Truxima Adverse Reactions

Clinical Trials: Experience from Clinical Trials in Haemato-Oncology: The frequencies of adverse drug reactions (ADRs) reported with rituximab alone or in combination with chemotherapy are summarized in the tables as follows and are based on data from clinical trials. These ADRs had either occurred in single arm studies or had occurred with at least a 2% difference compared to the control arm in at least one of the major randomized clinical trials. ADRs are added to the appropriate category in the tables as follows according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping ADRs are listed in descending order of severity. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100).
Rituximab monotherapy/maintenance therapy: The ADRs in Table 25 are based on data from single-arm studies including 356 patients with low-grade or follicular lymphoma, treated with rituximab weekly as single agent for the treatment or re-treatment of Non-Hodgkin's Lymphoma up to 4 weeks in most patients and from 25 patients who received doses other than 375 mg/m² for four doses and up to 500 mg/m² single dose in the Phase I setting (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions for further details). The table also contains ADRs based on data from 671 patients with follicular lymphoma who received rituximab as maintenance therapy for up to 2 years following response to initial induction with CHOP, R-CHOP, R-CVP or R-FCM (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions for further details). The ADRs were reported up to 12 months after treatment with monotherapy and up to 1 month after treatment with rituximab maintenance. (See Table 25.)

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Rituximab in combination with chemotherapy in NHL and CLL: The ADRs listed in Table 26 are based on rituximab-arm data from controlled clinical trials that occurred in addition to those seen with monotherapy/maintenance therapy and/or at a higher frequency grouping: 202 patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, and from 234 and 162 patients with follicular lymphoma treated with R-CHOP or R-CVP, respectively and from 397 previously untreated CLL patients and 274 relapsed/refractory CLL patients, treated with rituximab in combination with fludarabine and cyclophosphamide (R-FC) (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions for further details). (See Table 26.)

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The following terms have been reported as adverse events, however, were reported at a similar (< 2% difference between the groups) or lower incidence in the rituximab-arms compared to control arms: Haematotoxicity, neutropenic infection, urinary tract infection, septic shock, superinfection lung, implant infection, septicaemia staphylococcal, lung infection, rhinorrheoa, pulmonary oedema, cardiac failure, sensory disturbance, venous thrombosis, mucosal inflammation nos, influenza-like illness, oedema lower limb, abnormal ejection fraction, pyrexia, general physical health deterioration, fall, multi-organ failure, venous thrombosis deep limb, positive blood culture, diabetes mellitus inadequate control.
The safety profile for rituximab in combination with other chemotherapies (e.g. MCP, CHVP-IFN) is comparable to the safety profile as described for the combination of rituximab and CVP, CHOP or FC in equivalent populations.
Further information on selected, serious adverse drug reactions: Administration-related reactions: Monotherapy 4 weeks treatment: Signs and symptoms suggestive of an infusion-related reaction (IRR) were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion. Hypotension, fever, chills, rigors, urticarial, bronchospasm, sensation of tongue or throat swelling (angioedema), nausea, fatigue, headache, pruritus, dyspnea, rhinitis, vomiting, flushing, and pain at disease sites have occurred in associated with rituximab infusion as part of an infusion-related symptom complex. Some features of tumor lysis syndrome have also been observed.
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): Severe IRRs occurred in up to 12% of all patients at the time on the first treatment cycle with rituximab in combination with chemotherapy. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and in <1% of patients by the eighth cycle. Additional reactions reported were dyspepsia, rash, hypertension, tachycardia, and features of tumour lysis syndrome. Isolated cases of myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia were also reported.
Infusion-related reactions: Monotherapy - 4 weeks treatment: Hypotension, fever, chills, rigors, urticaria, bronchospasm, sensation of tongue or throat swelling (angioedema), nausea, fatigue, headache, pruritus, dyspnea, rhinitis, vomiting, flushing, and pain at disease sites have occurred in association with rituximab infusion as part of an infusion-related symptom complex. Such infusion-related symptoms occurred in the majority of patients during the first rituximab infusion (see General under Precautions). The incidence of infusion-related symptoms decreased from 77% (7% grade 3/4) with the first infusion to approximately 30% (2% grade 3/4) with the fourth infusion and to 14% (no grade 3/4 events) with the eighth infusion.
Maintenance Treatment (NHL) up to 2 years: Non-serious signs and symptoms suggestive of an infusion-related reaction were reported in 41% of patients under general disorders (mainly asthenia, pyrexia, influenza like illness, pain) and in 7% of patients for immune system disorders (hypersensitivity). Serious infusion-related reactions occurred in <1% of patients.
