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MabThera/Rituxan IV Monotherapy/Maintenance Therapy: The ADRs in Table 20, are based on data from single-arm studies including 356 patients with low-grade or follicular lymphoma, treated with MabThera/Rituxan IV weekly as single agent for the treatment or re-treatment of non-Hodgkin's lymphoma (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions). The table also contains ADRs based on data from 671 patients with follicular lymphoma who received MabThera/Rituxan IV 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). The ADRs were reported up to 12 months after treatment with monotherapy and up to 1 month after treatment with MabThera/Rituxan IV maintenance. (See Table 20.)
Click on icon to see table/diagram/imageMabThera/Rituxan IV in Combination with Chemotherapy in NHL and CLL: The ADRs listed in Table 21 are based on MabThera/Rituxan 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 R-CVP, respectively and from 397 previously untreated CLL patients and 274 relapsed/refractory CLL patients, treated with MabThera/Rituxan IV in combination with fludarabine and cyclophosphamide (R-FC) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions). (See Table 21.)
Click on icon to see table/diagram/imageThe following terms have been reported as adverse events, however, were reported at a similar (<2% difference between the groups) or lower incidence in the MabThera/Rituxan IV-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 MabThera/Rituxan IV in combination with other chemotherapies (e.g., MCP, CHVP-IFN) is comparable to the safety profile as described for the combination of MabThera/Rituxan IV and CVP, CHOP or FC in equivalent populations.
MabThera SC: Local cutaneous reactions, including injection site reactions, were very common (≥ 1/10) in patients receiving MabThera/Rituxan SC. In the phase 3 SABRINA (BO22334) study, local cutaneous reactions were reported in up to 23% of patients receiving MabThera/Rituxan SC. The most common local cutaneous reactions in the MabThera/Rituxan SC arm were: injection site erythema (13%), injection site pain (8%), and injection site oedema (4%). Similar events were observed in the SAWYER (BO25341) study and were reported in up to 42% of patients in the MabThera/Rituxan SC arm. The most common local cutaneous reactions were: injection site erythema (26%), injection site pain (16%), and injection site swelling (5%).
Events seen following subcutaneous administration were mild or moderate, apart from one patient in the SABRINA study who reported a local cutaneous reaction of Grade 3 intensity (injection site rash) and two patients in the SAWYER study who experienced Grade 3 local cutaneous reactions (injection site erythema, injection site pain, and injection site swelling). Local cutaneous reactions of any Grade in the MabThera/Rituxan SC arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections.
The safety profile of MabThera/Rituxan SC was otherwise comparable to that of the IV formulation.
No cases of anaphylaxis or severe hypersensitivity reactions, cytokine release syndrome or tumour lysis syndrome were observed following subcutaneous administration during the MabThera/Rituxan SC development program.
Further information on selected, serious adverse drug reactions: MabThera: 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 MabThera/Rituxan IV 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 of the first treatment cycle with MabThera/Rituxan IV 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.
MabThera SC: The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera/Rituxan was assessed in three clinical.
In the SparkThera (BP22333) study no severe administration-related reactions were reported.
In the SABRINA (BO22334) study severe administration-related reactions (Grade ≥3) were reported in two patients (1%) following MabThera/Rituxan SC administration. These events were Grade 3 injection site rash and dry mouth.
In the SAWYER (BO25341) study severe administration-related reactions (Grade ≥3) were reported in four patients (5%) following MabThera/Rituxan SC administration. These events were Grade 4 thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria.
MabThera: Combination Therapy at 90-Minute Infusion Rate (R-CVP in f-NHL; R-CHOP in DLBCL): In a study to characterize the safety profile of 90-minute MabThera/Rituxan IV infusions in patients who well tolerated their first standard MabThera/Rituxan IV infusion (Study U4391g), the incidence of Grade 3 and 4 IRRs on the day of and/or the day after the 90-minute MabThera/Rituxan IV infusion at Cycle 2 in the 363 evaluable patients was 1.1% (95% CI [0.3%, 2.8%]). The incidence of Grade 3 and 4 IRRs at any cycle (Cycles 2 to 8) at the 90-minute infusion rate was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal IRRs were observed (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Infections: Monotherapy 4 weeks treatment: MabThera/Rituxan IV 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 MabThera/Rituxan IV 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 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. 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 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.
In patients with CLL, the incidence of Grade 3 and 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. MabThera/Rituxan IV 5%) and neutropenia (observation 4% vs. MabThera/Rituxan IV 10%) in the MabThera/Rituxan IV arm compared to the observation arm. The incidence of Grade 3 and 4 thrombocytopenia (observation 1% vs. MabThera/Rituxan IV <1%) was low. In approximately half of the patients with available data on B-cell recovery after end of MabThera/Rituxan IV 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 MabThera/Rituxan IV 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 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV plus FC group.
