For Patients and Caregivers

THE RITUXAN SAFETY PROFILE HAS BEEN EXTENSIVELY STUDIED IN 8 TRIALS AND 2 OPEN-LABEL EXTENSIONS2,3

Safety Data From 24-week Placebo-controlled Studies

938 Patients

These data are based on 938 patients treated during a 24-week period in Phase II and Phase III studies of Rituxan (2 x 1000 mg) or placebo administered in combination with MTX13

Adverse Events

Most common adverse events in RA clinical trials up to Month 6

  • Adverse reactions reported in ≥5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia, and pruritus13
Table of incidence of RITUXAN® (rituximab) adverse events

Coded using MedDRA.

Infusion-related Reactions13,20

Infusion-related reactions were the most common adverse event

  • Most reactions were mild to moderate in severity; less than 1% were serious
  • The proportion of patients experiencing acute infusion-related reactions decreased with subsequent courses of Rituxan
  • Acute infusion-related reactions were experienced by more patients following their first infusion than after their second infusion

 

Infusion-related Reactions Up to Week 24 in Pooled Placebo-controlled Studies

Infusion related-reactions over first and second infusions

†Acute infusion-related reactions experienced during or within 24 hours following the first infusion, manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasms, with or without associated hypotension or hypertension.

Infections and Serious Infections

  • Infections of any type were experienced by 39% of patients taking Rituxan vs 34% of patients taking placebo13
    • The most common infections were nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and sinusitis

The serious infection rates at Week 24 were 2% for the Rituxan + MTX group (n=540) and 1% for the placebo + MTX group (n=398)13

7 Years of Safety Data Reflected in the PI2,13

2,578 Patients

2578 patients with RA were treated with Rituxan in controlled and long-term studies with a total exposure of 5014 patient-years over a period of 7 years.2,13

Serious Infection Rates: 7-year Data13

  • The most common serious infections (≥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
Serious infections per 100 patient-years over 7 years

‡Most common infections observed in 7-year data also included diarrhea and influenza.2
§Serious and/or those requiring IV antibiotics.

Rituxan Has 11 Years of Follow-up Safety Data3

3,595 Patients

As of September 2012, 3595 patients had been treated with up to 20 courses of RItuxan over a period of 11 years, providing 14,816 patient-years of observation in the all-exposure population.28

The number of patients available for analysis were:

  • Rituxan all-exposure: 3595 (14,816 patient-years)
  • Long-term population (>5 years): 1246 (8970 patient-years)
  • Pooled placebo group: 818 (1107 patient-years)

Incidence of Infusion-related Reactions in an Additional Long-term Follow-up Analysis at 11 Years3

Care should be exercised when interpreting open-label results, due to the inability to minimize bias.

  • Infusion-related reactions were the most common adverse event. Most reactions were mild to moderate in severity; less than 1% were serious

Proportion of Patients (%) With Infusion-related Reactions Through 10 Courses of Rituxan3

Proportion of patients with infusion-related reactions over 10 courses of RITUXAN® (rituximab)

Adapted from van Vollenhoven J Rheumatol 2015.

  • Patients received Rituxan + MTX or placebo + MTX in the original study, followed by Rituxan as rescue therapy or as part of an open-label extension study

Serious Infection Rates: 11-year Data3,28

Care should be exercised when interpreting open-label results, due to the inability to minimize bias.

Serious infections per 100 patient-years over 11 years

Adapted from van Vollenhoven EULAR 2013 and J Rheumatol 2015.

‖Serious and/or those requiring IV antibiotics.
All-exposure rate calculation includes up to 11 years of follow-up.

Rituxan does not need to be reconstituted prior to infusion.13

Learn more about dosing and administration for Rituxan

INF, infusion; MTX, methotrexate; PY, patient-years; RA, rheumatoid arthritis; SIE, serious infection event.

IMPORTANT SAFETY INFORMATION

INDICATIONS

  • Rituxan® (rituximab), in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more TNF antagonist therapies
  • Rituxan® (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)
  • Rituxan® (rituximab) is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris (PV)

BOXED WARNINGS and Additional Important Safety Information

BOXED WARNINGS

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

Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Rituxan-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. For GPA and MPA patients, glucocorticoids are given in combination with Rituxan. Institute medical management (eg, 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 Rituxan. Resume infusion at a minimum of 50% reduction in the 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 (≥25,000/mm3).

Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. 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 Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, 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 Rituxan. Discontinue Rituxan and concomitant medications in the event of 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 Rituxan. 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 (ie, 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 level 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, ie, 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 Rituxan. 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 Rituxan 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 Rituxan therapy. HBV reactivation has been reported up to 24 months following completion of Rituxan therapy. 

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

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML have received Rituxan 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 Rituxan. 

