Riabni

Description for Riabni

Rituximab-arrx is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab-arrx has an approximate molecular weight of 145 kD. Rituximab-arrx is produced in a mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium.

RIABNI (rituximab-arrx) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous infusion. RIABNI is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-dose vials. Each mL of solution contains 10 mg rituximabarrx, polysorbate 80 (0.7 mg), sodium chloride (9 mg), sodium citrate dihydrate (7.35 mg), and Water for Injection, USP. Hydrochloric acid is used to adjust the buffer solution pH. The pH is 6.5.

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)]

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)^a,b

	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
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
Any Adverse Reactions	99		57
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
aAdverse reactions observed up to 12 months following rituximab bAdverse reactions graded for severity by NCI-CTC criteria

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 2,578 RA patients treated with rituximab in controlled and long-term studies¹ with a total exposure of 5,014 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 3*. Incidence of All Adverse Reactions** 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=398 n (%)	Rituximab + MTX N=540 n (%)
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)
*These 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. **Coded using MedDRA.

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 (14.7)]. 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 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 6*

Adverse Reaction	Rituximab N = 99 n (%)	Cyclophosphamide N = 98 n (%)
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%)
*The 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.

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, 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, 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 5 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.

Table 5. Incidence of All Adverse Reactions Occurring in 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 with Short-term Prednisone
and the Group Treated with Prednisone Monotherapy in PV Study 1 (Up to Month 24)

Adverse Reactions	Non-U.S.-licensed Rituximab + Short-term Prednisone N = 38 n (%)	Prednisone N = 36 n (%)
Infusion-related reactions*	22 (58%)	N/A
Depression	7 (18%)	4 (11%)
Herpes simplex	5 (13%)	1 (3%)
Alopecia	5 (13%)	0 (0%)
Fatigue	3 (8%)	2 (6%)
Abdominal pain upper	2 (5%)	1 (3%)
Conjunctivitis	2 (5%)	0 (0%)
Dizziness	2 (5%)	0 (0%)
Headache	2 (5%)	1 (3%)
Herpes zoster	2 (5%)	1 (3%)
Irritability	2 (5%)	0 (0%)
Musculoskeletal pain	2 (5%)	0 (0%)
Pruritus	2 (5%)	0 (0%)
Pyrexia	2 (5%)	0 (0%)
Skin disorder	2 (5%)	0 (0%)
Skin papilloma	2 (5%)	0 (0%)
Tachycardia	2 (5%)	0 (0%)
Urticaria	2 (5%)	0 (0%)
N/A = not applicable * Infusion-related reactions included symptoms collected on the next scheduled visit after each infusion, and adverse reactions occurring on the day of or one day after the infusion. The most common infusion-related reactions included headaches, chills, high blood pressure, nausea, asthenia, and pain.

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 6.

Table 6. Incidence of All Adverse Reactions occurring in greater than or equal to 5% of
Rituximab-treated Pemphigus Vulgaris Patients (N = 67) from PV Study 2 (up to Week 52)

Adverse Reactions	Rituximab (N = 67)
Infusion-related reactions	15 (22%)*
Upper respiratory tract infection/ Nasopharyngitis	11 (16%)
Headache	10 (15%)
Asthenia/Fatigue	9 (13%)
Oral candidiasis	6 (9%)
Arthralgia	6 (9%)
Back pain	6 (9%)
Urinary tract infection	5 (8%)
Dizziness	4 (6%)
* The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 in the rituximab arm were dyspnea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic

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.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of rituximab or of other rituximab products.

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.

Using a new ELISA assay, a total of 19/34 (56%) patients with PV, who were treated with non-U.S.-licensed rituximab, tested positive for anti-rituximab antibodies by 18 months in PV Study 1. In PV Study 2, a total of 20/63 (32%) rituximab-treated PV patients tested positive for ADA by week 52 (19 patients had treatment-inducted ADA and 1 patient had treatment-enhanced ADA). The clinical relevance of anti-rituximab antibody formation in rituximab-treated PV patients is unclear.

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).

Drug Interactions for Riabni

Formal drug interaction studies have not been performed with rituximab products. In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab.

Warnings for Riabni

Included as part of the PRECAUTIONS section.

Precautions for Riabni

Infusion-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, and PV 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)].

Severe 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.

Hepatitis 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.

Progressive 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.

Tumor 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)].

Infections

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.

Cardiovascular 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)].

Renal 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)].

Bowel 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.

