Ruxience Drug Information

Important Dosing Information

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.

Premedicate before each infusion. Prior to First Infusion Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE. 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. 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. 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.

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/mm 3 before Cycle 2 should not be administered the 90-minute infusion. • Interrupt the infusion or slow the infusion rate for infusion-related reactions. Continue the infusion at one-half the previous rate upon improvement of symptoms.

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

The recommended dose is 375 mg/m 2 as an intravenous infusion according to the following schedules: • Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 or 8 doses. • Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses. • Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate RUXIENCE maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

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.

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/m 2 intravenous 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.

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.

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. 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. 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.

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. 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.

No incompatibilities between RUXIENCE and polyvinylchloride bags have been observed.

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).

Most NHL patients received rituximab as an infusion of 375 mg/m 2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. 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.

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.

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. 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. 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). 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).

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. 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. 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.

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%). 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). 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). 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. 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 studies Pooled 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. 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).

Incidence of All Adverse Reactions Coded 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) 9 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.

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.

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 was more common in patients who received corticosteroids.

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. 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.

In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either rituximab 375 mg/m 2 once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6-month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission.

The primary analysis was at the end of the 6-month remission induction period and the safety results for this period are described below. Adverse reactions presented below in Table 3 were adverse events which occurred at a rate of greater than or equal to 10% in the rituximab group. This table reflects experience in 99 GPA and MPA patients treated with rituximab, with a total of 47.6 patient-years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation.

Infection was the most common category of adverse events reported (47–62%) and is discussed below. 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 6 The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6-month study period. 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. 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 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. The most common infections in the rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster.

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. 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, 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. 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 ) 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.

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 patients and 16 Pemphigus Foliaceus patients). Safety results for the PV patient population during the 24-month treatment period are described below. 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) were the most commonly reported adverse drug reactions (58%, 22 patients).

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. 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). 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= Infusion-Related Reactions In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 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 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. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of rituximab or of other rituximab products. Using an ELISA assay, anti-rituximab antibody was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent rituximab.

Three of the four patients had an objective clinical response. A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving rituximab. Anti-rituximab antibody positivity was not associated with increased rates of infusion-related reactions or other adverse events.

Upon further treatment, the proportions of patients with infusion-related reactions were similar between anti-rituximab antibody positive and negative patients, and most reactions were mild to moderate. Four anti-rituximab antibody positive patients had serious infusion-related reactions, and the temporal relationship between anti-rituximab antibody positivity and infusion-related reaction was variable. The clinical relevance of anti-rituximab antibody formation in rituximab-treated adult patients is unclear.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rituximab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3–4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia. • 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. • 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).

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

Renal toxicity when used in combination with cisplatin.

Pregnancy Risk Summary Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero (see Clinical Considerations ). In animal reproduction studies, intravenous administration of rituximab to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B-cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Advise pregnant women of the risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.

Clinical Considerations Fetal/Neonatal Adverse Reactions Observe newborns and infants for signs of infection and manage accordingly. Data Human Data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.

Animal Data An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum Days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days mg/kg/day, and then weekly on PC Days mg/kg/week.

The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells.

A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in-utero. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.

Pediatric Use The safety and effectiveness of RUXIENCE have not been established in pediatric patients with NHL, CLL, PV or RA. Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system.