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mechanism of action is CD20-directed Antibody Interactions [MoA]

Ruxience

(Rituximab-Pvvr)

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Dosage & Administration

* •Administer only as an intravenous infusion (

2.1 Important Dosing Information

Administer only as an intravenous infusion

[see

Dosage and Administration (2.9)

]

. Do not administer as an intravenous push or bolus.

RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur

[see Warnings and Precautions (5.1)].

Premedicate before each infusion

[see

Dosage and Administration (2.8)

]

Prior to First Infusion

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE

[see Warnings and Precautions (5.3)]

. Obtain complete blood counts (CBC) including platelets prior to the first dose.

During RUXIENCE Therapy

In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias

[see Adverse Reactions (6.1)].

In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RUXIENCE therapy. Continue to monitor for cytopenias after final dose and until resolution.

* •

First Infusion

Standard Infusion:

Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
* •

Subsequent Infusions

Standard Infusion:

Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:

If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.

Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).

Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm³before Cycle 2 should not be administered the 90-minute infusion

[see Clinical Studies (14.4)]

.
* •Interrupt the infusion or slow the infusion rate for infusion-related reactions

[see Boxed Warning, Warnings and Precautions (5.1)].

Continue the infusion at one-half the previous rate upon improvement of symptoms.

).
* •Do not administer as an intravenous push or bolus (

2.1 Important Dosing Information

Administer only as an intravenous infusion

[see

Dosage and Administration (2.9)

]

. Do not administer as an intravenous push or bolus.

RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur

[see Warnings and Precautions (5.1)].

Premedicate before each infusion

[see

Dosage and Administration (2.8)

]

Prior to First Infusion

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE

[see Warnings and Precautions (5.3)]

. Obtain complete blood counts (CBC) including platelets prior to the first dose.

During RUXIENCE Therapy

[see Adverse Reactions (6.1)].

* •

First Infusion

Standard Infusion:

Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
* •

Subsequent Infusions

Standard Infusion:

Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:

[see Clinical Studies (14.4)]

.
* •Interrupt the infusion or slow the infusion rate for infusion-related reactions

[see Boxed Warning, Warnings and Precautions (5.1)].

Continue the infusion at one-half the previous rate upon improvement of symptoms.

).
* •RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur (

2.1 Important Dosing Information

Administer only as an intravenous infusion

[see

Dosage and Administration (2.9)

]

. Do not administer as an intravenous push or bolus.

RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur

[see Warnings and Precautions (5.1)].

Premedicate before each infusion

[see

Dosage and Administration (2.8)

]

Prior to First Infusion

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE

[see Warnings and Precautions (5.3)]

. Obtain complete blood counts (CBC) including platelets prior to the first dose.

During RUXIENCE Therapy

[see Adverse Reactions (6.1)].

* •

First Infusion

Standard Infusion:

Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
* •

Subsequent Infusions

Standard Infusion:

Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:

[see Clinical Studies (14.4)]

.
* •Interrupt the infusion or slow the infusion rate for infusion-related reactions

[see Boxed Warning, Warnings and Precautions (5.1)].

Continue the infusion at one-half the previous rate upon improvement of symptoms.

).
* •The dose for adult B-cell NHL is 375 mg/m² (

2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL)

The recommended dose is 375 mg/m²as an intravenous infusion according to the following schedules:

* •

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

Administer once weekly for 4 or 8 doses.
* •

Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

Administer once weekly for 4 doses.
* •

Previously Untreated, Follicular, CD20-Positive, B-Cell NHL

Administer on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate RUXIENCE maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer RUXIENCE as a single agent every 8 weeks for 12 doses.
* •

Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy

Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
* •

Diffuse Large B-Cell NHL

Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.

).
* •The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m² in Cycles 2–6, in combination with FC, administered every 28 days (

2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

The recommended dose is 375 mg/m²the day prior to the initiation of FC chemotherapy, then 500 mg/m²on Day 1 of Cycles 2–6 (every 28 days).

).
* •The dose as a component of Zevalin^® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m² (

2.4 Recommended Dose as a Component of Zevalin^®for Treatment of NHL

When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m²in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

).
* •The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion (

2.5 Recommended Dose for Rheumatoid Arthritis (RA)

* •Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks.
* •Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions.
* •Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
* •RUXIENCE is given in combination with methotrexate.

).
* •The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m² once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation (

2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Induction Treatment of Adult Patients with Active GPA/MPA

* •Administer RUXIENCE as a 375 mg/m²intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA.
* •Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RUXIENCE and may continue during and after the 4 week induction course of RUXIENCE treatment.

