Rituxan Hycela (Page 3 of 9)
5.8 Renal Toxicity
Severe, including fatal, renal toxicity can occur after administration of rituximab-containing products, including RITUXAN HYCELA. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN HYCELA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN HYCELA in patients with a rising serum creatinine or oliguria [see Warnings and Precautions (5.5)].
5.9 Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA, in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.
5.10 Immunization
The safety of immunization with live viral vaccines following rituximab-containing products, including RITUXAN HYCELA, therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.
5.11 Embryo-Fetal Toxicity
Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Mucocutaneous reactions [see Warnings and Precautions (5.1)]
- Hepatitis B reactivation including fulminant hepatitis [see Warnings and Precautions (5.2)]
- Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)]
- Hypersensitivity and other administration reactions [see Warnings and Precautions (5.4)]
- Tumor lysis syndrome [see Warnings and Precautions (5.5)]
- Infections [see Warnings and Precautions (5.6)]
- Cardiac arrhythmias [see Warnings and Precautions (5.7)]
- Renal toxicity [see Warnings and Precautions (5.8)]
- Bowel obstruction and perforation [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
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.
Administration-related reactions (ARRs)
Administration-related reactions (ARRs) with RITUXAN HYCELA were defined as all the adverse reactions related to the administration of RITUXAN HYCELA within the 24 hours post injection.
The incidence of ARRs with RITUXAN HYCELA was 34% in FL/DLBCL in combination with chemotherapy with injection site erythema (5%), chills (3%), dyspnea, erythema, flushing, injection site pain, nausea, pruritus, pyrexia, rash, and throat irritation (2% each) being the most common ARRs. The incidence of ARRs in FL maintenance setting was 20%. The most common ARRs were injection site erythema (7%), erythema (4%), injection site pain/edema, myalgia, and rash (2% each).
The incidence of ARRs with RITUXAN HYCELA in CLL was 44%.
With the exception of Local Cutaneous Reactions, the incidence and profile of adverse reactions reported for RITUXAN HYCELA were comparable with those for rituximab. The overall incidence of adverse reactions for intravenous rituximab versus RITUXAN HYCELA in combination with chemotherapy for FL/DLBCL was 93% versus 95% (BSA ≤ 1.73 m2), 89% versus 93% (1.73 < BSA ≤ 1.92 m2), and 94% versus 94% (BSA > 1.92 m2). The overall incidence of adverse reactions for rituximab versus RITUXAN HYCELA in CLL was 89% versus 100% (BSA ≤ 1.81 m2), 97% versus 88% (1.82 < BSA ≤ 1.99 m2), and 88% versus 93% (BSA > 2.00 m2).
Summary of Clinical Trial Experience in Follicular Lymphoma (FL)
The data in Table 1 were obtained in the SABRINA study, a two-stage randomized, controlled study in patients with previously untreated FL. The study compared patients receiving RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human; n=197) with patients receiving a rituximab product by intravenous infusion (375 mg/m2 ; n=210), both in combination with CHOP or CVP followed by maintenance treatment with RITUXAN HYCELA or a rituximab product by intravenous infusion.
The majority of patients completed all 8 cycles of combination treatment with chemotherapy (91% RITUXAN HYCELA vs. 90% rituximab). In addition, 69% of patients in each of the treatment groups completed all 20 cycles of combination plus maintenance treatment. In both RITUXAN HYCELA and rituximab groups, patients experienced similar median duration of exposure (27.1 months for each arm).
Across the two stages, the overall demographics and baseline characteristics were balanced between the treatment groups. However, there were more female patients (53%) randomized in the study than male patients (47%) and a higher proportion of females were randomized to receive RITUXAN HYCELA (59% female) compared with the rituximab group (48%). The treatment groups in the combined Stage 1 and 2 population were otherwise balanced in regard to baseline demographics, characterized by a median age of 57 years (56.0 years [range 28–85 years] for RITUXAN HYCELA and 57 years [range 28–86 years] for rituximab) and median BSA of 1.83 m2 (1.80 and 1.84 m2 for RITUXAN HYCELA and rituximab, respectively).
