In patients with previously untreated CLL , the frequency of prolonged neutropenia was 8.5 % for patients who received R-FC ( n = 402 ) and 5.8 % for patients who received FC ( n = 398 ). In patients who did not have prolonged neutropenia , the frequency of late-onset neutropenia was 14.8 % of 209 patients who received R-FC and 4.3 % of 230 patients who received FC .
For patients with previously treated CLL , the frequency of prolonged neutropenia was 24.8 % for patients who received R-FC ( n = 274 ) and 19.1 % for patients who received FC ( n = 274 ). In patients who did not have prolonged neutropenia , the frequency of late-onset neutropenia was 38.7 % in 160 patients who received R-FC and 13.6 % of 147 patients who received FC .
Relapsed or Refractory , Low-Grade NHL Adverse reactions presented in Table 1 occurred in 356 patients with relapsed or refractory , low-grade or follicular , CD20-positive , B-cell NHL treated in single-arm studies of rituximab administered as a single agent . Most patients received rituximab 375 mg / m 2 weekly for 4 doses .
Table 1
Incidence of Adverse Reactions in ≥5 % of Patients with Relapsed or Refractory , Low-Grade or Follicular NHL , Receiving Single-agent Rituximab ( N = 356 )* ,†
Any Adverse Reactions
Body as a Whole Fever Chills Infection Asthenia Headache Abdominal Pain Pain Back Pain Throat Irritation Flushing
Heme and Lymphatic System Lymphopenia Leukopenia Neutropenia Thrombocytopenia Anemia
Skin and Appendages Night Sweats Rash Pruritus Urticaria
Respiratory System Increased Cough Rhinitis Bronchospasm Dyspnea Sinusitis
Metabolic and Nutritional Disorders Angioedema Hyperglycemia Peripheral Edema LDH Increase
Digestive System Nausea Diarrhea Vomiting
Nervous System Dizziness Anxiety
Musculoskeletal System Myalgia Arthralgia
Cardiovascular System Hypotension Hypertension
All Grades (%) Grade 3 and 4 (%) 99
86 53 33 31 26 19 14 12 10 9 5
67 48 14 14 12 8
44 15 15 14 8
38 13 12 8 7 6
38 11 9 8 7
37 23 10 10
32 10 5
26 10 10
25 10 6
* Adverse reactions observed up to 12 months following rituximab .
†
Adverse reactions graded for severity by NCI-CTC criteria .
57
10 1 3 4 1 1 1 1 1 0 0
48 40 4 6 2 3
2 1 1 1 1
4 1 1 1 1 0
3 1 1 0 0
2 1 1 1
1 1 1
3 1 1
3 1 1
In these single-arm rituximab studies , bronchiolitis obliterans occurred during and up to 6 months after rituximab infusion .
Previously Untreated , Low-Grade or Follicular , NHL In NHL Study 4 , patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm . The following adverse reactions occurred more frequently ( ≥5 %) in patients receiving R-CVP compared to CVP alone : rash ( 17 % vs . 5 %), cough ( 15 % vs . 6 %), flushing ( 14 % vs . 3 %), rigors ( 10 % vs . 2 %), pruritus ( 10 % vs . 1 %), neutropenia ( 8 % vs . 3 %), and chest tightness ( 7 % vs . 1 %).
In NHL Study 5 , detailed safety data collection was limited to serious adverse reactions , Grade ≥2 infections , and Grade ≥3 adverse reactions . In patients receiving rituximab as single-agent maintenance therapy following rituximab plus chemotherapy , infections were reported more frequently compared to the observation arm ( 37 % vs . 22 %). Grade 3-4 adverse reactions occurring at a higher incidence ( ≥2 %) in the rituximab group were infections ( 4 % vs . 1 %) and neutropenia ( 4 % vs . < 1 %).