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): Severe infusion-related reactions occurred in up to 12% of all patients at the time of the first treatment cycle with rituximab in combination with chemotherapy. The incidence of severe infusion-related reactions decreased to less than 1% by the eighth cycle of therapy. The signs and symptoms were consistent with those observed during monotherapy (see Precautions and Experience from Clinical Trials in Haemato-Oncology: Rituximab monotherapy/maintenance therapy as previously mentioned), but also included dyspepsia, rash, hypertension, tachycardia, features of tumour lysis syndrome. Additional reactions reported in isolated cases at the time of R-chemotherapy were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Infections: Monotherapy - 4 weeks treatment: Rituximab induced B-cell depletion in 70% to 80% of patients but was associated with decreased serum immunoglobulins in only a minority of patients. Bacterial, viral, fungal and unknown etiology infections, irrespective of causal assessment, occurred in 30.3% of 356 patients: Severe infectious events (grade 3 or 4), including sepsis occurred in 3.9% of patients.
Maintenance Treatment (NHL) up to 2 years: Higher frequencies of infections overall, including Grade 3 and 4 infections, were observed during rituximab treatment. There was no cumulative toxicity in terms of infections reported over the 2-year maintenance period. Data from clinical trial included two cases of fatal PML in NHL patients that occurred after disease progression and retreatment (see Precautions).
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): No increase in the frequency of infections or infestations was observed. The most common infections were upper respiratory tract infections which were reported for 12.3% patients on R-CVP and 16.4% patients receiving CVP; No life-threatening infections were reported during this study.
In the R-CHOP study the overall incidence of grade 2 to 4 infections was 45.5% in the R-CHOP group and 42.3% in the CHOP group. Grade 2 to 4 fungal infections were more frequent in the R-CHOP group (4.5% vs 2.6% in the CHOP group); this difference was due to a higher incidence of localized Candida infections during the treatment period. The incidence of grade 2 to 4 herpes zoster was higher in the R-CHOP group (4.5%) than in the CHOP group (1.5%). The proportion of patients with grade 2 to 4 infections and/or febrile neutropenia was 55.4% in the R-CHOP group and 51.5% in the CHOP group. Febrile neutropenia (i.e. no report of concomitant documented infection) was reported only during the treatment period, in 20.8% in the R-CHOP group and 15.3% in the CHOP group.
In patients with CLL, the incidence of grade 3 or 4 hepatitis B infection (reactivation and primary infection) was 2% R-FC vs 0% in the FC group.
Hematologic events: Monotherapy - 4 weeks: Severe (grade 3 and 4) neutropenia was reported in 4.2% of patients, severe anaemia was reported in 1.1% of patients and severe thrombocytopenia was reported in 1.7% of patients.
Maintenance Treatment (NHL) up to 2 years: There was a higher incidence of grade 3-4 leucopenia (observation 2%, rituximab 5%) and neutropenia (observation 4%, rituximab 10%) in the rituximab arm compared to the observation arm. The incidence of grade 3 to 4 thrombocytopenia (observation 1%, rituximab <1%) was low. In approximately half of the patients with available data on B-cell recovery after end of rituximab induction treatment, it took 12 months or more for their B-cell levels to return to normal values.
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): During treatment course in studies with rituximab in combination with chemotherapy, Grade 3 and 4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%) and neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP were usually reported with higher frequencies when compared to chemotherapy alone). However, the higher incidence of neutropenia in patients treated with rituximab 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 some cases neutropenia was prolonged or with a late onset following treatment in rituximab plus FC group. No relevant difference between the treatment arms was observed with respect to Grade 3 and 4 anaemia or thrombocytopenia. In CLL first line, Grade 3 and 4 anaemia was reported by 4% of patients treated with R-FC compared to 7% of patients receiving FC, and Grade 3 and 4 thrombocytopenia was reported by 7% of patients in the R-FC group compared to 10% of patients in the FC group. In the relapsed/refractory CLL study, adverse events of Grade 3 and 4 anaemia were reported in 12% of patients treated with R-FC compared to 13% of patients receiving FC and Grade 3 and 4 thrombocytopenia was reported by 11% of patients in the R-FC group compared to 9% of patients in the FC group.