The incidence of all adverse reactions was 96% for RITUXAN HYCELA vs. 95% for rituximab (Table 1). Grade 3–4 adverse reactions were reported in 55% of patients receiving RITUXAN HYCELA vs. 53% in patients receiving rituximab. Serious adverse reactions were reported in 37% of patients receiving RITUXAN HYCELA vs. 34% of patients receiving rituximab. The most common adverse reactions (occurring in ≥ 20% of patients in any arm) were infections, neutropenia, nausea, constipation, cough, and fatigue.
A total of 36 patients died, including 14/197 patients (7%) who received RITUXAN HYCELA and 22/210 patients (10%) who received rituximab. Of these 36 patients, 19 patients (7 patients RITUXAN HYCELA [4%] vs. 12 patients rituximab [6%]) died due to adverse reactions and 13 patients (6 patients RITUXAN HYCELA [3%] vs. 7 patients rituximab [3%]) died due to disease progression.
The incidence of administration-related reactions (ARRs) due to the subcutaneous route of administration associated with RITUXAN HYCELA was assessed in combination with chemotherapy and during maintenance. Thirty patients (15%) experienced an ARR during the first administration of RITUXAN HYCELA (Cycle 2). Incidence of ARRs generally decreased at subsequent cycles with 18 patients (9%) reporting ARR at Cycle 3, 13 patients (7%) at Cycle 4, 11 patients (6%) at Cycles 5 and 6, 12 patients (7%) at Cycle 7, and 8 patients (4%) at Cycle 8. During RITUXAN HYCELA monotherapy in the maintenance setting the incidence of ARRs at each cycle was ≤ 7% and was observed in 24 patients (14%) overall. Grade 1–2 ARRs constituted 96% of the overall ARRs. Grade 3 ARRs were reported during the first administration of RITUXAN HYCELA at Cycle 2 by 2 patients. Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 32 patients. These events resolved within a median of 2 days from the onset (range 1 to 37 days). Majority of these reactions were Grade 1 and 2 and were observed in 31 patients (16%).
| Body System/Adverse Reactions | RITUXAN HYCELA (n=197) | Rituximab (n=210) | ||
|---|---|---|---|---|
| All Grades% | Grade 3–4% | All Grades% | Grade 3–4% | |
| Gastrointestinal Disorders | ||||
| Nausea | 31 | 0 | 22 | 0 |
| Constipation | 25 | 0 | 26 | < 1 |
| Diarrhea | 18 | 2 | 16 | < 1 |
| Abdominal Pain | 14 | 0 | 12 | < 1 |
| Vomiting | 14 | 0 | 12 | < 1 |
| Dyspepsia | 8 | 0 | 7 | 0 |
| Stomatitis | 6 | 0 | 5 | 0 |
| Abdominal Pain Upper | 5 | 0 | 5 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 20 | 0 | 18 | < 1 |
| Asthenia | 17 | 1 | 13 | 0 |
| Pyrexia | 15 | < 1 | 16 | < 1 |
| Injection Site Erythema | 13 | 0 | 0 | 0 |
| Injection Site Pain | 8 | 0 | 0 | 0 |
| Chills | 8 | 0 | 9 | 0 |
| Chest Pain | 6 | 1 | 3 | 0 |
| Edema Peripheral | 5 | < 1 | 6 | 0 |
| Mucosal Inflammation | 5 | 1 | 6 | < 1 |
| Influenza Like Illness | 3 | 0 | 6 | 0 |
| Infections | ||||
| Upper Respiratory Tract Infection | 15 | < 1 | 10 | 0 |
| Pneumonia | 11 | 5 | 4 | 2 |
| Nasopharyngitis | 10 | 0 | 10 | 0 |
| Bronchitis | 8 | < 1 | 8 | < 1 |
| Urinary Tract Infection | 8 | 1 | 14 | < 1 |
