Generic Name: rituximab
Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
Infusion Reactions
Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions, (6.1)].
Tumor Lysis Syndrome (TLS)
Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non Hodgkin’s lymphoma (NHL) with Rituxan monotherapy [see Warnings and Precautions (5.2), Adverse Reactions (6)].
Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions (5.3), Adverse Reactions (6)].
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions (5.4), Adverse Reactions (6)].
Indications and Usage for Rituxan
Non‑Hodgkin’s Lymphoma (NHL)
Rituxan® (rituximab) is indicated for the treatment of patients with:
- Relapsed or refractory, low‑grade or follicular, CD20‑positive, B‑cell NHL as a single agent
- Previously untreated follicular, CD20‑positive, B‑cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy.
- Non‑progressing (including stable disease), low‑grade, CD20‑positive, B‑cell NHL as a single agent after first‑line CVP chemotherapy
- Previously untreated diffuse large B‑cell, CD20‑positive NHL in combination with CHOP or other anthracycline‑based chemotherapy regimens
Chronic Lymphocytic Leukemia (CLL)
Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.
Rheumatoid Arthritis (RA)
Rituxan® (rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately‑to severely‑ active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)
Rituxan® (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA).
Limitations of Use
Rituxan is not recommended for use in patients with severe, active infections.
Rituxan Dosage and Administration
Administration
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Premedicate before each infusion [see Dosage and Administration (2.7)]. Administer only as an intravenous (IV) infusion [see Dosage and Administration (2.7)].
- First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
- Subsequent Infusions: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30‑minute intervals, to a maximum of 400 mg/hr.
- Interrupt the infusion or slow the infusion rate for infusion reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one half the previous rate upon improvement of symptoms.
Recommended Dose for Non‑Hodgkin’s Lymphoma (NHL)
The recommended dose is 375 mg/m2 as an intravenous infusion according to the following schedules:
- Relapsed or Refractory, Low‑Grade or Follicular, CD20‑Positive, B‑Cell NHL
Administer once weekly for 4 or 8 doses. - Retreatment for Relapsed or Refractory, Low‑Grade or Follicular, CD20‑Positive, B‑Cell NHL
Administer once weekly for 4 doses. - Previously Untreated, Follicular, CD20‑Positive, B‑Cell NHL
Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance eight weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses. - Non‑progressing, Low‑Grade, CD20‑Positive, B‑cell NHL, after first‑line CVP chemotherapy
Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6‑month intervals to a maximum of 16 doses. - Diffuse Large B‑Cell NHL
Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.
Recommended Dose for Chronic Lymphocytic Leukemia (CLL)
The recommended dose is:
- 375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2-6 (every 28 days).
Recommended Dose as a Component of Zevalin®
- Infuse rituximab 250 mg/m2 within 4 hours prior to the administration of Indium‑111‑(In‑111‑) Zevalin and within 4 hours prior to the administration of Yttrium‑90‑ (Y‑90‑) Zevalin.
- Administer Rituxan and In‑111‑Zevalin 7–9 days prior to Rituxan and Y‑90‑ Zevalin.
- Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
Recommended Dose for Rheumatoid Arthritis (RA)
- Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks.
- Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions.
- Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
- Rituxan is given in combination with methotrexate.
Recommended Dose for Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)
- Administer Rituxan as a 375 mg/m2 intravenous infusion once weekly for 4 weeks.
- Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituxan and may continue during and after the 4 week course of Rituximab treatment.
- Safety and efficacy of treatment with subsequent courses of Rituxan have not been established [see Warnings and Precautions (5.14)].
Recommended Concomitant Medications
Premedicate before each infusion with acetaminophen and an antihistamine.
For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.
For WG and MPA patients, glucocorticoids are given in combination with Rituxan [see Dosage and Administration (2.6)].
Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate.
PCP prophylaxis is also recommended for patients with WG and MPA during treatment and for at least 6 months following the last Rituxan infusion
Preparation for Administration
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.
Dosage Forms and Strengths
100 mg/10 mL single‑use vial
500 mg/50 mL single‑use vial
Contraindications
None.
Warnings and Precautions
Infusion Reactions
Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan‑induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.
Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre‑existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells ( ≥ 25,000/mm3). [See Boxed Warning, Warnings and Precautions (5.7), Adverse Reactions (6.1).]
Tumor Lysis Syndrome (TLS)
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients with NHL. A high number of circulating malignant cells ( ≥ 25,000/mm3) or high tumor burden, confers a greater risk of TLS.
Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning, Warnings and Precautions (5.8).]
Severe Mucocutaneous Reactions
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens‑Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions (6, 6.1).]
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in Rituxan‑treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan.