Immunization

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.

Embryo-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)].

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

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 or PV patients exhibiting peripheral B-cell depletion following treatment with rituximab products.

Use 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)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab products or to determine potential effects on fertility in males or females.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Infusion-Related Reactions

Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions including urticaria, hypotension, angioedema, sudden cough, breathing problems, weakness, dizziness, palpitations, or chest pain [see Warnings and Precautions (5.1)].

Severe Mucocutaneous Reactions

Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules [see Warnings and Precautions (5.2)].

Hepatitis B Virus Reactivation

Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.3)].

Progressive Multifocal Leukoencephalopathy (PML)

Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems [see Warnings and Precautions (5.4)]

Tumor Lysis Syndrome (TLS)

Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.5)].

Infections

Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the increased risk of infections during and after treatment with RIABNI [see Warnings and Precautions (5.6)].

Cardiovascular Adverse Reactions

Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats [see Warnings and Precautions (5.7)].

Renal Toxicity

Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function [see Warnings and Precautions (5.8)].

Bowel Obstruction and Perforation

Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting [see Warnings and Precautions (5.9)].

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with RIABNI and for 12 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with RIABNI and for 6 months after the last dose [see Use in Specific Populations (8.2)].

Overdose Information for Riabni

No information provided

Contraindications for Riabni

No information provided

Clinical Pharmacology for Riabni

Mechanism of Action

Rituximab-arrx is a monoclonal antibody. Rituximab products target the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab products mediate B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production.

Pharmacodynamics

Non-Hodgkin’s Lymphoma (NHL)

In NHL patients, administration of rituximab resulted in depletion of circulating and tissue-based B cells. Among 166 patients in NHL Study 1 (NCT000168740), circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment.

There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range.

Rheumatoid Arthritis

In RA patients, treatment with rituximab induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/μL) within 2 weeks after receiving the first dose of rituximab. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment.

Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of rituximab treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with rituximab in RA patients during repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab are unclear.

Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis

In GPA and MPA patients in GPA/MPA Study 1, peripheral blood CD19 B-cells depleted to less than 10 cells/μL following the first two infusions of rituximab, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts greater than 10 cells/μL. By Month 18, most patients (87%) had counts greater than 10 cells/μL.

In GPA/MPA Study 2 where patients received non-U.S.-licensed rituximab as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion at Month 6, 12, and 18, 70% (30 out of 43) of the rituximab-treated patients with CD19+ peripheral B cells evaluated post-baseline had undetectable CD19+ peripheral B cells at Month 24. At Month 24, all 37 patients with evaluable baseline CD19+ peripheral B cells and Month 24 measurements had lower CD19+ B cells relative to baseline.

Pharmacokinetics

Non-Hodgkin’s Lymphoma (NHL)

Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m² rituximab weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab.

Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days).

Rheumatoid Arthritis

Following administration of 2 doses of rituximab in patients with RA, the mean (± S.D.; % CV) concentrations after the first infusion (C_max first) and second infusion (C_max second) were 157 (± 46; 29%) and 183 (± 55; 30%) mcg/mL, and 318 (± 86; 27%) and 381 (± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1,000 mg doses, respectively.

Based on a population pharmacokinetic analysis of data from 2,005 RA patients who received rituximab, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis

The pharmacokinetic parameters in adult patients with GPA/MPA receiving 375 mg/m² intravenous rituximab or non-U.S.-licensed rituximab once weekly for four doses are summarized in Table 7.

Table 7. Population PK in Adult Patients with GPA/MPA

Parameter	Statistic	GPA/MPA Study 1
N	Number of Patients	97
Terminal Half-life (days)	Median (Range)	25 (11 to 52)
AUC0-180d (μg/mL*day)	Median (Range)	10,302 (3,653 to 21,874)
Clearance (L/day)	Median (Range)	0.279 (0.113 to 0.653)
Volume of Distribution (L)	Median (Range)	3.12 (2.42 to 3.91)

The population PK analysis in adults with GPA and MPA showed that male patients and patients with higher BSA or positive anti-rituximab antibody levels have higher clearance. However, further dose adjustment based on gender or anti-drug antibody status is not necessary.

Pemphigus Vulgaris

The PK parameters in adult PV patients receiving 1,000 mg IV infusion of rituximab at Days 1, 15, 168, and 182 are summarized in Table 8.