Cardiovascular events: Monotherapy - 4 weeks treatment: Cardiovascular events were reported in 18.8% of patients during the treatment period. The most frequently reported events were hypotension and hypertension. Cases of Grade 3 and 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during a rituximab infusion were reported.
Maintenance Treatment (NHL) up to 2 years: The incidence of grade 3 to 4 cardiac disorders was comparable between the two treatment groups. Cardiac events were reported as serious adverse event in < 1% of patients on observation and in 3% of patients on rituximab: atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure (< 1%), myocardial ischemia (< 1%).
Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): In the R-CHOP study 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 (6.9%) as compared to the CHOP group (1.5%). All of these arrhythmias either occurred in the context of a rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease (see Precautions). 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).
IgG levels: Maintenance Treatment (NHL) up to 2 years: After induction treatment, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) in both the observation and the rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during rituximab treatment. The proportion of patients with IgG levels below the LLN was about 60% in the rituximab 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 pediatric patients treated with rituximab, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long-term B cell depletion in pediatric patients are unknown.
Neurologic events: Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL): During the treatment period, (2% of patients) in the R-CHOP group, 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).
Subpopulations: Monotherapy - 4 weeks treatment: Elderly patients (≥ 65 years): The incidence of any ADR and of grade 3 and 4 ADRs was similar in elderly (n = 94) and younger (n = 237) patients (88.3% versus 92.0% for any ADR and 16.0% versus 18.1% for grade 3 and 4 ADRs).
Combination Therapy: Elderly patients (≥ 65 years): The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients (≥ 65 years of age) compared to younger patients, with previously untreated or relapsed/refractory CLL.
Bulky disease: Patients with bulky disease (n = 39) had a higher incidence of grade 3 and 4 ADRs than patients without bulky disease (n = 195; 25.6% versus 15.4%). The incidence of any ADR was similar in these two groups (92.3% in bulky disease versus 89.2% in non-bulky disease).
Re-treatment with Monotherapy: The percentage of patients reporting any ADR and grade 3 and 4 ADRs upon re-treatment with further courses of rituximab was similar to the percentage of patients reporting any ADR and grade 3 and 4 ADRs upon initial exposure (95.0% versus 89.7% for any ADR and 13.3% versus 14.8% for grade 3 and 4 ADRs).
Experience from pediatric DLBCL/BL/BAL/BLL Clinical Trials: Summary of safety profile: A multicenter, open-label randomized study of Lymphome Malin B chemotherapy (LMB) with or without rituximab was conducted in pediatric patients (aged ≥ 6 months to < 18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.
A total of 309 pediatric patients received rituximab and were included in the safety analysis population. Pediatric patients randomized to the LMB chemotherapy arm with rituximab, or enrolled in the single arm part of the study, were administered rituximab at a dose of 375 mg/m² BSA and received a total of six intravenous infusions of rituximab (two during each of the two induction courses and one during each of the two consolidation courses of the LMB scheme).
The safety profile of rituximab in pediatric patients (aged ≥ 6 months to < 18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent in type, nature and severity with the known safety profile in adult NHL and CLL patients. Addition of rituximab to chemotherapy did result in an increased risk of some events including infections (including sepsis) compared to chemotherapy only.
Experience from Rheumatoid Arthritis Clinical Trials: The safety profile of rituximab in the treatment of patients with moderate to severe RA is summarized in the sections as follows. In the all exposure population more than 3000 patients have received at least one treatment course and were followed for periods ranging from 6 months to over 5 years with an overall exposure equivalent to 7198 patient years; approximately 2300 patients received two or more courses of treatment during the follow-up period.
The ADRs listed in Table 27 are based on data from placebo-controlled periods of four multicenter, RA clinical trials. The patient populations receiving rituximab differed between studies, ranging from early active RA patients who were methotrexate (MTX) naïve, through MTX inadequate responders (MTX-IR) to patients who had inadequate response to anti-TNF therapies (TNF-IR) (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions for further information).
Patients received either 2 x 1000 mg or 2 x 500 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10 - 25 mg/week) (see Rheumatoid arthritis (RA) under Dosage & Administration). The ADRs listed in Table 27 are those which occurred at a rate of at least 2%, with at least a 2% difference compared to the control arm and are presented regardless of dose. Frequencies in Table 25 and corresponding footnote are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). (See Table 27.)

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In the all exposure population, the safety profile was consistent with that seen in the controlled period of the clinical trials with no new ADRs identified.
Multiple Courses: Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The safety profile improved with subsequent courses due to a decrease in IRRs, RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.