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

Warnings and Precautions

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 Rituxan in patients with Non–Hodgkin’s Lymphoma (NHL). 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.

Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after Rituxan 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 Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections.

Cardiovascular Adverse Reactions: Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving Rituxan. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.

Renal Toxicity: Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with Non–Hodgkin’s Lymphoma (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 Rituxan is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria.

Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

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

For patients treated with Rituxan, 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 Rituxan and administer non-live vaccines at least 4 weeks prior to a course of Rituxan. 

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

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

Embryo-Fetal Toxicity: Based on human data, Rituxan can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating Rituxan. Advise females of reproductive potential to use effective contraception while receiving Rituxan and for 12 months after the last dose.

Concomitant Use with Biologic Agents and DMARDs Other Than MTX: Limited data are available on the safety of the use of biologic agents or DMARDs other than MTX in RA patients exhibiting peripheral B-cell depletion following treatment with Rituxan. 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, MPA, or PV patients exhibiting peripheral B-cell depletion following treatment with Rituxan.

Use in Patients With RA Who Had No Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists: While the efficacy of Rituxan was supported in 4 controlled trials in patients with RA with prior inadequate responses to nonbiologic 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 Rituxan in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended.

Adverse Reactions

Clinical Trials Experience in RA

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, adverse reactions reported in ≥5% of patients were hypertension (8% vs 5%), nausea (8% vs 5%), upper respiratory tract infection (7% vs 6%), arthralgia (6% vs 4%), pyrexia (5% vs 2%), and pruritus (5% vs 1%) of Rituxan-treated vs placebo, respectively.

Infusion-Related Reactions: In the Rituxan RA pooled, placebo-controlled studies, incidence of any adverse event within 24 hours of an infusion was 32% vs 23% after the first infusion, and 11% vs 13% after the second infusion in the Rituxan-treated patients and placebo group, respectively. Incidence of acute infusion-related reactions was 27% vs 19% after the first infusion, 9% vs 11% after the second infusion in the Rituxan-treated patients and placebo group, respectively. Serious acute infusion-related reactions were experienced by <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 Rituxan or placebo, respectively, after the first course.

Infections: In the pooled, placebo controlled studies, incidence of any type of infection was 39% vs 34%, Rituxan-treated vs placebo. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis. The incidence of serious infections was 2% vs 1%, Rituxan-treated vs placebo group.

In the experience with Rituxan in 2578 RA patients, the rate of serious infection was 4.31 per 100 patient-years. The most common serious infections (≥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 remain stable in patients receiving subsequent courses.

In 185 Rituxan-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, incidence of serious cardiovascular reactions was 1.7% vs 1.3% Rituxan-treated vs placebo. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all Rituxan regimens (3/769=0.4%) compared to none in the placebo treatment group (0/389). In the experience with Rituxan in 2578 RA patients, the rate of myocardial infarction (MI) was consistent with MI rates in the general RA population. Rituxan 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 (<2.0 mg/dL) was 12% vs 10%, Rituxan-treated vs placebo, respectively. Hypophosphatemia was more common in patients who received corticosteroids. Newly occurring hyperuricemia (>10 mg/dL) was observed in 1.5% vs 0.3%, Rituxan-treated vs placebo, respectively.

Retreatment in Patients With RA: In the experience with Rituxan in RA patients, 2578 patients have been exposed to Rituxan and have received up to 10 courses of Rituxan in RA clinical trials, with 1890, 1043, and 425 patients having received at least 2, 3, and 4 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 Rituxan were similar to rates and types seen for a single course of Rituxan. In RA Study 2, where all patients initially received Rituxan, the safety profile of patients who were retreated with Rituxan was similar to those who were retreated with placebo.

Immunogenicity

A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving Rituxan. Anti-rituximab antibody positivity was not associated with increased infusion-related reactions or other adverse reactions. 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 Rituxan-treated patients is unclear.

Clinical Trials Experience in GPA and MPA

Adverse reactions reported in ≥15% of Rituxan-treated patients were infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions.

Induction Treatment of Patients with Active GPA/MPA (GPA/MPA Study 1)
Infusion-Related Reactions: In GPA/MPA Study 1, 12% vs 11% (Rituxan-treated vs cyclophosphamide) of patients experienced at least one infusion-related reaction. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituxan 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 premedicated with antihistamine and acetaminophen before each Rituxan 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% vs 47% (Rituxan-treated vs cyclophosphamide-treated, respectively) of patients experienced an infection by Month 6. The most common infections in the Rituxan group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% vs 10% (Rituxan-treated vs cyclophosphamide, respectively), 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 Rituxan in GPA/MPA Study 1. At 6 months, in the Rituxan 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 cyclophosphamide group.

Treatment of Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment (GPA/MPA Study 2)
In GPA/MPA Study 2, the safety profile was consistent with the known safety profile of Rituxan in immunologic indications.

