Riabni Dailymed

• Tumor lysis syndrome: Administer aggressive intravenous hydration, anti-hyperuricemic agents, monitor renal function (5.5).
• Infections: Withhold RIABNI and institute appropriate anti-infective therapy (5.6).
• Cardiac adverse reactions: Discontinue infusions in case of serious or life-threatening events (5.7).
• Renal toxicity: Discontinue in patients with rising serum creatinine or oliguria (5.8).
• Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, or related symptoms (5.9).
• Immunizations: Live virus vaccinations prior to or during RIABNI treatment is not recommended (5.10).
• Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception (5.11).

5.1Infusion-Related Reactions

Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituximab product-induced infusion-related 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, GPA and MPA 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-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RIABNI. 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 (greater than or equal to 25,000/mm³) [see Warnings and Precautions (5.7), Adverse Reactions (6.1)].

5.2Severe Mucocutaneous Reactions

Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue RIABNI in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined.

5.3Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RIABNI. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RIABNI treatment.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RIABNI therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.

In patients who develop reactivation of HBV while on RIABNI, immediately discontinue RIABNI and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RIABNI treatment in patients who develop HBV reactivation. Resumption of RIABNI treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

5.4Progressive Multifocal Leukoencephalopathy (PML)

JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab 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 rituximab.

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 RIABNI and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

5.5Tumor Lysis Syndrome (TLS)

Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12–24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells (greater than or equal to 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 Warnings and Precautions (5.8)].

5.6Infections

Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia greater than 11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RIABNI for serious infections and institute appropriate anti-infective therapy [see Adverse Reactions (6.1, 6.3)]. RIABNI is not recommended for use in patients with severe, active infections.

5.7Cardiovascular Adverse Reactions

Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RIABNI for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina [see Adverse Reactions (6.1)].

5.8Renal Toxicity

Severe, including fatal, renal toxicity can occur after rituximab product 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 RIABNI is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RIABNI in patients with a rising serum creatinine or oliguria [see Warnings and Precautions (5.5)].

5.9Bowel Obstruction and Perforation

Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

5.10Immunization

The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

For patients treated with RIABNI, physicians should review the patient's vaccination status and patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating RIABNI and administer non-live vaccines at least 4 weeks prior to a course of RIABNI.

The effect of rituximab on immune responses was assessed in a randomized, controlled study in patients with RA treated with rituximab 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 rituximab plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the rituximab 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 rituximab 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 rituximab plus MTX vs. 70% of patients on MTX alone).

Most patients in the rituximab-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.

5.11Embryo-Fetal Toxicity

Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving RIABNI and for 12 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.12Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA

Limited data are available on the safety of the use of biologic agents or disease modifying antirheumatic drugs (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 GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products.

5.13Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists

While the efficacy of rituximab 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 RIABNI in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended [see Clinical Studies (14.6)].

6 Adverse Reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Infusion-related reactions [see Warnings and Precautions (5.1)]
• Severe mucocutaneous reactions [see Warnings and Precautions (5.2)]
• Hepatitis B reactivation with fulminant hepatitis [see Warnings and Precautions (5.3)]
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.4)]
• Tumor lysis syndrome [see Warnings and Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Cardiovascular adverse reactions [see Warnings and Precautions (5.7)]
• Renal toxicity [see Warnings and Precautions (5.8)]
• Bowel obstruction and perforation [see Warnings and Precautions (5.9)]

Most common adverse reactions in clinical trials were:

• NHL (greater than or equal to 25%): infusion-related reactions, fever, lymphopenia, chills, infection and asthenia (6.1).
• CLL (greater than or equal to 25%): infusion-related reactions and neutropenia (6.1).
• RA (greater than or equal to 10%): upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events) (6.2).
• GPA and MPA (greater than or equal to 15%): infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions (6.2).

To report SUSPECTED ADVERSE REACTIONS, contact Amgen, Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

B-Cell Malignancies

The data described below reflect exposure to rituximab in 3,092 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n = 356 and n = 2,427). The population included 1,180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 patients with another indication. Most NHL patients received rituximab 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 rituximab 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 rituximab-based therapy.

The most common adverse reactions of rituximab (incidence greater than or equal to 25%) observed in clinical trials of patients with NHL were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia.

The most common adverse reactions of rituximab (incidence greater than or equal to 25%) observed in clinical trials of patients with CLL were: infusion-related reactions and neutropenia.

Infusion-Related Reactions

In the majority of patients with NHL, infusion-related reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first rituximab infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest during the first infusion (77%) and decreased with each subsequent infusion [see Warnings and Precautions (5.1)]. In adult patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of rituximab at Cycle 2, the incidence of Grade 3-4 infusion-related reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]) [see Warnings and Precautions (5.1), Clinical Studies (14.4)].

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 (5.6)].

