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The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were infusion-related reactions (IRRs) 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 rituximab.
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 (ADRs) were: IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see Precautions.
Infections, see Precautions.
Cardiovascular events, see Precautions.
Other serious ADRs reported include hepatitis B reactivation and PML (see Precautions).
Tabulated list of adverse reactions: The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in Table 12 as follows. 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 < 1/1,000) and very rare (< 1/10,000) and not known (cannot be estimated from the available data).
The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under "not known". (See Table 12.)
Click on icon to see table/diagram/imageThe following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the rituximab arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.
Further information on selected, serious adverse drug reactions: Intravenous Formulation: Administration-related reactions: 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, 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 rituximab (containing) treatment.
Infections: Rituximab induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.
Localised candida infections as well as Herpes zoster were reported at a higher incidence in the rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab 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 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, 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 patients receiving rituximab 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 rituximab-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Maintenance Treatment (NHL) up to 2 years: Data from a phase III clinical trial included 2 cases of fatal PML in NHL patients that occurred after disease progression and retreatment (see Precautions).
Haematologic events: In clinical trials with rituximab 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 rituximab 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 rituximab 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 rituximab and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone and the neutropenia was not prolonged in the rituximab group plus chemotherapy group. 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 rituximab 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 rituximab 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 events: Cardiovascular reactions during clinical trials with rituximab 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 rituximab and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to < 1% on observation.
In studies evaluating rituximab 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 rituximab 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).
IgG levels: In the clinical trial evaluating rituximab 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 rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the rituximab group. 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).
Neurologic events: During 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.
Respiratory system: Respiratory failure/insufficiency and pulmonary infiltrates in the context of infusion-related reactions (see Precautions). In addition to pulmonary events associated with infiltrates outside of infusions-related reactions and interstitial lung disease, pneumonitis have some with fatal outcome, has been reported rarely.
Gastrointestinal disorders: Gastrointestinal perforation in some cases leading to death has been observed in patients receiving rituximab for treatment of non-Hodgkin's lymphoma (NHL). In the majority of these cases, rituximab was administered with chemotherapy.
Skin and subcutaneous tissue disorders: Toxic Epidermal Necrolysis and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Subpopulations: Monotherapy: Elderly patients (≥ 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).
Combination Therapy: Elderly patients (≥ 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.
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-treatment with monotherapy: The percentage of patients reporting ADRs upon re-treatment with further courses of rituximab was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).
Experience from Rheumatoid Arthritis: Intravenous Formulation: The overall safety profile of rituximab IV in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance. The safety profile of rituximab IV in patients with 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 rituximab (see Precautions).
Patients received 2 x 1000 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). Rituximab 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 13. Frequencies are defined as very common (≥1/10) and 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 reactions considered due to receipt of rituximab 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 rituximab, progressive multifocal leukoencephalopathy (PML) (see Precautions) and serum sickness-like reaction have been reported during post marketing experience. (See Table 13.)
Click on icon to see table/diagram/imageMultiple Courses: Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first rituximab 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.
Further information on selected adverse drug reactions: Infusion-related reactions: The most frequent ADRs following receipt of rituximab IV in RA clinical studies were infusion-related reactions (IRRs) (refer to Table 13). Among the 3189 patients treated with rituximab, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. 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. 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 (e.g., nausea, pruritis, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic edema, 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 intravenous glucocorticoid significantly reduced the incidence and severity of these events (see Precautions).
In a study designed to evaluate the safety of a 120-minute rituximab infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious infusion-related reaction (IRR) during or within 24 hours of their first studied infusion were allowed to receive a 120-minute infusion of rituximab IV. Patients with a history of a serious infusion reaction to a biologic therapy for RA were excluded from entry. The incidence, types and severity of infusion-related reactions (IRRs) were consistent with that observed historically. No serious IRRs were observed.
Infections: The overall rate of infection was approximately 94 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 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 rituximab. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the rituximab arms compared to control arms.
Cases of Progressive Multifocal Leukoencephalopathy with fatal outcome have been reported following use of rituximab for the treatment of autoimmune diseases. This includes Rheumatoid Arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and Vasculitis. All the reported cases had multiple risk factors for PML, including either the underlying disease and or long-term immunosuppressive therapy or chemotherapy.
Malignancies: In RA clinical studies, the incidence of malignancy following exposure to rituximab is 0.8 per 100 patient years, which is within the range expected for an age- and gender-matched population.
Cardiovascular: Cardiac events were observed in 11% patients in clinical studies with rituximab. In placebo controlled studies, serious cardiac events were reported equally in rituximab and placebo treated patients (2%).
Neurologic events: 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.
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