Table 8. Population PK in adult PV patients from PV Study 2

Parameter	Infusion Cycle
	1st cycle of 1,000 mg Day 1 and Day 15 N = 67	2nd cycle of 1,000 mg Day 168 and Day 182 N = 67
Terminal Half-life (days) Median (Range)	21.1 (9.3 to 36.2)	26.2 (16.4 to 42.8)
Clearance (L/day) Median (Range)	0.30 (0.16 to 1.51)	0.24 (0.13 to 0.45)
Central Volume of Distribution (L) Median (Range)	3.49 (2.48 to 5.22)	3.49 (2.48 to 5.22)

Following the first cycle of rituximab administration, the PK parameters of rituximab in patients with PV were similar to those in patients with RA and in patients with GPA/MPA. Following the 2nd cycle of rituximab administration, rituximab clearance decreased by 22% assuming Pemphigus Disease Area Index (PDAI) activity score of 0 at the start of both cycles, while the central volume of distribution remained unchanged. The presence of anti-rituximab antibodies was associated with a higher clearance resulting in lower rituximab concentrations.

Specific Populations

The clearance and volume of distribution of rituximab increased with increasing body surface area (BSA).

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab products.

Drug Interaction Studies

Formal drug interaction studies have not been performed with rituximab products.

MEDICATION GUIDE RIABNI (re AB nee) (rituximab-arrx) injection

What is the most important information I should know about RIABNI? RIABNI can cause serious side effects that can lead to death, including: Infusion-related reactions. Infusion-related reactions are very common side effects of RIABNI treatment. Serious infusion-related reactions can happen during your infusion or within 24 hours after your infusion of RIABNI. Your healthcare provider should give you medicines before your infusion of RIABNI to decrease your chance of having a severe infusion-related reaction. Tell your healthcare provider or get medical help right away if you get any of these symptoms during or after an infusion of RIABNI: hives (red itchy welts) or rash shortness of breath, difficulty breathing, or wheezing itching weakness swelling of your lips, tongue, throat or face dizziness or feel faint palpitations (feel like your heart is racing or fluttering) sudden cough chest pain Severe skin and mouth reactions. Tell your healthcare provider or get medical help right away if you get any of these symptoms at any time during your treatment with RIABNI: painful sores or ulcers on your skin, lips or in your mouth blisters peeling skin rash pustules Hepatitis B virus (HBV) reactivation. Before you receive your RIABNI treatment, your healthcare provider will do blood tests to check for HBV infection. If you have had hepatitis B or are a carrier of hepatitis B virus, receiving RIABNI could cause the virus to become an active infection again. Hepatitis B reactivation may cause serious liver problems including liver failure, and death. You should not receive RIABNI if you have active hepatitis B liver disease. Your healthcare provider will monitor you for hepatitis B infection during and for several months after you stop receiving RIABNI. Tell your healthcare provider right away if you get worsening tiredness, or yellowing of your skin or white part of your eyes, during treatment with RIABNI. Progressive Multifocal Leukoencephalopathy (PML). PML is a rare, serious brain infection caused by a virus that can happen in people who receive RIABNI. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML. Tell your healthcare provider right away if you have any new or worsening symptoms or if anyone close to you notices these symptoms: confusion decreased strength or weakness on one side of your body dizziness or loss of balance difficulty walking or talking vision problems See "What are the possible side effects of RIABNI?" for more information about side effects.

What is RIABNI? RIABNI is a prescription medicine used to treat: Adults with Non-Hodgkin's Lymphoma (NHL): alone or with other chemotherapy medicines. Adults with Chronic Lymphocytic Leukemia (CLL): with the chemotherapy medicines fludarabine and cyclophosphamide. Adults with Rheumatoid Arthritis (RA): with another prescription medicine called methotrexate, to reduce the signs and symptoms of moderate to severe active RA in adults, after treatment with at least one other medicine called a Tumor Necrosis Factor (TNF) antagonist has been used and did not work well. Adults with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA): with glucocorticoids, to treat GPA and MPA. Adults with Pemphigus Vulgaris (PV): to treat moderate to severe PV. RIABNI is not indicated for treatment of children.