Further information on selected adverse drug reactions: Infusion-related reactions: The most frequent ADRs following receipt of rituximab in RA clinical studies were IRRs. Among the 3095 patients treated with rituximab, 1077 (35%) experienced at least one IRR. The vast majority of IRRs were CTC Grade 1 or 2. In clinical studies less than 1% (14/3095 patients) of patients with RA who received an infusion of rituximab at any dose experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs. The proportion of CTC Grade 3 events, and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Signs and or symptoms suggesting an infusion-related reaction (nausea, pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 720/3095 (23%) patients following first infusion of the first exposure to rituximab.
Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events (see General: Rheumatoid Arthritis Patients (RA), Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA) Patients and Pemphigus Vulgaris (PV) Patients under Precautions).
Infections: The overall rate of infection was approximately 97 per 100 patient years in rituximab treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The rate of serious infections was approximately 4 per 100 patient years, some of which were fatal. In addition to the ADRs in Table 25, medically serious events reported also include pneumonia at a frequency of 1.9%.
Malignancies: The incidence of malignancy following exposure to rituximab in clinical studies (0.8 per 100 patient years) lies within the range expected for an age and gender matched population.
Clinical Trial Experience in Adult and Pediatric Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA): Adult Induction of Remission (GPA/MPA Study 1): Ninety-nine adult GPA/MPA patients were treated for induction of remission of GPA and MPA in a clinical trial with rituximab (375 mg/m², once weekly for 4 weeks) and glucocorticoids (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
The ADRs listed in Table 26 were all adverse events which occurred at an incidence of ≥10% in the rituximab treated group. Frequencies in Table 28 are defined as very common (≥1/10). (See Table 28.)

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Adult Maintenance Treatment (GPA/MPA Study 2): In a further clinical study, a total of 57 adult patient with severe active GPA and MPA were treated for the maintenance of remission (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
No new safety concerns were identified and the safety profile was consistent with the well-established safety profile for rituximab in approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the rituximab arm experienced adverse events leading to discontinuation.
Most adverse events in the rituximab arm were mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events. ADRs were all adverse events which occurred at an incidence of ≥10% in the rituximab treated group. The very commonly (≥10%) reported events considered ADRs were: infusion-related reactions and infections.
Adult Long-term Follow-up (GPA/MPA Study 3): In a long-term observational safety study, 97 adult GPA/MPA patients received treatment with rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician's standard practice and discretion.
The overall safety profile was consistent with the well-established safety profile of rituximab in RA and GPA/MPA and no new adverse drug reactions were reported.
Pediatric Population: An open-label, single arm study was conducted in 25 pediatric patients with active GPA/MPA. The overall study period consisted of a 6-month remission induction phase and a minimum 18-month follow-up phase, up to 4.5 yrs. During the follow-up phase, rituximab was given at the discretion of the investigator (17 out of 25 patients received additional rituximab treatment). Concomitant treatment with other immunosuppressive therapy was permitted (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
All identified ADRs were considered all adverse events that occurred at an incidence of ≥10%. These included: infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in the overall study period), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] in the overall study period), and nausea (4 patients [16%] in the remission induction phase; 5 patients [20%] in the overall study period).
During the overall study period, the safety profile of rituximab in pediatric GPA/MPA patients was consistent in type, nature and severity with the known safety profile in adult patients for autoimmune disease, including adult GPA/MPA.
Further information on selected adverse drug reactions: Infusion-related reactions: In the clinical trial studying induction of remission (GPA/MPA study 1) in adult patients with severe active GPA and MPA infusion-related reactions (IRRs) 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. Of the 99 patients treated with rituximab 12/99 patients (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.
Rituximab was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.
In the maintenance therapy clinical trial (GPA/MPA study 2) in adult patients, 7/57 (12%) patients in the rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decrease with subsequent infusion (<4%). All IRR symptoms were mild to moderate and most were reported from the Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorder SOCs.
In the clinical trial in pediatric patients with GPA/MPA, the reported IRRs were predominantly seen with the first infusion (8 patients [32%]), and then decreased over time with the number of rituximab infusions (20% with the second infusion, 12% with the third infusion and 8% with the fourth Infusion). The most common IRR symptoms reported during the remission of induction phase were headache, rash, rhinorrhea and pyrexia (8% for each symptom). The observed symptoms of IRRs were similar to those known in adult GPA/MPA patients treated with rituximab. The majority of IRRs were Grade 1 and Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4-5 IRRs reported. One serious Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (see Precautions).