In NHL Study 6 , the following adverse reactions were reported more frequently ( ≥5 %) in patients receiving rituximab following CVP compared to patients who received no further therapy : fatigue ( 39 % vs . 14 %), anemia ( 35 % vs . 20 %), peripheral sensory neuropathy ( 30 % vs . 18 %), infections ( 19 % vs . 9 %), pulmonary toxicity ( 18 % vs . 10 %), hepato-biliary toxicity ( 17 % vs . 7 %), rash and / or pruritus ( 17 % vs . 5 %), arthralgia ( 12 % vs . 3 %), and weight gain ( 11 % vs . 4 %). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently ( ≥2 %) in the rituximab arm compared with those who received no further therapy ( 4 % vs . 1 %).
DLBCL In NHL Studies 7 ( NCT00003150 ) and 8 , the following adverse reactions , regardless of severity , were reported more frequently ( ≥5 %) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone : pyrexia ( 56 % vs . 46 %), lung disorder ( 31 % vs . 24 %), cardiac disorder ( 29 % vs . 21 %), and chills ( 13 % vs . 4 %). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions .
In NHL Study 8 , a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders ( 4.5 % for R-CHOP vs . 1.0 % for CHOP ).
The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm : thrombocytopenia ( 9 % vs . 7 %) and lung disorder ( 6 % vs . 3 %). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection ( NHL Study 8 ), neutropenia ( NHL Studies 8 and 9 ( NCT00064116 )), and anemia ( NHL Study 9 ).
CLL The data below reflect exposure to rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in CLL Study 1 ( NCT00281918 ) or CLL Study 2 ( NCT00090051 ). The age range was 30-83 years and 71 % were men . Detailed safety data collection in CLL Study 1 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions .
Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion : nausea , pyrexia , chills , hypotension , vomiting , and dyspnea .
In CLL Study 1 , the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients : infusion-related reactions ( 9 % in R-FC arm ), neutropenia ( 30 % vs . 19 %), febrile neutropenia ( 9 % vs . 6 %), leukopenia ( 23 % vs . 12 %), and pancytopenia ( 3 % vs . 1 %).
In CLL Study 2 , the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients : infusion-related reactions ( 7 % in R-FC arm ), neutropenia ( 49 % vs . 44 %), febrile neutropenia ( 15 % vs . 12 %), thrombocytopenia ( 11 % vs . 9 %), hypotension ( 2 % vs . 0 %), and hepatitis B ( 2 % vs . < 1 %). Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity .
Immunogenicity As with all therapeutic proteins , there is a potential for immunogenicity . The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other rituximab products may be misleading .
Using an ELISA assay , anti-rituximab antibody was detected in 4 of 356 ( 1.1 %) patients with low-grade or follicular NHL receiving single-agent rituximab . Three of the four patients had an objective clinical response .
Postmarketing Experience The following adverse reactions have been identified during post-approval use of rituximab . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
• Hematologic : prolonged pancytopenia , marrow hypoplasia , Grade 3-4 prolonged or late-onset neutropenia , hyperviscosity syndrome in Waldenstrom ’ s macroglobulinemia , prolonged hypogammaglobulinemia .
• Cardiac : fatal cardiac failure .
• Immune / Autoimmune Events : uveitis , optic neuritis , systemic vasculitis , pleuritis , lupus-like syndrome , serum sickness , polyarticular arthritis , and vasculitis with rash .
• Infection : viral infections , including progressive multifocal leukoencephalopathy ( PML ), increase in fatal infections in HIV-associated lymphoma , and a reported increased incidence of Grade 3 and 4 infections .
• Neoplasia : disease progression of Kaposi ’ s sarcoma .
• Skin : severe mucocutaneous reactions , pyoderma gangrenosum ( including genital presentation ).
• Gastrointestinal : bowel obstruction and perforation .
• Pulmonary : fatal bronchiolitis obliterans and fatal interstitial lung disease .
• Nervous system : Posterior Reversible Encephalopathy Syndrome ( PRES )/ Reversible Posterior Leukoencephalopathy Syndrome ( RPLS ).