| Sinusitis | 7 | < 1 | 4 | 0 |
| Conjunctivitis | 5 | 0 | 5 | 0 |
| Influenza | 4 | 0 | 6 | < 1 |
| Blood and Lymphatic System Disorders | ||||
| Neutropenia | 32 | 26 | 27 | 21 |
| Anemia | 15 | 5 | 13 | 0 |
| Febrile Neutropenia | 8 | 7 | 6 | 6 |
| Leukopenia | 6 | 4 | 11 | 2 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgia | 13 | < 1 | 10 | 0 |
| Bone Pain | 10 | < 1 | 8 | 0 |
| Pain In Extremity | 10 | 0 | 5 | 0 |
| Back Pain | 9 | < 1 | 12 | < 1 |
| Muscle Spasms | 8 | 0 | 3 | 0 |
| Myalgia | 8 | 0 | 5 | 0 |
| Nervous System Disorders | ||||
| Paresthesia | 16 | 0 | 12 | 0 |
| Headache | 13 | 0 | 9 | 0 |
| Neuropathy Peripheral | 12 | 2 | 14 | < 1 |
| Dizziness | 7 | 0 | 7 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Alopecia | 14 | < 1 | 10 | < 1 |
| Pruritus | 10 | 0 | 12 | < 1 |
| Rash | 10 | 0 | 7 | 0 |
| Erythema | 9 | 0 | 5 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 23 | 0 | 13 | < 1 |
| Dyspnea | 11 | 1 | 8 | 2 |
| Oropharyngeal Pain | 9 | 0 | 8 | 0 |
| Psychiatric Disorders | ||||
| Insomnia | 9 | 0 | 9 | 0 |
| Vascular Disorders | ||||
| Hypertension | 6 | 1 | 6 | 0 |
Summary of Clinical Trial Experience in Diffuse Large B-Cell Lymphoma (DLBCL)
The data in Table 2 were obtained in the MabEASE study, a comparative, randomized, parallel-group, multicenter study to investigate the efficacy of RITUXAN HYCELA (1,400 mg rituximab and 23,400 Units hyaluronidase human; n=369) versus 375 mg/m2 a rituximab product by intravenous infusion (n=203) both in combination with CHOP (R-CHOP) in previously untreated patients with CD20-positive DLBCL.
Eighty two percent of patients receiving RITUXAN HYCELA or rituximab completed all 8 cycles of study treatment. In both RITUXAN HYCELA and rituximab treatment groups, patients experienced 4.9 months median duration of rituximab exposure in each arm.
The demographic characteristics were balanced. Most patients were White (79%) and 54% were male. The median was 64 years and median BSA was 1.83 m2.
The incidences of adverse reactions of any grade (RITUXAN HYCELA [94%] vs. rituximab [92%]) (Table 2), Grade 3–4 adverse reactions (RITUXAN HYCELA [63%] vs. rituximab [57%]), and serious adverse reactions (RITUXAN HYCELA [42%] vs. rituximab [37%]) were generally comparable between the two treatment groups. The common adverse reactions (occurring in ≥ 20% of patients in any treatment group) were neutropenia, alopecia, nausea, and anemia.
A total of 91 patients (16%) died, including 58/369 patients (16%) in RITUXAN HYCELA and 33/203 patients (16%) in rituximab. Of these patients, 44 patients (29 patients RITUXAN HYCELA [8%] vs. 15 patients rituximab [7%]) died due to adverse reactions and 35 patients (22 patients RITUXAN HYCELA [6%] vs. 13 patients rituximab [6%]) died due to disease progression. Pneumonia (4 patients RITUXAN HYCELA vs. 1 patient rituximab), septic shock (2 patients RITUXAN HYCELA vs. 3 patients rituximab), and cardiac arrest (1 patient RITUXAN HYCELA vs. 3 patients rituximab) were the most common adverse reactions leading to death.