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

* •Administer RUXIENCE as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.
* •If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RUXIENCE within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product.
* •If induction treatment of active disease was with other standard of care immunosuppressants, initiate RUXIENCE follow up treatment within the 4 week period that follows achievement of disease control.

).
* •The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion (

2.7 Recommended Dose for Pemphigus Vulgaris (PV)

* •

Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids.

* •

Maintenance treatment

Administer RUXIENCE as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation.

* •

Treatment of relapse

Administer RUXIENCE as a 1,000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation.

Subsequent infusions of RUXIENCE may be administered no sooner than 16 weeks following the previous infusion.

). Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion (

2.8 Recommended Dose for Premedication and Prophylactic Medications

Premedicate with acetaminophen and an antihistamine before each infusion of RUXIENCE. For adult patients administered RUXIENCE according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion

[see Clinical Studies (14.4)]

For RA, GPA and MPA

, and PV

patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.

Provide prophylaxis treatment for

Pneumocystis jirovecii

pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate

[see Warnings and Precautions (5.6)]

PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RUXIENCE infusion.

PCP prophylaxis should be considered for patients with PV during and following RUXIENCE treatment.

Ruxience Prescribing Information

Infusion-Related Reactions

Administration of rituximab products can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RUXIENCE infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions

[see

5.1 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 to 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 RUXIENCE. 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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

B-Cell Malignancies

The data described below reflect exposure to rituximab in 3,092 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2,427). The population included 1,180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 patients with another indication. Most NHL patients received rituximab as an infusion of 375 mg/m²per 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/m²as an initial infusion followed by 500 mg/m²for 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 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/m²weekly for 4 doses.

Table 1 Incidence of Adverse Reactions in Greater than or Equal to 5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituximab (N=356)Adverse reactions observed up to 12 months following rituximab.^,Adverse reactions graded for severity by NCI-CTC criteria.
	All Grades (%)	Grade 3 and 4 (%)
Any Adverse Reactions	99	57
Body as a Whole	86	10
Fever	53	1
Chills	33	3
Infection	31	4
Asthenia	26	1
Headache	19	1
Abdominal Pain	14	1
Pain	12	1
Back Pain	10	1
Throat Irritation	9	0
Flushing	5	0
Heme and Lymphatic System	67	48
Lymphopenia	48	40
Leukopenia	14	4
Neutropenia	14	6
Thrombocytopenia	12	2
Anemia	8	3
Skin and Appendages	44	2
Night Sweats	15	1
Rash	15	1
Pruritus	14	1
Urticaria	8	1
Respiratory System	38	4
Increased Cough	13	1
Rhinitis	12	1
Bronchospasm	8	1
Dyspnea	7	1
Sinusitis	6	0
Metabolic and Nutritional Disorders	38	3
Angioedema	11	1
Hyperglycemia	9	1
Peripheral Edema	8	0
LDH Increase	7	0
Digestive System	37	2
Nausea	23	1
Diarrhea	10	1
Vomiting	10	1
Nervous System	32	1
Dizziness	10	1
Anxiety	5	1
Musculoskeletal System	26	3
Myalgia	10	1
Arthralgia	10	1
Cardiovascular System	25	3
Hypotension	10	1
Hypertension	6	1

In these single-arm rituximab studies, bronchiolitis obliterans occurred during and up to 6 months after rituximab infusion.

Previously Untreated, Low-Grade or Follicular, NHL

In NHL Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (greater than or equal to 5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%)

[see Clinical Studies (14.2)]

In NHL Study 5, detailed safety data collection was limited to serious adverse reactions, Grade greater than or equal to 2 infections, and Grade greater than or equal to 3 adverse reactions. In patients receiving rituximab as single-agent maintenance therapy following rituximab plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. 22%). Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in the rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. less than 1%).

In NHL Study 6, the following adverse reactions were reported more frequently (greater than or equal to 5%) in patients receiving rituximab following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (greater than or equal to 2%) in the rituximab arm compared with those who received no further therapy (4% vs. 1%)

[see Clinical Studies (14.3)]

DLBCL

In NHL Studies 7 (NCT00003150) and 8,

[see Clinical Studies (14.3)]

, the following adverse reactions, regardless of severity, were reported more frequently (greater than or equal to 5%) in patients age greater than or equal to 60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

In NHL Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP).

