infections, +bronchitis
||sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 || ||serious viral infection2Pneumo-cystis jirovecii
|Blood and lymphatic system disorders||neutropenia, leucopenia, +febrile neutropenia, +thrombo-cytopenia
||anaemia, +pancytopenia, +granulo-cytopenia
||coagulation disorders, aplastic anaemia, haemolytic anaemia, lymph-adenopathy
|| ||transient increase in serum IgM levels3||late neutropenia3|
|Immune system disorders||infusion related reactions4, angioedema
||tumour lysis syndrome, cytokine release syndrome4, serum sickness
||infusion-related acute reversible thrombo-cytopenia4|
|Metabolism and nutrition disorders|| ||hyper-glycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypo-calcaemia
|| || || || |
|Psychiatric disorders|| || ||depression, nervousness,
|| || || |
|Nervous system disorders|| ||paraesthesia, hypo-aesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety
|| ||peripheral neuropathy, facial nerve palsy5||cranial neuropathy, loss of other senses5|
|Eye disorders|| ||lacrimation disorder, conjunctivitis
|| || ||severe vision loss5|| |
|Ear and labyrinth disorders|| ||tinnitus, ear pain
|| || || ||hearing loss5|
|Cardiac disorders|| ||+myocardial infarction4 and 6, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder
||+left ventricular failure, +supra-ventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia
||severe cardiac events4 and 6||heart failure4 and 6|| |
|Vascular disorders|| ||hypertension, orthostatic hypotension, hypotension
|| || ||vasculitis (predominately cutaneous), leuko-cytoclastic vasculitis
|Respiratory, thoracic and mediastinal disorders|| ||Broncho-spasm4, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis
||asthma, bronchiolitis obliterans, lung disorder, hypoxia
||interstitial lung disease7||respiratory failure4,
||vomiting , diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation
|| ||gastro-intestinal perforation7|| |
|Skin and subcutaneous tissue disorders||pruritus, rash, +alopecia
||urticaria, sweating, night sweats, +skin disorder
|| || ||severe bullous skin reactions, Stevens-Johnson Syndrome toxic epidermal necrolysis (Lyell's Syndrome) 7,
|Musculoskeletal, connective tissue and bone disorders|| ||hypertonia, myalgia, arthralgia, back pain, neck pain, pain
|| || || || |
|Renal and urinary disorders|| || || || ||renal failure4|| |
|General disorders and administration site conditions||fever , chills, asthenia, headache
||tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure4||infusion site pain|| || || |
|Investigations||decreased IgG levels
|| || || || || |
|For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported
includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL
see also section infection below
see also section haematologic adverse reactions below
see also section infusion-related reactions below. Rarely fatal cases reported
signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy
observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions7
includes fatal cases
Frequency not known (cannot be estimated from the available data)
Infusion-related reactionsSigns and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.
Infections MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients. Localized candida infections as well as Herpes zoster was reported at a higher incidence in the MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation.There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in subjects receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi's sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Haematologic adverse reactionsIn clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7 % of the patients. During MabThera maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4 %, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1%, grade 3/4%) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group. In studies of MabThera in patients with Waldenstrom's macroglobulinaemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.
Cardiovascular reactionsCardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).
Respiratory systemCases of interstitial lung disease, some with fatal outcome have been reported.
Neurologic eventsDuring the treatment period, four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC). Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized risk factors for PRES/RPLS, including the patients' underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.
Gastrointestinal disordersGastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non-Hodgkin lymphoma. In the majority of these cases, MabThera was administered with chemotherapy.
IgG levelsIn the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the MabThera groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the MabThera group. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).
A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed in paediatric patients treated with MabThera, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.
Skin and subcutaneous tissue disorders:Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.
Patient subpopulations - MabThera monotherapyOlder people (≥ 65 years): The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to younger patients (<65 years). Bulky disease There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these two groups.Re-treatmentThe percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).
Patient subpopulations - MabThera combination therapyOlder people (≥ 65 years) The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL.
Experience from rheumatoid arthritis The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.The safety profile of MabThera in patients with moderate to severe rheumatoid arthritis (RA) is summarized in the sections below. In clinical trials more than 3100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2400 patients received two or more courses of treatment with over 1000 having received 5 or more courses. The safety information collected during post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for MabThera (see section 4.4). Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). MabThera infusions were administered after an intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days. Events are listed in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.The most frequent adverse reaction considered due to receipt of MabThera were infusion related reactions. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for MabThera, progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have been reported during post marketing experience.Table 2 Summary of adverse drug reactions reported in clinical trials or during postmarketing surveillance occurring in patients with rheumatoid arthritis receiving MabThera
|System Organ Class||Very Common||Common||Uncommon||Rare||Very rare|
|Infections and Infestations||upper respiratory tract infection, urinary tract infections
||Bronchitis, sinusitis, gastroenteritis, tinea pedis
|| || ||PML, reactivation of hepatitis B
|Blood and lymphatic system disorders|| ||neutropenia1|| ||late neutropenia2||Serum sickness-like reaction
|Cardiac Disorders|| || || ||Angina pectoris, atrial fibrillation, heart failure, myocardial infarction
|Immune System Disorders||3Infusion related reactions (hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat irritation, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythema)
|| ||3Infusion related reactions (generalized oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalized pruritis, anaphylaxis, anaphylactoid reaction)
|| || |
|General disorders and administration site conditions|
|Metabolism and Nutritional Disorders|| ||hypercholesterolemia
|| || || |
|Nervous System disorders||headache
||paraesthesia, migraine, dizziness, sciatica
|| || || |
|Skin and Subcutaneous Tissue Disorders|| ||alopecia
|| || ||Toxic Epidermal Necrolysis (Lyell's Syndrome), Stevens-Johnson Syndrome5|
|Psychiatric Disorders|| ||depression, anxiety
|| || || |
|Gastrointestinal Disorders|| ||Dyspepsia, diarrhoea, gastro-oesophageal reflux, mouth ulceration, upper abdominal pain
|| || || |
|Musculo skeletal disorders|| ||arthralgia / musculoskeletal pain, osteoarthritis, bursitis
|| || || |
|Investigations||decreased IgM levels4||decreased IgG levels4|| || || |
Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials
Frequency category derived from post-marketing data.
Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. Infusion related reactions may occur as a result of hypersensitivity and/or to the mechanism of action.
Includes observations collected as part of routine laboratory monitoring.
Includes fatal cases
Multiple coursesMultiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by infusion-related reactions (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.
Infusion-related reactionsThe most frequent ADRs following receipt of MabThera in clinical studies were infusion-related reactions (IRRs) (refer to Table 2). Among the 3189 patients treated with MabThera, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to MabThera. The incidence of IRRs decline for all subsequent infusions. In clinical studies fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see section 4.2 and 4.4). Severe infusion-related reactions with fatal outcome have been reported in the post-marketing setting.
InfectionsThe overall rate of infection was approximately 94 per 100 patient years in MabThera treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of infections that were serious or required IV antibiotic was approximately 4 per 100 patient years. The rate of serious infections did not show any significant increase following multiple courses of MabThera. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the MabThera arms compared to control arms.Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following use of MabThera for the treatment of autoimmune diseases. This includes Rheumatoid Arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis.In patients with non-Hodgkin's lymphoma receiving MabThera in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin's lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera (see Section 4.4).
CardiovascularSerious cardiac events were reported at a rate of 1.3 per 100 patient years in the MabThera treated patients compared to 1.3 per 100 patients years in placebo treated patients. The proportions of patients experiencing cardiac events (all or serious) did not increase over multiple courses.
NeutropeniaEvents of neutropenia were observed with MabThera treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of MabThera (see section 4.4).In placebo-controlled periods of clinical trials, 0.94% (13/1382) of MabThera treated patients and 0.27% (2/731) of placebo patients developed severe neutropenia.Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.
Skin and subcutaneous tissue disorders:Toxic Epidermal Necrolysis (Lyell's Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.
Laboratory abnormalitiesHypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA patients treated with MabThera. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM (see section 4.4). A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed in pediatric patients treated with MabThera, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.
Experience from Granulomatosis with polyangiitis and Microscopic polyangiitisIn the clinical study in Granulomatosis with polyangiitis and Microscopic polyangitis, 99 patients were treated with MabThera (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the MabThera group.Table 3. Adverse Drug Reactions occurring at 6-months in ≥ 5% of patients receiving MabThera, and at a higher frequency than the comparator group, in the pivotal clinical study.
|Body System Adverse event ||Rituximab (n=99) |
|Blood and lymphatic system disorders
|General disorders and administration site conditions
|Immune system disorders|
|Cytokine release syndrome
|Infections and infestations|
|Urinary tract infection
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders
|Pain in extremities
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorders
|Skin and subcutaneous tissue disorders
Further information on selected adverse drug reactions:
Infusion-related reactions:Infusion-related reactions (IRRs) in the GPA and MPA clinical study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Ninety nine patients were treated with MabThera and 12% experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor. MabThera was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.
Infections: In the 99 MabThera patients, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections. The rate of serious infections was approximately 25 per 100 patient years. The most frequently reported serious infection in the MabThera group was pneumonia at a frequency of 4%.
Malignancies The incidence of malignancy in MabThera treated patients in the Granulomatosis with polyangiitis and Microscopic polyangiitis clinical study was 2.00 per 100 patient years at the study common closing date (when the final patient had completed the follow-up period). On the basis of standardized incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.
CardiovascularCardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3 -15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see Section 4.4).
Hepatitis-B reactivationA small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in Granulomatosis with polyangiitis and Microscopic polyangiitis patients receiving MabThera in the postmarketing setting.
HypogammaglobulinaemiaHypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in Granulomatosis with polyangiitis and Microscopic polyangiitis patients treated with MabThera. At 6 months, in the active-controlled, randomized, double-blind, multicenter, non-inferiority study, in the MabThera group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. There was no increased rate in overall infections or serious infections in patients with low IgA, IgG or IgM.
NeutropeniaIn the active-controlled, randomized, double-blind, multicenter, non-inferiority study of MabThera in Granulomatosis with polyangiitis and Microscopic polyangiitis, 24% of patients in the MabThera group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in MabThera-treated patients. The effect of multiple MabThera courses on the development of neutropenia in Granulomatosis with polyangiitis and Microscopic polyangiitis patients has not been studied in clinical trials.
Skin and subcutaneous tissue disorders:Toxic Epidermal Necrolysis (Lyell's Syndrome) and Stevens-Johnson Syndrome, some with fatal outcome, have been reported very rarely.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).
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.iee-mail: firstname.lastname@example.orgMaltaADR Reporting
The Medicines Authority
203 Level 3, Rue D'Argens
Website: www.medicinesauthority.gov.mte-mail: email@example.comUnited KingdomYellow Card Scheme