No relevant difference between the treatment arms was observed with respect to Grade 3 and 4 anaemia or thrombocytopenia. In the CLL first-line study 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV: 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 arrhythmias either occurred in the context of a MabThera/Rituxan IV 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 MabThera/Rituxan IV groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during MabThera/Rituxan IV treatment. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera/Rituxan IV group throughout the 2 year 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 during 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 first-line 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 ADRs was similar in elderly (≥ 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 re-treatment with further courses of MabThera/Rituxan IV 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).
Experience from Rheumatoid Arthritis Clinical Trials: MabThera: The safety profile of MabThera/Rituxan IV in the treatment of patients with moderate to severe RA is summarized as follows. In the all-exposure population more than 3000 patients 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 22 are based on data from placebo-controlled periods of four multicenter, RA clinical trials. The patient populations receiving MabThera/Rituxan IV 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-tumour necrosis factor (TNF) therapies (TNF-IR) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Patients received 2 x 1000 mg or 2 x 500 mg of MabThera/Rituxan IV separated by an interval of two weeks; in addition to methotrexate (10 to 25 mg/week) (see Rheumatoid Arthritis under Dosage and Administration).
The ADRs listed in Table 22 are those which occurred at a rate of at least 2%, with at least 2% difference compared to the control arm and are presented regardless of dose. Frequencies in Table 3 and the 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 22.)
Click on icon to see table/diagram/imageIn 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 MabThera/Rituxan IV in RA clinical studies were IRRs. Among the 3095 patients treated with MabThera/Rituxan IV, 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 MabThera/Rituxan IV at any dose experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical studies (see Post-Marketing under Adverse Reactions). The proportion of CTC Grade 3 events and IRRs leading to withdrawal decreased by course and were rare from course 3 onwards.
Signs and/or symptoms suggesting an IRR (i.e., 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 the first infusion of the first exposure to MabThera/Rituxan IV.
Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events (see Precautions).
In a study designed to evaluate the safety of a 120-minute MabThera/Rituxan IV infusion in patients with RA, patients with moderate-to-severe active RA who did not experience a serious IRR during or within 24 hours of their first studied infusion were allowed to receive a 120-minute infusion of MabThera/Rituxan 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 IRRs were consistent with that observed historically. No serious IRRs were observed (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Infections: The overall rate of infection was approximately 97 per 100 patient years in MabThera/Rituxan IV 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 22, medically serious events reported also include pneumonia at a frequency of 1.9%.
Malignancies: The incidence of malignancy following exposure to MabThera/Rituxan IV in RA 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): MabThera: Adult Induction of Remission: Ninety-nine adult GPA/MPA patients were treated for induction of remission of GPA and MPA in a clinical trial with MabThera/Rituxan IV (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
The ADRs listed in Table 23 were all adverse events which occurred at an incidence of ≥ 10% in the MabThera/Rituxan IV-treated group. Frequencies in Table 23 are defined as very common (≥1/10). (See Table 23.)
Click on icon to see table/diagram/imageAdult Maintenance Treatment: 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 MabThera/Rituxan IV in approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the MabThera/Rituxan IV arm experienced adverse events leading to discontinuation. Most adverse events in the MabThera/Rituxan IV arm were mild or moderate in intensity. No patients in the MabThera/Rituxan IV arm had fatal adverse events.
ADRs were all adverse events which occurred at an incidence of ≥ 10% in the MabThera/Rituxan IV-treated group. The very commonly (≥ 10%) reported events considered ADRs were: infusion-related reactions and infections.
Adult Long-term Follow-up: In a long-term observational safety study, 97 adult GPA/MPA patients received treatment with MabThera/Rituxan (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 MabThera 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, MabThera/Rituxan was given at the discretion of the investigator (17 out of 25 patients received additional MabThera/Rituxan 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 MabThera/Rituxan IV was consistent with that reported during the remission induction phase. The safety profile of MabThera/Rituxan IV in pediatric GPA/MPA patients was consistent in type, nature and severity with the known safety profile in adult patients for autoimmune diseases, including adult GPA/MPA.
Further information on selected adverse drug reactions: Infusion-related reactions: In the clinical trial studying induction of remission 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 MabThera/Rituxan IV 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. MabThera/Rituxan IV was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.
In the maintenance therapy clinical trial in adult patients, 7/57 (12%) patients in the MabThera/Rituxan IV arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms were mild to moderate and most were reported from the Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorders 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV. 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 of remission, 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 MabThera/Rituxan IV group was pneumonia at a frequency of 4%.