In randomized, controlled studies where rituximab was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received rituximab. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received rituximab.

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 rituximab therapy occurred during the single-arm studies.

In studies of monotherapy, rituximab-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.

In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with rituximab in combination with fludarabine and cyclophosphamide (R-FC) compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 neutropenia starting at least 42 days after the last treatment dose.

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 2 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 [see Clinical Studies (14.1)]. Most patients received rituximab 375 mg/m² weekly for 4 doses.

Table 2. Incidence of Adverse Reactions in Greater Than or Equal to 5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituximab (N=356)Adverse reactions observed up to 12 months following rituximab ^, Adverse reactions graded for severity by NCI-CTC criteria

	All Grades (%)	Grade 3 and 4 (%)
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 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 (greater than or equal to 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 NHL Study 5, detailed safety data collection was limited to serious adverse reactions, Grade greater than or equal to 2 infections, and Grade greater than or equal to 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 (greater than or equal to 2%) in the rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. less than 1%).

In NHL Study 6, the following adverse reactions were reported more frequently (greater than or equal to 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 (greater than or equal to 2%) in the rituximab arm compared with those who received no further therapy (4% vs. 1%) [see Clinical Studies (14.3)].

DLBCL

In NHL Studies 7 (NCT00003150) and 8 [see Clinical Studies (14.3)], the following adverse reactions, regardless of severity, were reported more frequently (greater than or equal to 5%) in patients age greater than or equal to 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) [see Clinical Studies (14.5)]. 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.

Rheumatoid Arthritis

The data presented below reflect the experience in 2578 RA patients treated with rituximab in controlled and long-term studiesPooled studies: NCT00074438, NCT00422383, NCT00468546, NCT00299130, NCT00282308, NCT00266227, NCT02693210, NCT02093026 and NCT02097745. 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 × 500 mg or 2 × 1,000 mg intravenous infusions of rituximab or placebo, in combination with methotrexate, during a 24-week period. From these studies, 938 patients treated with rituximab (2 × 1,000 mg) or placebo have been pooled (see Table 3). Adverse reactions reported in greater than or equal to 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus (see Table 3). The rates and types of adverse reactions in patients who received rituximab 2 × 500 mg were similar to those observed in patients who received rituximab 2 × 1,000 mg.

Table 3These data are based on 938 patients treated in Phase 2 and 3 studies of rituximab (2 × 1,000 mg) or placebo administered in combination with methotrexate.. Incidence of All Adverse ReactionsCoded using MedDRA. Occurring in Greater Than or Equal to 2% and at Least 1% Greater than Placebo Among Rheumatoid Arthritis Patients in Clinical Studies Up to Week 24 (Pooled)

Adverse Reactions	Placebo + MTX N=398n (%)	Rituximab + MTX N=540n (%)
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-Related Reactions

In the rituximab RA pooled placebo-controlled studies, 32% of rituximab-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, rituximab or placebo, decreased to 11% and 13%, respectively. Acute infusion-related 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 rituximab-treated patients following their first infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. The incidence of these acute infusion-related reactions following the second infusion of rituximab or placebo decreased to 9% and 11%, respectively. Serious acute infusion-related reactions were experienced by less than 1% of patients in either treatment group. Acute infusion-related reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion-related reactions decreased with subsequent courses of rituximab. The administration of intravenous glucocorticoids prior to rituximab infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion-related reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to rituximab infusions.

Infections

In the pooled, placebo-controlled studies, 39% of patients in the rituximab group experienced an infection of any type compared to 34% of patients in the placebo group. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis.

The incidence of serious infections was 2% in the rituximab-treated patients and 1% in the placebo group.

In the experience with rituximab in 2,578 RA patients, the rate of serious infections was 4.31 per 100 patient years. The most common serious infections (greater than or equal to 0.5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis and colitis. Rates of serious infection remained stable in patients receiving subsequent courses. In 185 rituximab-treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. Thirteen serious infections were observed in 186.1 patient years (6.99 per 100 patient years) prior to exposure and 10 were observed in 182.3 patient years (5.49 per 100 patient years) after exposure.

Cardiovascular Adverse Reactions

In the pooled, placebo-controlled studies, the proportion of patients with serious cardiovascular reactions was 1.7% and 1.3% in the rituximab and placebo treatment groups, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all rituximab regimens (3/769 = 0.4%) as compared to none in the placebo treatment group (0/389).

In the experience with rituximab in 2,578 RA patients, the rate of serious cardiac reactions was 1.93 per 100 patient years. The rate of myocardial infarction (MI) was 0.56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population. These rates did not increase over three courses of rituximab.

Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and RIABNI should be discontinued in the event of a serious or life-threatening cardiac event.