Consider the diagnosis of PML in any patient presenting with new‑onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions (6).]
Hepatitis B Virus (HBV) Reactivation
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients treated with Rituxan. The median time to the diagnosis of hepatitis among patients with hematologic malignancies was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose.
Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions (6.5).]
Infections
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and up to one year following the completion of Rituxan-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. [See Adverse Reactions (6, 6.1).]
Cardiovascular
Discontinue infusions for serious or life‑threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions (6).]
Renal
Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria. [See Warnings and Precautions (5.2).]
Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain. [See Adverse Reactions (6).]
Immunization
The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended.
For RA patients, physicians should follow current immunization guidelines and administer non‑live vaccines at least 4 weeks prior to a course of Rituxan.
The effect of Rituxan on immune responses was assessed in a randomized, controlled study in patients with RA treated with Rituxan and methotrexate (MTX) compared to patients treated with MTX alone.
A response to pneumococcal vaccination (a T‑cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with Rituxan plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the Rituxan plus MTX group developed detectable levels of anti‑keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs. 93%).
A positive response to tetanus toxoid vaccine (a T‑cell dependent antigen with existing immunity) was similar in patients treated with Rituxan plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on Rituxan plus MTX vs. 70% of patients on MTX alone).
Most patients in the Rituxan‑treated group had B‑cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known.
Laboratory Monitoring
In patients with lymphoid malignancies, during treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias [see Adverse Reactions (6.1)]. In patients with RA, WG or MPA, obtain CBC and platelet counts at two to four month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period.
Concomitant Use with Biologic Agents and DMARDS other than Methotrexate in RA, WG and MPA
Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in RA patients exhibiting peripheral B‑cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in WG or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituxan.
Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists
While the efficacy of Rituxan was supported in four controlled trials in patients with RA with prior inadequate responses to non‑biologic DMARDs, and in a controlled trial in MTX‑naïve patients, a favorable risk‑benefit relationship has not been established in these populations. The use of Rituxan in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended [see Clinical Studies (14.5)].
5.14 Retreatment in Patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)
Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with WG and MPA. The safety and efficacy of retreatment with Rituxan have not been established [see Dosage and Administration (2.6), Adverse Reactions (6.3), and Clinical Studies (14.6)].
Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Infusion reactions [see Warnings and Precautions (5.1)]
- Tumor lysis syndrome [see Warnings and Precautions (5.2)]
- Mucocutaneous reactions [see Warnings and Precautions (5.3)]
- Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.4)]
- Hepatitis B reactivation with fulminant hepatitis [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)]
The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia.
The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia.
Clinical Trials Experience in Lymphoid Malignancies
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 practice.
The data described below reflect exposure to Rituxan in 2783 patients, with exposures ranging from a single infusion up to 2 years. Rituxan was studied in both single-arm and controlled trials (n = 356 and n = 2427=1926). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy.
Infusion Reactions
In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions (5.1).]
Infections
Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single‑arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions (5.4), (5.5), (5.6).]
In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low‑grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B‑cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan.
Cytopenias and hypogammaglobulinemia
In patients with NHL receiving rituximab monotherapy, NCI‑CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single‑arm studies.
In studies of monotherapy, Rituxan‑induced B‑cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients.
Relapsed or Refractory, Low-Grade NHL
Adverse reactions 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 Rituxan administered as a single agent [see Clinical Studies (14.1)]. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.
| All Grades (%) | Grade 3 and 4 (%) | |
| a Adverse reactions observed up to 12 months following Rituxan. b Adverse reactions graded for severity by NCI‑CTC criteria. | ||
| Any Adverse Reactions | 99 | 57 |
| Body as a Whole | 86 | 10 |
| Fever | 53 | 1 |
| Chills | 33 | 3 |
| Infection | 31 | 4 |
| Asthenia | 26 | 1 |
| Headache | 19 | 1 |
| Abdominal Pain | 14 | 1 |
| Pain | 12 | 1 |
| Back Pain | 10 | 1 |
| Throat Irritation | 9 | 0 |
| Flushing | 5 | 0 |
| Heme and Lymphatic System | 67 | 48 |
| Lymphopenia | 48 | 40 |
| Leukopenia | 14 | 4 |
| Neutropenia | 14 | 6 |
| Thrombocytopenia | 12 | 2 |
| Anemia | 8 | 3 |
| Skin and Appendages | 44 | 2 |
| Night Sweats | 15 | 1 |
| Rash | 15 | 1 |
| Pruritus | 14 | 1 |
| Urticaria | 8 | 1 |
| Respiratory System | 38 | 4 |
| Increased Cough | 13 | 1 |
| Rhinitis | 12 | 1 |
| Bronchospasm | 8 | 1 |
| Dyspnea | 7 | 1 |
| Sinusitis | 6 | 0 |
| Metabolic and Nutritional Disorders | 38 | 3 |
| Angioedema | 11 | 1 |
| Hyperglycemia | 9 | 1 |
| Peripheral Edema | 8 | 0 |
| LDH Increase | 7 | 0 |
| Digestive System | 37 | 2 |
| Nausea | 23 | 1 |
| Diarrhea | 10 | 1 |
| Vomiting | 10 | 1 |
| Nervous System | 32 | 1 |
| Dizziness | 10 | 1 |
| Anxiety | 5 | 1 |
| Musculoskeletal System | 26 | 3 |
| Myalgia | 10 | 1 |
| Arthralgia | 10 | 1 |
| Cardiovascular System | 25 | 3 |
| Hypotension | 10 | 1 |
| Hypertension | 6 | 1 |
In these single‑arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion.