Infections: In the clinical trial studying induction or remission (GPA/MPA study 1), which included 99 adult patients with severe GPA/MPA, the overall rate of infection was approximately 210 per 100 patient years (95% CI 173-256). 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 rituximab group was pneumonia at a frequency of 4%.
In the maintenance therapy clinical trial (GPA/MPA study 2) in adult patients, 30/57 (53%) patients in the rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. Infections were predominately mild to moderate. The most common infections in the rituximab arm included upper respiratory tract infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the rituximab arm was mild or moderate bronchitis.
In the clinical studying pediatric GPA/MPA, the majority of reported infections were non-serious and predominately mild to moderate. The most common infections in the overall study period were: upper respiratory tract infections (URTIs) (48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tract infections (16%), sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%) pharyngitis (12%), urinary tract infection (12%). Serious infections were reported in 7 patients (28%), and included: influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events.
Malignancies: In the clinical trial studying induction of remission (GPA/MPA study 1) the incidence of malignancy in rituximab treated patients was 2.05 per 100 patient years. On the basis of standardized incidence ratios, this malignancy rate appears to be similar to rates previously reported in GPA and MPA populations.
In the pediatric clinical trial, no malignancies were reported with a follow-up period of up to 54 months.
Laboratory Abnormalities: Hypogammaglobulinaemia (lgG or lgM below the lower limit of normal) has been observed in pediatric GPA/MPA patients treated with rituximab. During the overall study period, 3/25 (12%) patients reported an event of hypogammaglobulinaemia, 18 patients (72%) had prolonged low lgG levels (of whom 15 patients also had prolonged low lgM). Three patients received treatment with intravenous Immunoglobulin (IV-IG). There was no association between prolonged low lgG and lgM and an increased risk of serious infection.
Clinical Trial Experience in Pemphigus Vulgaris: Summary of the safety profile: The safety profile of rituximab in combination with short term, low dose, glucocorticoids in the treatment of patients with pemphigus vulgaris was studied in a randomized, controlled, multicenter, open-label study (PV study 1) in 38 pemphigus vulgaris (PV) and 8 pemphigus foliaceus (PF) patients. Patients randomized to the rituximab group received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15. Maintenance doses of 500 mg IV were administered at Months 12 and 18. Patients could receive 1000 mg IV at the time of relapse (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
In the maintenance therapy clinical trial (PV study 2), a randomized, double-blind, double-dummy, active-comparator, multicenter study evaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with rituximab (initial 1000 mg intravenous on Study Day 1 and a second 1000 mg intravenous on Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks (see PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
The safety profile of rituximab in PV was consistent with the established safety profile in other approved autoimmune indications.
Tabulated list of adverse reactions for PV Studies 1 and 2: Adverse reactions from PV Studies 1 and 2 are presented in Table 29. In PV Study 1, ADRs were defined as adverse events which occurred at a rate of ≥ 5% among rituximab-treated PV patients, with a ≥ 2% absolute difference in incidence between the rituximab-treated group and the standard-dose prednisone group up to month 24. No patients were withdrawn due to ADRs in Study 1. In PV Study 2, ADRs were defined as adverse events occurring in ≥5% of patients in the rituximab arm and assessed as related. (See Table 29.)

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Further information on selected adverse drug reactions: Infusion-related reactions: In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion related reactions were similar in type and severity to those seen in RA and GPA/MPA patients. In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 17.9%, 4.5%, 3% and 3% of patients experienced IRRs at the first, second, third, and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1 or 2. In 4/15 patients, Grade ≥3 IRRs were reported and led to discontinuation of rituximab treatment; three of the four patients experienced serious (life-threatening) IRRs. Serious IRRs occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.
Infections: In PV Study 1, 14 patients (37%) in the rituximab group experienced treatment-related infections compared to 15 patients (42%) in the standard dose prednisone group. The most common infections in the rituximab group were herpes simplex and zoster infection, bronchitis, urinary tract infection, fungal infection, and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of 5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and one patient (3%) in the standard dose prednisone group experienced a serious infection (Pneumocystis jirovecii pneumonia).
In PV Study 2, 42 patients (62.7%) in the rituximab arm experienced infections. The most common infections in the rituximab group were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the rituximab arm experienced serious infections.
Laboratory Abnormalities: PV Study 2, in the rituximab arm, transient decreases in lymphocyte count, driven by decreases in the peripheral T-cell populations, as well as a transient decrease in phosphorus level were very commonly observed post-infusion. These were considered to be induced by intravenous methylprednisolone premedication infusion.