The incidence of administration-related reactions was balanced between the RITUXAN HYCELA and rituximab groups (28% vs. 29%). Grade 1–2 ARRs constituted 97% of the overall ARRs for the RITUXAN HYCELA arm and 80% for the rituximab arm. Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 17 patients. These events resolved within a median of 2 days from the onset (range 1 to 32 days). Majority of these reactions were Grade 1 and 2 and were observed in 16 patients (4%).
| Body System/Adverse Reactions | RITUXAN HYCELA + CHOP(n=369) | Rituximab + CHOP(n=203) | ||
|---|---|---|---|---|
| All Grades% | Grade 3–4% | All Grades% | Grade 3–4% | |
| Gastrointestinal Disorders | ||||
| Nausea | 22 | < 1 | 24 | < 1 |
| Constipation | 15 | < 1 | 17 | < 1 |
| Diarrhea | 14 | 1 | 10 | 1 |
| Vomiting | 11 | < 1 | 8 | < 1 |
| Abdominal Pain | 7 | < 1 | 7 | < 1 |
| Stomatitis | 6 | < 1 | 5 | 0 |
| Dyspepsia | 5 | 0 | 7 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 19 | 1 | 15 | 1 |
| Pyrexia | 13 | < 1 | 13 | 0 |
| Asthenia | 11 | < 1 | 12 | < 1 |
| Mucosal Inflammation | 8 | < 1 | 8 | 1 |
| Edema Peripheral | 8 | < 1 | 4 | 0 |
| Infections | ||||
| Pneumonia | 7 | 3 | 4 | 2 |
| Blood and Lymphatic System Disorders | ||||
| Neutropenia | 31 | 25 | 29 | 19 |
| Anemia | 23 | 5 | 21 | 4 |
| Febrile Neutropenia | 14 | 14 | 12 | 11 |
| Leukopenia | 7 | 3 | 7 | 3 |
| Lymphopenia | 5 | 1 | 6 | 3 |
| Investigations | ||||
| Neutrophil Count Decreased | 14 | 11 | 14 | 11 |
| White Blood Cell Count Decreased | 7 | 4 | 7 | 5 |
| Weight Decreased | 8 | < 1 | 4 | < 1 |
| Lymphocyte Count Decreased | 5 | 2 | 3 | 2 |
| Metabolism and Nutrition Disorders | ||||
| Decreased Appetite | 8 | < 1 | 9 | < 1 |
| Nervous System Disorders | ||||
| Neuropathy Peripheral | 12 | < 1 | 12 | 0 |
| Paresthesia | 9 | < 1 | 6 | 0 |
| Headache | 6 | 0 | 7 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Alopecia | 24 | 0 | 24 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 11 | < 1 | 9 | 0 |
| Dyspnea | 6 | 0 | 4 | < 1 |
| Psychiatric Disorders | ||||
| Insomnia | 7 | < 1 | 6 | < 1 |
Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia
The data in Table 3 were obtained in part 2 of the SAWYER study, a two-part, comparative, randomized, parallel-group, multicenter study of RITUXAN HYCELA versus a rituximab product by intravenous infusion both in combination with fludarabine and cyclophosphamide (FC) chemotherapy in patients with previously untreated CLL.
The safety analysis population in part 2 of the study included 85 patients receiving RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) and 89 patients receiving 500 mg/m2 rituximab. In both RITUXAN HYCELA and rituximab groups, patients had similar median duration of rituximab exposure (4.9 vs. 4.7 months). The majority of patients received all 6 cycles of study treatment (86% RITUXAN HYCELA vs. 81% rituximab).
The patient population was predominantly White (96%) and male (65%), with a median age of 60 years and median BSA of 1.9 m2 (1.97 and 1.86 m2 for the RITUXAN HYCELA and intravenous rituximab groups, respectively). Overall, the treatment groups were balanced with respect to demographic characteristics, with the exception of more males in the RITUXAN HYCELA arm (71% RITUXAN HYCELA vs. 60% rituximab). Baseline disease characteristics were similar between the two groups. Over half of the patients (62%) had Binet Stage B disease and the majority had typical CLL characterizations (93%), with median time from first CLL diagnosis to randomization being 18.5 months.