Hypophosphatemia and Hyperuricemia

In the pooled, placebo-controlled studies, newly-occurring hypophosphatemia (less than 2.0 mg/dL) was observed in 12% (67/540) of patients on rituximab versus 10% (39/398) of patients on placebo. Hypophosphatemia was more common in patients who received corticosteroids. Newly-occurring hyperuricemia (greater than 10 mg/dL) was observed in 1.5% (8/540) of patients on rituximab versus 0.3% (1/398) of patients on placebo.

In the experience with rituximab in RA patients, newly-occurring hypophosphatemia was observed in 21% (528/2570) of patients and newly-occurring hyperuricemia was observed in 2% (56/2570) of patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient.

Retreatment in Patients with RA

In the experience with rituximab in RA patients, 2,578 patients have been exposed to rituximab and have received up to 10 courses of rituximab in RA clinical trials, with 1,890, 1,043, and 425 patients having received at least two, three, and four courses, respectively. Most of the patients who received additional courses did so 24 weeks or more after the previous course and none were retreated sooner than 16 weeks. The rates and types of adverse reactions reported for subsequent courses of rituximab were similar to rates and types seen for a single course of rituximab.

In RA Study 2, where all patients initially received rituximab, the safety profile of patients who were retreated with rituximab was similar to those who were retreated with placebo [see Clinical Studies (14.6), and Dosage and Administration (2.5)].

Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Induction Treatment of Adult Patients with Active GPA/MPA (GPA/MPA Study 1)

The data presented below from GPA/MPA Study 1 (NCT00104299) reflect the experience in 197 adult patients with active GPA and MPA treated with rituximab or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase [see Clinical Studies (14.6)]. In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either rituximab 375 mg/m² once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6-month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6-month remission induction period and the safety results for this period are described below.

Adverse reactions presented below in Table 4 were adverse events which occurred at a rate of greater than or equal to 10% in the rituximab group. This table reflects experience in 99 GPA and MPA patients treated with rituximab, with a total of 47.6 patient-years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation. Infection was the most common category of adverse events reported (47-62%) and is discussed below.

Table 4. Incidence of All Adverse Reactions Occurring in Greater Than or Equal to 10% of Rituximab-treated Patients with Active GPA and MPA in the GPA/MPA Study 1 Up to Month 6The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6 month study period.

Adverse Reaction	Rituximab N = 99n (%)	Cyclophosphamide N = 98n (%)
Nausea	18 (18%)	20 (20%)
Diarrhea	17 (17%)	12 (12%)
Headache	17 (17%)	19 (19%)
Muscle spasms	17 (17%)	15 (15%)
Anemia	16 (16%)	20 (20%)
Peripheral edema	16 (16%)	6 (6%)
Insomnia	14 (14%)	12 (12%)
Arthralgia	13 (13%)	9 (9%)
Cough	13 (13%)	11 (11%)
Fatigue	13 (13%)	21 (21%)
Increased ALT	13 (13%)	15 (15%)
Hypertension	12 (12%)	5 (5%)
Epistaxis	11 (11%)	6 (6%)
Dyspnea	10 (10%)	11 (11%)
Leukopenia	10 (10%)	26 (27%)
Rash	10 (10%)	17 (17%)

Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment (GPA/MPA Study 2)

In GPA/MPA Study 2 (NCT00748644), an open-label, controlled, clinical study [see Clinical Studies (14.6)], evaluating the efficacy and safety of non-U.S.-licensed rituximab versus azathioprine as follow up treatment in adult patients with GPA, MPA or renal-limited ANCA-associated vasculitis who had achieved disease control after induction treatment with cyclophosphamide, a total of 57 GPA and MPA patients in disease remission received follow up treatment with two 500 mg intravenous infusions of non-U.S.-licensed rituximab, separated by two weeks on Day 1 and Day 15, followed by a 500 mg intravenous infusion every 6 months for 18 months.

The safety profile was consistent with the safety profile for rituximab in RA, GPA and MPA.

Long-term, Observational Study with Rituximab in Patients with GPA/MPA (GPA/MPA Study 3)

In a long-term observational safety study (NCT01613599), 97 patients with GPA or MPA received treatment with rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to physician standard practice and discretion. Majority of patients received doses ranging from 500 mg to 1,000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for rituximab in RA, GPA and MPA.

6.2 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.

A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving rituximab. Anti-rituximab antibody positivity was not associated with increased rates of infusion-related reactions or other adverse events. Upon further treatment, the proportions of patients with infusion-related reactions were similar between anti-rituximab antibody positive and negative patients, and most reactions were mild to moderate. Four anti-rituximab antibody positive patients had serious infusion-related reactions, and the temporal relationship between anti-rituximab antibody positivity and infusion-related reaction was variable.

A total of 23/99 (23%) rituximab-treated adult patients with GPA and MPA developed anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximab-treated adult patients is unclear.

6.3 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 [see Warnings and Precautions (5.6)].
• 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 [see Warnings and Precautions (5.6)].
• 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).