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 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of rituximab administered as a single agent [see Clinical Studies (14.1)]. Most patients received rituximab 375 mg/m2 weekly for 4 doses.

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. less than 1%). Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity.

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 RUXIENCE 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), Dosage and Administration (2.5)].

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 (14.7)]. 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 3 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.

Infusion-Related Reactions
Infusion-related reactions in GPA/MPA Study 1 were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with rituximab, 12% experienced at least one infusion-related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the rituximab group, the proportion of patients experiencing an infusion-related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each rituximab infusion and were on background oral corticosteroids which may have mitigated or masked an infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion-related reactions.

Infections
In GPA/MPA Study 1, 62% (61/99) of patients in the rituximab group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster.

The incidence of serious infections was 11% in the rituximab-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.

Hypogammaglobulinemia
Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with rituximab in GPA/MPA Study 1. At 6 months, in the rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50%, and 46% in the cyclophosphamide group.

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 (14.7)], 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 and GPA and MPA.

Infusion-Related Reactions
In GPA/MPA Study 2, 7/57 (12%) patients in the non-U.S.-licensed rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (less than 4%). One patient had two serious IRRs, two IRRs led to a dose modification, and no IRRs were severe, fatal, or led to withdrawal from the study.

Infections
In GPA/MPA Study 2, 30/57 (53%) patients in the non-U.S.-licensed rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis.

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 and GPA and MPA.

Pemphigus Vulgaris (PV)

PV Study 1
PV Study 1 (NCT00784589), a randomized, controlled, multicenter open-label study, evaluated the efficacy and safety of non-U.S.-licensed rituximab in combination with short-term prednisone compared to prednisone monotherapy in 90 patients (74 Pemphigus Vulgaris [PV] patients and 16 Pemphigus Foliaceus [PF] patients) [see Clinical Studies (14.8)]. Safety results for the PV patient population during the 24-month treatment period are described below.

The safety profile of the non-U.S.-licensed rituximab in patients with PV was consistent with that observed in patients with rituximab-treated RA and GPA and MPA [see Adverse Reactions (6.1)].

Adverse reactions from PV Study 1 are presented below in Table 4 and were adverse events which occurred at a rate greater than or equal to 5% among PV patients treated with non-U.S.-licensed rituximab and with at least 2% absolute difference in incidence between the group treated with non-U.S.-licensed rituximab and the prednisone monotherapy group up to Month 24. No patients in the group treated with non-U.S.-licensed rituximab withdrew due to adverse reactions. The clinical study did not include sufficient number of patients to allow for direct comparison of adverse reaction rates between treatment groups.

Infusion-Related Reactions
Infusion-related reactions were the most commonly reported adverse drug reactions (58%, 22 patients). All infusion-related reactions were mild to moderate (Grade 1 or 2) except one Grade 3 serious infusion-related reaction (arthralgia) associated with the Month 12 maintenance infusion. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA and MPA patients [see Adverse Reactions (6.1)].

Infections
Fourteen patients (37%) in the group treated with non-U.S.-licensed rituximab experienced treatment-related infections compared to 15 patients (42%) in the prednisone group. The most common infections in the group treated with non-U.S.-licensed rituximab were herpes simplex, herpes zoster, bronchitis, urinary tract infection, fungal infection, and conjunctivitis. Three patients (8%) in the group treated with non-U.S.-licensed rituximab experienced a total of 5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and 1 patient (3%) in the prednisone group experienced 1 serious infection (Pneumocystis jirovecii pneumonia).

PV Study 2
In PV Study 2 (NCT02383589), a randomized, double-blind, double-dummy, active-comparator, multicenter study evaluating the efficacy and safety of rituximab compared to mycophenolate mofetil (MMF) in patients with moderate to severe PV requiring oral corticosteroids, 67 PV patients received treatment with rituximab (initial 1,000 mg IV on Study Day 1 and a second 1,000 mg IV on Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks [see Clinical Studies (14.8)].

In PV Study 2, ADR defined as adverse events occurring in greater than or equal to 5% of patients in the rituximab arms and assessed as related are shown in Table 5.

Infusion-Related Reactions
In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 17.9%, 4.7%, 3.5%, and 3.5% of patients experienced IRRs at the first, second, third, and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1 or 2. In 4/15 patients, Grade greater than or equal to 3 IRRs were reported and led to discontinuation of rituximab treatment; three of the four patients experienced serious [life-threatening] IRRs. Serious IRRs occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.

Infections
In PV Study 2, 42/67 patients (62.7%) in the rituximab arm experienced infections. The most common infections in the rituximab arm were upper respiratory tract infection, nasopharyngitis, oral candidiasis, and urinary tract infection. Six patients (9%) in the rituximab arm experienced serious infections.

Laboratory Abnormalities
In PV Study 2, in the rituximab arm, transient decreases in T-cell lymphocytes and phosphorus level were very commonly observed post-infusion. In some cases, treatment of hypophosphatemia was required.

Hypogammaglobulinemia (IgG or IgM below the lower limit of normal), including prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months) was observed in PV Study 2. Based on levels less than LLN measured at Week 16, Week 24, Week 40, and Week 52, 16.4% (11/67) of patients with normal baseline immunoglobulins had prolonged hypogammaglobulinemia (10 patients – IgM, 1 patient – both IgG and IgM) after treatment with rituximab.