The incidences of adverse reactions were balanced between the two treatment groups (96% RITUXAN HYCELA vs. 91% rituximab), and the common adverse reactions (occurring in ≥ 20% of patients in any arm) were infections, neutropenia, nausea, thrombocytopenia, pyrexia, anemia, vomiting, and injection site erythema. The incidences of Grade 3–4 adverse reactions were also balanced between the two treatment groups (69% RITUXAN HYCELA vs. 71% rituximab). The incidence of serious adverse reactions was 29% for RITUXAN HYCELA and 33% for rituximab. The incidence of administration-related reactions was 44% for RITUXAN HYCELA and 45% for rituximab). Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 15 patients. These events resolved within a median of 6 days from the onset (range 3 to 29 days). Majority of these reactions were Grade 1 and 2 and were observed in 14 patients (16%).
A total of 9 patients (5%) died, including 5 patients in the RITUXAN HYCELA group and 4 patients in the rituximab group. In the RITUXAN HYCELA group, 1 patient died due to herpes zoster infection, 1 patient died as a result of progressive multifocal leukoencephalopathy (PML) (considered by the investigator as related to rituximab), and 3 patients died due to disease progression. In the rituximab group, 2 patients died due to diarrhea and listeriosis and 2 patients died due to disease progression.
| Body System/Adverse Reactions | RITUXAN HYCELA + FC(n=85) | Rituximab + FC(n=89) | ||
|---|---|---|---|---|
| All Grades% | Grade 3–4% | All Grades% | Grade 3–4% | |
| Gastrointestinal Disorders | ||||
| Nausea | 38 | 1 | 35 | 0 |
| Vomiting | 21 | 2 | 22 | 1 |
| Diarrhea | 12 | 0 | 11 | 3 |
| Abdominal Pain | 9 | 0 | 6 | 0 |
| Constipation | 8 | 0 | 8 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Pyrexia | 32 | 5 | 25 | 1 |
| Injection Site Erythema | 26 | 2 | 0 | 0 |
| Injection Site Pain | 16 | 1 | 0 | 0 |
| Chills | 13 | 0 | 10 | 1 |
| Fatigue | 11 | 0 | 10 | 0 |
| Asthenia | 8 | 1 | 17 | 2 |
| Infections | ||||
| Upper Respiratory Tract Infection | 13 | 0 | 12 | 1 |
| Respiratory Tract Infection | 8 | 1 | 4 | 1 |
| Bronchitis | 7 | 0 | 6 | 0 |
| Urinary Tract Infection | 2 | 0 | 8 | 1 |
| Pneumonia | 2 | 2 | 6 | 2 |
| Blood and Lymphatic System Disorders | ||||
| Neutropenia | 65 | 56 | 58 | 52 |
| Thrombocytopenia | 24 | 6 | 26 | 9 |
| Leukopenia | 19 | 14 | 16 | 12 |
| Anemia | 13 | 5 | 24 | 9 |
| Febrile Neutropenia | 11 | 8 | 8 | 8 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgia | 9 | 0 | 1 | 0 |
| Pain In Extremity | 7 | 1 | 2 | 0 |
| Bone Pain | 6 | 0 | 2 | 0 |
| Nervous System Disorders | ||||
| Headache | 7 | 0 | 9 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Erythema | 15 | 0 | 7 | 0 |
| Rash | 12 | 0 | 10 | 1 |
| Pruritus | 8 | 0 | 4 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 13 | 0 | 11 | 0 |
| Oropharyngeal Pain | 6 | 0 | 3 | 0 |
| Dyspnea | 4 | 0 | 8 | 1 |
| Psychiatric Disorders | ||||
| Insomnia | 1 | 0 | 7 | 0 |
| Vascular Disorders | ||||
| Hypotension | 1 | 0 | 7 | 1 |
| Hypertension | 0 | 0 | 6 | 1 |
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