The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (NHL Study 8), neutropenia (NHL Studies 8 and 9 (NCT00064116)), and anemia (NHL Study 9).

CLL

The data below reflect exposure to rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in CLL Study 1 (NCT00281918) or CLL Study 2 (NCT00090051)

[see Clinical Studies (14.5)]

. The age range was 30–83 years and 71% were men. Detailed safety data collection in CLL Study 1 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea.

In CLL Study 1, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion-related reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%).

In CLL Study 2, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion-related reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. less than 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 studiesPooled studies: NCT00074438, NCT00422383, NCT00468546, NCT00299130, NCT00282308, NCT00266227, NCT02693210, NCT02093026 and NCT02097745.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 2). 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 2). 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 2These data are based on 938 patients treated in Phase 2 and 3 studies of rituximab (2 × 1,000 mg) or placebo administered in combination with methotrexate.Incidence of All Adverse ReactionsCoded using MedDRA.Occurring in Greater than or Equal to 2% and at Least 1% Greater than Placebo Among Rheumatoid Arthritis Patients in Clinical Studies Up to Week 24 (Pooled)
Adverse Reaction	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)

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)]

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/m²once 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.

Table 3 Incidence of All Adverse Reactions Occurring in Greater than or Equal to 10% of Rituximab-treated Patients with Active GPA and MPA in the GPA/MPA Study 1 Up to Month 6The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6-month study period.
Adverse Reaction	Rituximab N=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%)

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.

Table 4 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)
N/A = not applicable
Adverse Reaction	Non-U.S.-Licensed Rituximab + Short-term Prednisone N=38 n (%)	Prednisone N=36 n (%)
Infusion-related reactionsInfusion-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.	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%)

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.

Table 5 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%)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.
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%)

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.

]

Severe Mucocutaneous Reactions

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products

[see

5.2 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 RUXIENCE 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

HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RUXIENCE. Discontinue RUXIENCE and concomitant medications in the event of HBV reactivation

[see

5.3 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 RUXIENCE. 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 RUXIENCE 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 RUXIENCE therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.

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

]

Progressive Multifocal Leukoencephalopathy (PML)

Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products

[see

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

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rituximab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3–4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia
[see Warnings and Precautions (5.6)]
.
•Cardiac: fatal cardiac failure.
•Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash.
•Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections
[see Warnings and Precautions (5.6)]
.
•Neoplasia: disease progression of Kaposi's sarcoma.
•Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).
•Gastrointestinal: bowel obstruction and perforation.
•Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.
•Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

]

Administer only as an intravenous infusion .

Do not administer as an intravenous push or bolus .

RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur .

The dose for adult B-cell NHL is 375 mg/m².

The dose for CLL is 375 mg/m²in the first cycle and 500 mg/m²in Cycles 2–6, in combination with FC, administered every 28 days .

The dose as a component of Zevalin^®(ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m².

The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion .

The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m²once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation .

The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion . Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion .

2.1 Important Dosing Information

Administer only as an intravenous infusion

[see

Dosage and Administration (2.9)

]

. Do not administer as an intravenous push or bolus.

RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur

[see Warnings and Precautions (5.1)].

Premedicate before each infusion

[see

Dosage and Administration (2.8)

]

Prior to First Infusion

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE

[see Warnings and Precautions (5.3)]

. Obtain complete blood counts (CBC) including platelets prior to the first dose.

During RUXIENCE Therapy

[see Adverse Reactions (6.1)].

First Infusion

Standard Infusion:

Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

Subsequent Infusions

Standard Infusion:

Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:

[see Clinical Studies (14.4)]

Interrupt the infusion or slow the infusion rate for infusion-related reactions

[see Boxed Warning, Warnings and Precautions (5.1)].

Continue the infusion at one-half the previous rate upon improvement of symptoms.

2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL)

The recommended dose is 375 mg/m²as an intravenous infusion according to the following schedules:

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

Administer once weekly for 4 or 8 doses.

Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

Administer once weekly for 4 doses.

Previously Untreated, Follicular, CD20-Positive, B-Cell NHL

Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy

Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.

Diffuse Large B-Cell NHL

Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.

2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

The recommended dose is 375 mg/m²the day prior to the initiation of FC chemotherapy, then 500 mg/m²on Day 1 of Cycles 2–6 (every 28 days).

2.4 Recommended Dose as a Component of Zevalin^®for Treatment of NHL

2.5 Recommended Dose for Rheumatoid Arthritis (RA)

Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks.

Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions.

Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.

RUXIENCE is given in combination with methotrexate.

