Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to RITUXAN HYCELA in 892 patients in four controlled trials with exposures ranging from a single injection up to 27 months of treatment.

The population included 382 patients with follicular lymphoma (FL), 369 patients with diffuse large B-cell lymphoma (DLBCL), and 141 patients with chronic lymphocytic leukemia (CLL). The median age was 60 years (range: 18–85 years, 53% were male, and 84% were White. In the SABRINA study patients with FL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), in combination with chemotherapy for up to 7 doses (i.e., total of 8 doses in combination with chemotherapy), or as monotherapy for up to 12 doses (maintenance treatment). In the MabEase study patients with DLBCL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), given in combination with chemotherapy for up to 7 doses (i.e., up to a total of 8 doses). In the SAWYER study patients with CLL on part 2 received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) for up to 5 doses, in combination with fludarabine and cyclophosphamide (i.e., total of 6 doses).

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with FL on the SABRINA study were: infections, neutropenia, nausea, constipation, cough, and fatigue.

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with DLBCL on the MabEase study were: infections, neutropenia, alopecia, nausea, and anemia.

The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with CLL on part 2 of the SAWYER study were: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema.

As with all therapeutic proteins, there is 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 to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In the SABRINA study, where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP, the incidence of treatment-induced/enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group (2.0% RITUXAN HYCELA vs. 1.9% rituximab). The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 15% in the RITUXAN HYCELA group compared with 8% in the rituximab group, and the overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies remained generally constant over the follow-up period in both cohorts. All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies.

In the SAWYER study, where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC, the incidence of treatment-induced/enhanced anti-rituximab antibodies was 12% in the RITUXAN HYCELA group and 15% in the rituximab group. The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 11% in the RITUXAN HYCELA treatment arm. None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies.

The clinical relevance of the development of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with RITUXAN HYCELA is not known.

The following adverse reactions have been identified during post-approval use of rituximab-containing products. 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.