In PV Study 2, low IgG levels were commonly observed and low IgM levels were very commonly observed; however, there was no evidence of an increased risk of serious infections after the development of low IgG or IgM.
Hypogammaglobulinaemia (IgG and IgM below the lower limit of normal) has been observed in RA and adult and pediatric GPA/MPA patients treated with rituximab. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM.
Rheumatoid Arthritis Patients: Events of neutropenia associated with rituximab treatment, the majority of which were transient and mild or moderate in severity, were observed in clinical trials in RA patients after the first course of treatment. Neutropenia can occur several months after the administration of rituximab.
In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 0.27% (2/731) of placebo patients developed severe (Grade 3 or 4) neutropenia. In these studies, rates of severe neutropenia were 1.06 and 0.53 per 100 patient years, respectively, after the first treatment course and 0.97 and 0.88 per 100 patient years, respectively, after multiple courses. Therefore, neutropenia can be considered an ADR for the first course only. Time to onset of neutropenia was variable. In clinical trials neutropenia was not associated with an observed increase in serious infection, and most patients continued to receive additional courses of rituximab after episodes of neutropenia.
Adult Patients with Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA) Patients: In the induction of remission clinical trial (GPA/MPA Study 1), at 6 months, in the rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low lgA, lgG and lgM levels, respectively compared to 25%, 50% and 46%, respectively in the cyclophosphamide group.
In the maintenance therapy clinical trial, no clinically meaningful differences between the two treatment arms or decreases in total immunoglobulin, lgG, lgM or lgA levels were observed throughout the trial.
In the induction of remission clinical trial, 24% of patients in the rituximab 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 rituximab treated patients.
Post Marketing: Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukaemia Patients: The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and largely data derived from spontaneous reports. Additional cases of severe infusion-related reactions have been reported during post-marketing use of rituximab (see Precautions).
As part of the continuing post-marketing surveillance of rituximab safety, the following serious adverse reactions have been observed: Cardiovascular system: Severe cardiac events, including heart failure and myocardial infarction have been observed, mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with infusion-related reactions. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rarely.
Respiratory system: Respiratory failure/insufficiency and pulmonary infiltrates in the context of infusion-related reactions (see Precautions). In addition to pulmonary events associated with infusions, interstitial lung disease, some with fatal outcome, has been reported.
Blood and lymphatic system: Cases of infusion-related acute reversible thrombocytopenia have been reported.
Skin and appendages: Severe bullous skin reactions including fatal cases of toxic epidermal necrolysis have been reported rarely.
Nervous system: Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms include 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.
Cases of cranial neuropathy with or without peripheral neuropathy have been reported rarely. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses and facial nerve palsy, occurred at various times up to several months after completion of rituximab therapy.
Body as a whole: Serum sickness-like reactions have been reported rarely.
Infections and infestations: Cases of hepatitis B reactivation have been reported, the majority of which were in subjects receiving rituximab in combination with cytotoxic chemotherapy (see Precautions). Other serious viral infections, either new, reactivation or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus (CMV), Varicella zoster virus and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML), see Precautions) and Hepatitis C virus.
Progression of Kaposi's sarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Gastro-intestinal system: Gastro-intestinal perforation, in some cases leading to death, has been observed in patients receiving rituximab in combination with chemotherapy for non-Hodgkin's lymphoma.
Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA) Patients: As part of continuing post-marketing surveillance of rituximab safety, the following have been observed in the RA setting and are also expected, if not already observed, in GPA/MPA patients: Infections and infestations: Progressive multifocal leukoencephalopathy (PML) and reactivation of hepatitis B infection have been reported.
Body as a whole: Serum sickness-like reaction has been reported.
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis and Stevens-Johnson syndrome some with fatal outcome have been reported very rarely.
Blood and lymphatic system disorders: Neutropenic events, including severe late onset and persistent neutropenia have been reported rarely, some of which were associated with fatal infections.
Nervous system: Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms include 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 hypertension, immunosuppressive therapy and/or other concomitant therapies.
General disorders and administration site conditions: Severe IRRs some with fatal outcome have been reported (see Clinical Trials as previously mentioned).
Laboratory Abnormalities: Non-Hodgkin's Lymphoma: Blood and lymphatic system: Rarely the onset of neutropenia has occurred more than four weeks after the last infusion of rituximab. In post-marketing: studies of rituximab in patients with Waldenstrom's macroglobulinemia, 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.