2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Induction Treatment of Adult Patients with Active GPA/MPA

Administer RUXIENCE as a 375 mg/m²intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA.

Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RUXIENCE and may continue during and after the 4 week induction course of RUXIENCE treatment.

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

Administer RUXIENCE as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.

If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RUXIENCE within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product.

If induction treatment of active disease was with other standard of care immunosuppressants, initiate RUXIENCE follow up treatment within the 4 week period that follows achievement of disease control.

2.7 Recommended Dose for Pemphigus Vulgaris (PV)

Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids.

Maintenance treatment

Administer RUXIENCE as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation.

Treatment of relapse

Administer RUXIENCE as a 1,000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation.

Subsequent infusions of RUXIENCE may be administered no sooner than 16 weeks following the previous infusion.

2.8 Recommended Dose for Premedication and Prophylactic Medications

[see Clinical Studies (14.4)]

For RA, GPA and MPA

, and PV

patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.

Provide prophylaxis treatment for

Pneumocystis jirovecii

pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate

[see Warnings and Precautions (5.6)]

PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RUXIENCE infusion.

PCP prophylaxis should be considered for patients with PV during and following RUXIENCE treatment.

2.9 Administration and Storage

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. RUXIENCE should be a clear to slightly opalescent, colorless to pale brownish-yellow liquid. Do not use vial if particulates or discoloration is present.

Administration

Use a sterile needle and syringe to prepare RUXIENCE. Withdraw the necessary amount of RUXIENCE and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.

Storage

If not used immediately, store diluted RUXIENCE solutions as shown in the table below.

•
Indications and Usage, Pemphigus Vulgaris (PV) ( 1.5 Pemphigus Vulgaris (PV) RUXIENCE is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris. )	6/2025
Dosage and Administration ( 2 DOSAGE AND ADMINISTRATION

Diluted RUXIENCE Solution Storage Conditions
Diluent Used to Prepare Solution for Infusion	Diluted RUXIENCE Solution Storage Conditions
0.9% Sodium Chloride Injection, USP	Store RUXIENCE solution diluted in 0.9% Sodium Chloride Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 16 days after preparation.
5% Dextrose Injection, USP	Store RUXIENCE solution diluted in 5% Dextrose Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours after preparation.

No incompatibilities between RUXIENCE and polyvinylchloride bags have been observed.

)

6/2025

Warnings and Precautions (

5 WARNINGS AND PRECAUTIONS

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

5.1 Infusion-Related Reactions

Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA and MPA

, and PV

[see Warnings and Precautions (5.7), Adverse Reactions (6.1)]

5.2 Severe Mucocutaneous Reactions

5.3 Hepatitis B Virus (HBV) Reactivation

5.4 Progressive Multifocal Leukoencephalopathy (PML)

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

5.5 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)]

5.6 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 RUXIENCE for serious infections and institute appropriate anti-infective therapy

[see Adverse Reactions (6.1 , 6.3)]

. RUXIENCE is not recommended for use in patients with severe, active infections.

5.7 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 RUXIENCE for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

[see Adverse Reactions (6.1)]

5.8 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 RUXIENCE is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RUXIENCE in patients with a rising serum creatinine or oliguria

[see Warnings and Precautions (5.5)]

5.9 Bowel Obstruction and Perforation

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

5.10 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 RUXIENCE, 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 RUXIENCE and administer non live vaccines at least 4 weeks prior to a course of RUXIENCE.

The effect of rituximab on immune responses was assessed in a randomized, controlled study in patients with RA treated with rituximab and methotrexate (MTX) compared to patients treated with MTX alone.

A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with rituximab plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the rituximab plus MTX group developed detectable levels of anti-keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs. 93%).

A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar in patients treated with rituximab plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on rituximab plus MTX vs. 70% of patients on MTX alone).

Most patients in the rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known.

5.11 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 RUXIENCE and for 12 months after the last dose

[see Use in Specific Populations (8.1, 8.3)]

5.12 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 anti-rheumatic 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.

