Rituxsanbe Adverse Reactions

Clinical Trials: Experience from Clinical Trials in Hemato-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 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 IV Monotherapy/Maintenance Therapy: The ADRs in Table 5, are based on data from single-arm studies including 356 patients with lowgrade or follicular lymphoma, treated with Rituximab weekly as single agent for the treatment or re-treatment of non-Hodgkin's lymphoma. 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. The ADRs ware reported up to 12 months after treatment with monotherapy and up to 1 month after treatment with Rituximab maintenance. See Table 5.


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Rituximab in Combination with Chemotherapy in NHL and CLL: The ADRs listed in Table 6 are based on Rituximab IV-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 RCVP, respectively and from 397 previously untreated CLL patients and 274 relapsed/refractory CLL patients, treated with Rituximab in combination with Fludarabine and Cyclophosphamlde (R-FC). See Table 6.


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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 IV arms compared to control arms: Hematotoxicity, neutropenic infection, urinary tract infection, septic shock, superinfection lung, implant infection, septicemia staphylococcal, lung infection, rhinorrheoa, pulmonary edema, cardiac failure, sensory disturbance, venous thrombosis, mucosal inflammation nos, influenza-like illness, edema 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, CHVPIFN) 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 Reaction: 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, 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. 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 IRR 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 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 edema and acute reversible thrombocytopenia were also reported.
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 trials included cases of fatal PML in NHL patients that occurred after disease progression and re-treatment (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 RCVP and 16.4% patients receiving CVP. Serious infections were reported in 4.3% of the patients receiving R-CVP and 4.4% of the 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 RCHOP 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.
In patients with CLL, the incidence of Grade 3 or 4 hepatitis B infection (reactivation and primary infection) was 2% in the R-FC group vs. 0% in the FC group.
Haematologic events: Monotherapy 4 weeks treatment: 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 and 4 leucopenia (observation 2% vs. Rituximab 5%) and neutropenia (observation 4% vs. Rituximab 10%) in the Rituximab IV arm compared to the observation arm. The incidence of Grade 3and 4 thrombocytopenia (observation 1% vs. 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 IV in combination with chemotherapy, Grade 3 and 4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), and neutropenia (RCVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% 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. 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 the Rituximab plus FC group.
No relevant difference between the treatment arms was observed with respect to Grade 3 and 4 anemia or thrombocytopenia. In the CLL first-line study, Grade 3 and 4 anemia was reported by 4% of patients treated with R-FC compared to 7% of patients receiving FC, and Grade 3 and 4 thrombocytopenla 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 anemia were reported in 12% of patients treated with R-FC compared to 13% of patients receiving FC and Grade 3/4 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 supraventriculer tachycardia) and angina pectoris during a Rituximab infusion were reported.
Maintenance Treatment (NHL) up to 2 years: The incidence of Grade 3 and 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 ischemla (< 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 RCHOP group (6.9%) as compared to the CHOP group (1.5%). All 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 and 4 cardiac disorders was low both in the first-line study (4% R-FC vs. 3% FC) and in the relapsed/refractory study (4% R-FC vs. 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 years treatment period, while it decreased in the observation group (36% after 2 years).
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 durtng the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, 1.5% of patients had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.
In CLL, the overall incidence of Grade 3 and 4 nervous system disorders was low both in the firstline study (4% R-FC vs. 4% FC) and in the relapsed/refractory study (3% R-FC vs. 3% FC).
Subpopulations: Monotherapy - 4 weeks treatment: Elderly patients (≥65 years): The incidence of any ADR and of Grade 3 and 4 ADR was similar in elderiy (65 years of age) and younger patients (88.3% vs. 92.0% for any ADR and 16.0% vs. 18.1% for Grade 3 and 4 ADRs).
Combination Therapy: Elderly patients (65 years): The incidence of Grade 3 and 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 had a higher incidence of Grade 3 and 4 ADRs than patients without bulky disease (25.6% vs. 15.4%). The incidence of any ADR was similar in these two groups (92.3% in bulky disease vs. 89.2% in non-bulky disease).
Re-treatment with Monotherapy: The percentage of patients reporting any ADR and Grade 3 and 4 ADRs upon retreatment 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% vs. 89.7% for any ADR and 13.3% vs. 14.8% for Grade 3 and 4 ADRs).
Adverse Reactions Reported in Other Monotherapy Clinical Trials: One case of serum sickness has been reported in a clinical trial using Rituximab monotherapy for treatment of diffuse large B-cell lymphoma.
Post-Marketing: Non-Hodgkin's Lymphoma: The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and data largely derived from spontaneous reports.
Additional cases of severe IRRs 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 bean observed, mainly in patients with prior cardiac condition and for cardiotoxic chemotherapy and mostly associated with IRRs. Vasculitis, predominantly cutaneous, such as leukocytoclastic vesculitis, has been reported very rare.
Respiratory system: Severe cardiac events, induding heart failure and myocardial infarction have been observed, mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with IRRs. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rare.
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 and Stevens-Johnson syndrome 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: Gases 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 hematopoietic 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 preexisting Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Gastro-intestinal system: Gastrointestinal perforation, in some cases leading to death, has been observed in patients receiving Rituximab in combination with chemotherapy for non-Hodgkin's lymphoma.
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.
Post Marketing: In 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.