Previously Untreated, Low-Grade or Follicular, NHL
In 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%). [See Clinical Studies (14.2).]
In Study 5, detailed safety data collection was limited to serious adverse reactions, Grade ≥ 2 infections, and Grade ≥ 3 adverse reactions. In patients receiving Rituxan as single-agent maintenance therapy following Rituxan 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 Rituxan group were infections (4% vs. 1%) and neutropenia (4% vs. <1%).
In Study 6, the following adverse reactions were reported more frequently ( ≥ 5%) in patients receiving Rituxan 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 Rituxan arm compared with those who received no further therapy (4% vs. 1%). [See Clinical Studies (14.3).]
DLBCL
In Studies 7 and 8, [see Clinical Studies (14.3)], 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 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 (Study 8), neutropenia (Studies 8 and 9), and anemia (Study 9).
CLL
The data below reflect exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 10 or Study 11 [see Clinical Studies (14.4)]. The age range was 30-83 years and 71% were men. Detailed safety data collection in Study 10 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 Study 10, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion 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 Study 11, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion 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 reaction of any severity.
Clinical Trials Experience in Rheumatoid Arthritis
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice.
The data presented below reflect the experience in 2578 RA patients treated with Rituxan in controlled and long‑term studies with a total exposure of 5014 patient‑years.
Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis.
In placebo‑controlled studies, patients received 2 x 500 mg or 2 x 1000 mg intravenous infusions of Rituxan or placebo, in combination with methotrexate, during a 24‑week period. From these studies, 938 patients treated with Rituxan (2 x 1000 mg) or placebo have been pooled (see Table 2). Adverse reactions reported in ≥ 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus (see Table 2). The rates and types of adverse reactions in patients who received Rituxan 2 x 500 mg were similar to those observed in patients who received Rituxan 2 x 1000 mg.
| Preferred Term | Placebo + MTX N = 398 n (%) | Rituxan + MTX N = 540 n (%) |
| *These data are based on 938 patients treated in Phase 2 and 3 studies of Rituxan (2 × 1000 mg) or placebo administered in combination with methotrexate. | ||
| **Coded using MedDRA. | ||
| Hypertension | 21 (5) | 43 (8) |
| Nausea | 19 (5) | 41 (8) |
| Upper Respiratory Tract Infection | 23 (6) | 37 (7) |
| Arthralgia | 14 (4) | 31 (6) |
| Pyrexia | 8 (2) | 27 (5) |
| Pruritus | 5 (1) | 26 (5) |
| Chills | 9 (2) | 16 (3) |
| Dyspepsia | 3 (<1) | 16 (3) |
| Rhinitis | 6 (2) | 14 (3) |
| Paresthesia | 3 (<1) | 12 (2) |
| Urticaria | 3 (<1) | 12 (2) |
| Abdominal Pain Upper | 4 (1) | 11 (2) |
| Throat Irritation | 0 (0) | 11 (2) |
| Anxiety | 5 (1) | 9 (2) |
| Migraine | 2 (<1) | 9 (2) |
| Asthenia | 1 (<1) | 9 (2) |
Infusion Reactions
In the Rituxan RA pooled placebo‑controlled studies, 32% of Rituxan‑treated patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo‑treated patients receiving their first infusion. The incidence of adverse reactions during the 24‑hour period following the second infusion, Rituxan or placebo, decreased to 11% and 13%, respectively. Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituxan‑treated patients following their first infusion, compared to 19% of placebo‑treated patients receiving their first placebo infusion. The incidence of these acute infusion reactions following the second infusion of Rituxan or placebo decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by < 1% of patients in either treatment group. Acute infusion reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively,
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