5.13 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 RUXIENCE in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended

[see Clinical Studies (14.6)]

)

6/2025

RUXIENCE is a CD20-directed cytolytic antibody indicated for the treatment of:

•Adult patients with Non-Hodgkin's Lymphoma (NHL) (
1.1 Non-Hodgkin's Lymphoma (NHL)
RUXIENCE is indicated for the treatment of adult patients with:
- •Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
- •Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
- •Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
- •Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
).
- oRelapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent.
- oPreviously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
- oNon-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
- oPreviously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens.
•Adult patients with Chronic Lymphocytic Leukemia (CLL) (
1.2 Chronic Lymphocytic Leukemia (CLL)
RUXIENCE, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.
).
- oPreviously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC).
•Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to-severely-active RA who have inadequate response to one or more TNF antagonist therapies (
1.3 Rheumatoid Arthritis (RA)
RUXIENCE, in combination with methotrexate, is indicated for the treatment of adult patients with moderately-to-severely-active rheumatoid arthritis who have had an inadequate response to one or more Tumor Necrosis Factor (TNF) antagonist therapies.
).
•Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids (
1.4 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
RUXIENCE, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).
).
•Moderate to severe Pemphigus Vulgaris (PV) in adult patients (
1.5 Pemphigus Vulgaris (PV)
RUXIENCE is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.
).

•Administer only as an intravenous infusion (
2.1 Important Dosing Information
Administer only as an intravenous infusion
[see
Dosage and Administration (2.9)
]
. Do not administer as an intravenous push or bolus.
RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur
[see Warnings and Precautions (5.1)].
Premedicate before each infusion
[see
Dosage and Administration (2.8)
]
.
Prior to First Infusion
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE
[see Warnings and Precautions (5.3)]
. Obtain complete blood counts (CBC) including platelets prior to the first dose.
During RUXIENCE Therapy
In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias
[see Adverse Reactions (6.1)].
In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RUXIENCE therapy. Continue to monitor for cytopenias after final dose and until resolution.
•
First Infusion

Standard Infusion:
Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
•
Subsequent Infusions

Standard Infusion:
Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:
If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.

Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).

Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm³before Cycle 2 should not be administered the 90-minute infusion
[see Clinical Studies (14.4)]
.
•Interrupt the infusion or slow the infusion rate for infusion-related reactions
[see Boxed Warning, Warnings and Precautions (5.1)].
Continue the infusion at one-half the previous rate upon improvement of symptoms.
).
•Do not administer as an intravenous push or bolus (
2.1 Important Dosing Information
Administer only as an intravenous infusion
[see
Dosage and Administration (2.9)
]
. Do not administer as an intravenous push or bolus.
RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur
[see Warnings and Precautions (5.1)].
Premedicate before each infusion
[see
Dosage and Administration (2.8)
]
.
Prior to First Infusion
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE
[see Warnings and Precautions (5.3)]
. Obtain complete blood counts (CBC) including platelets prior to the first dose.
During RUXIENCE Therapy
In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias
[see Adverse Reactions (6.1)].
In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RUXIENCE therapy. Continue to monitor for cytopenias after final dose and until resolution.
•
First Infusion

Standard Infusion:
Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
•
Subsequent Infusions

Standard Infusion:
Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:
If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.

Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).

Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm³before Cycle 2 should not be administered the 90-minute infusion
[see Clinical Studies (14.4)]
.
•Interrupt the infusion or slow the infusion rate for infusion-related reactions
[see Boxed Warning, Warnings and Precautions (5.1)].
Continue the infusion at one-half the previous rate upon improvement of symptoms.
).
•RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur (
2.1 Important Dosing Information
Administer only as an intravenous infusion
[see
Dosage and Administration (2.9)
]
. Do not administer as an intravenous push or bolus.
RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur
[see Warnings and Precautions (5.1)].
Premedicate before each infusion
[see
Dosage and Administration (2.8)
]
.
Prior to First Infusion
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE
[see Warnings and Precautions (5.3)]
. Obtain complete blood counts (CBC) including platelets prior to the first dose.
During RUXIENCE Therapy
In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias
[see Adverse Reactions (6.1)].
In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RUXIENCE therapy. Continue to monitor for cytopenias after final dose and until resolution.
•
First Infusion

Standard Infusion:
Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
•
Subsequent Infusions

Standard Infusion:
Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour.

For Previously Untreated Follicular NHL and DLBCL Adult Patients:
If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.

Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8).

Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm³before Cycle 2 should not be administered the 90-minute infusion
[see Clinical Studies (14.4)]
.
•Interrupt the infusion or slow the infusion rate for infusion-related reactions
[see Boxed Warning, Warnings and Precautions (5.1)].
Continue the infusion at one-half the previous rate upon improvement of symptoms.
).
•The dose for adult B-cell NHL is 375 mg/m² (
2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL)
The recommended dose is 375 mg/m²as an intravenous infusion according to the following schedules:
- •
  Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
  
  Administer once weekly for 4 or 8 doses.
- •
  Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
  
  Administer once weekly for 4 doses.
- •
  Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
  
  Administer on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate RUXIENCE maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer RUXIENCE as a single agent every 8 weeks for 12 doses.
- •
  Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy
  
  Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
- •
  Diffuse Large B-Cell NHL
  
  Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.
).
•The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m² in Cycles 2–6, in combination with FC, administered every 28 days (
2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)
The recommended dose is 375 mg/m²the day prior to the initiation of FC chemotherapy, then 500 mg/m²on Day 1 of Cycles 2–6 (every 28 days).
).
•The dose as a component of Zevalin^® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m² (
2.4 Recommended Dose as a Component of Zevalin^®for Treatment of NHL
When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m²in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
).
•The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion (
2.5 Recommended Dose for Rheumatoid Arthritis (RA)
- •Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks.
- •Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions.
- •Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
- •RUXIENCE is given in combination with methotrexate.
).
•The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m² once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation (
2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
Induction Treatment of Adult Patients with Active GPA/MPA
•Administer RUXIENCE as a 375 mg/m²intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA.
•Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RUXIENCE and may continue during and after the 4 week induction course of RUXIENCE treatment.
Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment
•Administer RUXIENCE as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation.
•If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RUXIENCE within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product.
•If induction treatment of active disease was with other standard of care immunosuppressants, initiate RUXIENCE follow up treatment within the 4 week period that follows achievement of disease control.
).
•The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion (
2.7 Recommended Dose for Pemphigus Vulgaris (PV)
- •
  Administer RUXIENCE as two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids.
- •
  Maintenance treatment
  
  Administer RUXIENCE as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation.
- •
  Treatment of relapse
  
  Administer RUXIENCE as a 1,000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation.
Subsequent infusions of RUXIENCE may be administered no sooner than 16 weeks following the previous infusion.
). Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion (
2.8 Recommended Dose for Premedication and Prophylactic Medications
Premedicate with acetaminophen and an antihistamine before each infusion of RUXIENCE. For adult patients administered RUXIENCE according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion
[see Clinical Studies (14.4)]
.
For RA, GPA and MPA
, and PV
patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.
Provide prophylaxis treatment for
Pneumocystis jirovecii
pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate
[see Warnings and Precautions (5.6)]
.
PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RUXIENCE infusion.
PCP prophylaxis should be considered for patients with PV during and following RUXIENCE treatment.
).

•Lactation: Advise not to breastfeed (
8.2 Lactation
There are limited data on the presence of rituximab in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab is detected in the milk of lactating cynomolgus monkeys, and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RUXIENCE and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.
).
•Geriatric Use: In CLL patients older than 70 years of age, exploratory analyses suggest no benefit with the addition of rituximab to FC (
8.5 Geriatric Use
Diffuse Large B-Cell NHL
Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis.
Low-Grade or Follicular Non-Hodgkin's Lymphoma
Patients with previously untreated follicular NHL evaluated in NHL Study 5 were randomized to rituximab as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
Chronic Lymphocytic Leukemia
Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older; of these, 100 rituximab-treated patients (15%) were 70 years of age or older.
In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2
[see Clinical Studies (14.5)]
. Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of rituximab. In CLL Study 1, the dose intensity of rituximab was similar in older and younger patients, however in CLL Study 2 older patients received a lower dose intensity of rituximab.
The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (CLL Study 1); 56% vs. 39% (CLL Study 2)], febrile neutropenia [16% vs. 6% (NHL Study 10 (NCT00719472))], anemia [5% vs. 2% (CLL Study 1); 21% vs. 10% (CLL Study 2)], thrombocytopenia [19% vs. 8% (CLL Study 2)], pancytopenia [7% vs. 2% (CLL Study 1); 7% vs. 2% (CLL Study 2)], and infections [30% vs. 14% (CLL Study 2)].
Rheumatoid Arthritis
Among the 2,578 patients in global RA studies completed to date, 12% were 65–75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis
Of the 99 rituximab-treated GPA and MPA patients in GPA/MPA Study 1, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
In GPA/MPA Study 2, 30 (26%) of the enrolled patients were at least 65 years old, of which 12 patients were exposed to non-U.S.-licensed rituximab and 18 were exposed to azathioprine. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.
Pemphigus Vulgaris
Of the 46 patients treated with non-U.S.-licensed rituximab, 15 (33%) patients were 65 years of age and older. The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
).

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