In the maintenance therapy clinical trial in adult patients, 30/57 (53%) patients in the MabThera/Rituxan IV 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV arm was mild or moderate bronchitis.
In the clinical trial 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 the incidence of malignancy in MabThera/Rituxan IV 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 (IgG or IgM below the lower limit of normal) has been observed in pediatric GPA/MPA patients treated with MabThera/Rituxan IV. During the overall study period, 3/25 (12%) patients reported an event of hypogammaglobulinaemia, 18 patients (72%) had prolonged low IgG levels (of whom 15 patients also had prolonged low IgM). Three patients received treatment with intravenous immunoglobulin (IV-IG). There was no association between prolonged low IgG and IgM and an increased risk of serious infection.
Clinical Trial Experience in Pemphigus Vulgaris: Summary of the safety profile: The safety profile of MabThera/Rituxan IV 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 in 38 pemphigus vulgaris (PV) and 8 pemphigus foliaceus (PF) patients. Patients randomized to the MabThera/Rituxan IV 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).
The safety profile of MabThera/Rituxan IV in patients with PV was consistent with that observed in RA and GPA/MPA patients (see Experience from Rheumatoid Arthritis Clinical Trials and Clinical Trial Experience in Granulomatosis with Polyangiitis (Wegener's) (GPA) and Microscopic Polyangiitis (MPA) as previously mentioned).
Adverse drug reactions presented in Table 23 were adverse events which occurred at a rate of ≥ 5% among MabThera/Rituxan IV treated PV patients, with a ≥ 2% absolute difference in incidence between the MabThera/Rituxan IV treated group and the standard dose prednisone group up to Month 24. No patients were withdrawn due to ADRs. Frequencies in Table 24 are defined as very common (≥1/10) and common (≥1/100). (See Table 24.)
Click on icon to see table/diagram/imageFurther information on selected adverse drug reactions: Infusion-related reactions: Infusion-related reactions in the pemphigus vulgaris clinical study were retrospectively collected and assessed, and included symptoms of intolerance or adverse events considered to be infusion-related. Infusion-related reactions were reported very commonly (58%). All infusion-related reactions were mild to moderate (Grade 1 or 2) except one Grade 3 serious infusion-related reaction (arthralgia) associated with the month 12 maintenance infusion. 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. There were no fatal infusion-related reactions and 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.
Infections: Fourteen patients (37%) in the MabThera/Rituxan IV group experienced treatment-related infections compared to 15 patients (42%) in the standard dose prednisone group. The most common infections in the MabThera/Rituxan IV group were herpes simplex and zoster infection, bronchitis, urinary tract infection, fungal infection, and conjunctivitis. Three patients (8%) in the MabThera/Rituxan IV 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).
Laboratory Abnormalities: MabThera: Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA and adult and pediatric GPA/MPA patients treated with MabThera/Rituxan IV. 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV.
In placebo-controlled periods of clinical trials, 0.94% (13/1382) of MabThera/Rituxan IV 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 MabThera/Rituxan IV 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, at 6 months, in the MabThera/Rituxan IV 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%, 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, IgG, IgM or IgA levels were observed throughout the trial.
In the induction of remission clinical trial, 24% of patients in the MabThera/Rituxan IV 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/Rituxan IV-treated patients.
In the maintenance therapy clinical trial, the incidence of all-grade neutropenia was 0% for MabThera/Rituxan IV treated patients vs 5% for azathioprine treated patients.
Post-Marketing: MabThera: 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 data largely derived from spontaneous reports.
Additional cases of severe IRRs have been reported during post-marketing use of MabThera/Rituxan IV (see Precautions).
As part of the continuing post-marketing surveillance of MabThera/Rituxan IV 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 IRRs. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported very rarely.
Respiratory system: Respiratory failure/insufficiency and lung infiltration in the context of IRRs have been observed (see Precautions). In addition to pulmonary events associated with infusions, interstitial lung disease, some with fatal outcome, have been reported.
Blood and lymphatic system: Cases of infusion-related acute reversible thrombocytopenia have been reported.
Skin and appendages: Severe bullous skin reactions including some 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV 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 MabThera/Rituxan IV treatment. The majority of patients had received MabThera/Rituxan IV 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 MabThera/Rituxan IV-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.
Gastrointestinal system: Gastrointestinal perforation, in some cases leading to death, has been observed in patients receiving MabThera/Rituxan IV 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 the continuing post-marketing surveillance of MabThera/Rituxan IV 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: Mabthera: Non-Hodgkin's Lymphoma.
Blood and lymphatic system: Rarely the onset of neutropenia has occurred more than four weeks after the last infusion of MabThera/Rituxan IV.
In studies of MabThera/Rituxan IV 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.
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