Before you receive RIABNI, tell your healthcare provider about all of your medical conditions, including if you: have had a severe reaction to RIABNI or another rituximab product. have a history of heart problems, irregular heart beat or chest pain. have lung or kidney problems. have an infection or weakened immune system. have or have had any severe infections including: Hepatitis B virus (HBV) Parvovirus B19 Hepatitis C virus (HCV) Varicella zoster virus (chickenpox or shingles) Cytomegalovirus (CMV) West Nile Virus Herpes simplex virus (HSV) have had a recent vaccination or are scheduled to receive vaccinations. You should not receive certain vaccines before or during treatment with RIABNI. are pregnant or plan to become pregnant. Talk to your healthcare provider about the risks to your unborn baby if you receive RIABNI during pregnancy. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test to see if you are pregnant before starting RIABNI. You should use effective birth control (contraception) during treatment with RIABNI and for 12 months after your last dose of RIABNI. Talk to your healthcare provider about effective birth control. Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with RIABNI. are breastfeeding or plan to breastfeed. RIABNI may pass into your breast milk. Do not breastfeed during treatment and for 6 months after your last dose of RIABNI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take or have taken: a Tumor Necrosis Factor (TNF) inhibitor medicine. a Disease Modifying Anti-Rheumatic Drug (DMARD). If you are not sure if your medicine is one listed above, ask your healthcare provider.

How will I receive RIABNI? RIABNI is given by infusion through your central catheter or through a needle placed in a vein (intravenous infusion), in your arm. Talk to your healthcare provider about how you will receive RIABNI. Your healthcare provider may prescribe medicines before each infusion of RIABNI to reduce infusion side effects such as fever and chills. Your healthcare provider should do blood test regularly to check for side effects to RIABNI. Before each RIABNI treatment, your healthcare provider or nurse will ask you questions about your general health. Tell your healthcare provider or nurse about any new symptoms.

What are the possible side effects of RIABNI? RIABNI can cause serious side effects, including: See "What is the most important information I should know about RIABNI?" Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have: kidney failure and the need for dialysis treatment abnormal heart rhythm TLS can happen within 12 to 24 hours after an infusion of RIABNI. Your healthcare provider may do blood tests to check you for TLS. Your healthcare provider may give you medicine to help prevent TLS. Tell your healthcare provider right away if you have any of the following signs or symptoms or TLS: nausea diarrhea vomiting lack of energy Serious infections. Serious infections can happen during and after treatment with RIABNI, and can lead to death. RIABNI can increase your risk of getting infections and can lower the ability of your immune system to fight infections. Types of serious infections that can happen with RIABNI include bacterial, fungal, and viral infections. After receiving RIABNI, some people have developed low levels of certain antibodies in their blood for a long period of time (longer than 11 months). Some of these people with low antibody levels developed infections. People with serious infections should not receive RIABNI. Tell your healthcare provider right away if you have any symptoms of infection: fever cold symptoms, such as runny nose or sore throat that do not go away flu symptoms, such as cough, tiredness, and body aches earache or headache pain during urination cold sores in the mouth or throat cuts, scrapes or incisions that are red, warm, swollen or painful Heart problems. RIABNI may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with RIABNI if you have symptoms of heart problems or have a history of heart problems. Tell your healthcare provider right away if you have chest pain or irregular heartbeats during treatment with RIABNI. Kidney problems, especially if you are receiving RIABNI for NHL. RIABNI can cause severe kidney problems that lead to death. Your healthcare provider should do blood tests to check how well your kidneys are working. Stomach and serious bowel problems that can sometimes lead to death. Bowel problems, including blockage or tears in the bowel can happen if you receive RIABNI with chemotherapy medicines. Tell your healthcare provider right away if you have any severe stomach-area (abdomen) pain or repeated vomiting during treatment with RIABNI. Your healthcare provider will stop treatment with RIABNI if you have severe, serious or life-threatening side effects. The most common side effects of RIABNI include: infusion-related reactions (see "What is the most important information I should know about RIABNI?" infections (may include fever, chills) body aches tiredness nausea In adults with GPA or MPA the most common side effects of RIABNI also include: low white and red blood cells swelling diarrhea muscle spasms Other side effects with RIABNI include: aching joints during or within hours of receiving an infusion more frequent upper respiratory tract infection These are not all of the possible side effects with RIABNI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of RIABNI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about RIABNI that is written for healthcare providers.

What are the ingredients in RIABNI? Active ingredient: rituximab-arrx Inactive ingredients: polysorbate 80, sodium chloride, sodium citrate dihydrate, and Water for Injection, USP. Hydrochloric acid is used to adjust the buffer solution pH. RIABNI (rituxumab-arrx) Manufactured by: Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S. License Number 1080 For more information, go to www.RIABNI.com or call 1-805-447-1000. This Medication Guide has been approved by the U.S. Food andDrug Administration.