Infusion-Related Reactions: In GPA/MPA Study 2, 7/57 (12%) patients in the EU-approved 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 (<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 EU-approved 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.

Treatment of Pediatric Patients with GPA/MPA (GPA/MPA Study 4)
The safety profile in pediatric GPA and MPA patients was consistent in type, nature and severity with the known safety profile of Rituxan in adult patients with FDA-approved immunological indications.

Infusion-Related Reactions
In GPA/MPA Study 4, the proportion of patients experiencing an IRR was 32%, 20%, 12%, and 8% following the first, second, third, and fourth infusions, respectively. The observed symptoms of IRRs were similar to those in adult GPA and MPA patients treated with Rituxan.

Serious Infections
In GPA/MPA Study 4, serious infections were reported in 7 patients (28%), and included influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events.

Hypogammaglobulinemia
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 GPA/MPA Study 4. During the overall study period, 18/25 patients (72%) had prolonged low IgG levels, including 15 patients who also had prolonged low IgM. Three patients received treatment with intravenous immunoglobulin

Immunogenicity

A total of 23/99 (23%) Rituxan-treated patients with GPA or MPA tested positive for anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in Rituxan-treated patients is unclear. In GPA/MPA Study 4, a total of 4/21 (19%) Rituxan-treated pediatric patients with GPA and MPA developed anti-rituximab antibodies during the overall study period (assessed at Month 18).

Clinical Trials Experience in Pemphigus Vulgaris (PV)

Adverse reactions reported in ≥10% of patients treated with the Ritux 3 regimen* vs patients treated with prednisone monotherapy were infusion-related reactions (58% vs N/A), depression (18% vs 11%), herpes simplex (13% vs 3%), and alopecia (13% vs 0%). 

Infusion-Related Reactions
Infusion-related reactions were the most commonly reported adverse drug reactions (58%) with the Ritux 3 regimen. Infusion-related reactions included symptoms collected on the next scheduled visit after each infusion, and adverse events 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. 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%, 40%, 13%, and 10% following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. 

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

Immunogenicity

Using a new ELISA assay, a total of 19/34 (56%) patients with PV treated with the Ritux 3 regimen tested positive for anti-rituximab antibodies by 18 months. The clinical relevance of anti-rituximab antibody formation in Rituxan treated PV patients is unclear.

Additional Important Safety Information

Lactation

Rituxan has 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 Rituxan and for 6 months after the last dose due to the potential for serious adverse reactions in breastfed children.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

For additional Important Safety Information, please see the Rituxan full Prescribing Information, including BOXED WARNINGS.

*Ritux 3 regimen = Roche-manufactured, EU-approved rituximab product
EU=European Union

Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion.

See full safety and Boxed Warning for more information.

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      Genovese MC, Breedveld FC, Emery P, et al. Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients. Ann Rheum Dis. 2009;68(12):1894-1897.

    • Genovese MC, et al. Presented at American College of Rheumatology; November 6-11, 2010; Atlanta, GA. Poster 403.

      Genovese MC, et al. Presented at American College of Rheumatology; November 6-11, 2010; Atlanta, GA. Poster 403.

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      Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol. 2010;37(5):917-927.

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      van Vollenhoven RF, Emery P, Bingham CO III, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010;37(3):558-567.

    • Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010;69(9):1629-1635.

      Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010;69(9):1629-1635.

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      Bingham CO III, Looney RJ, Deodhar A, et al. Immunization responses in rheumatoid arthritis patients treated with rituximab; results from a controlled clinical trial. Arthritis Rheum. 2010;62(1):64-74.

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      Rubbert-Roth A, Tak PP, Zerbini C, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a phase III randomized study (MIRROR). Rheumatology (Oxford). 2010;49(9):1683-1693.

    • Tak PP, Rigby WF, Rubbert-Roth A, et al; for the IMAGE Investigators. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis. 2011;70(1):39-46.

      Tak PP, Rigby WF, Rubbert-Roth A, et al; for the IMAGE Investigators. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis. 2011;70(1):39-46.

    • Greenwald MW, Shergy WJ, Kaine JL, et al. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011;63(3):622-632.

      Greenwald MW, Shergy WJ, Kaine JL, et al. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011;63(3):622-632.

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      Haraoui B, Bokarewa M, Kallmeyer I, Bykerk VP; for the RESET Investigators. Safety and effectiveness of rituximab in patients with rheumatoid arthritis following an inadequate response to 1 prior tumor necrosis factor inhibitor: the RESET Trial. J Rheumatol. 2011;38(12):2548-2556.

    • Keystone EC, Cohen SB, Emery P, et al. Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study. J Rheumatol. 2012;39(12):2238-2246.

      Keystone EC, Cohen SB, Emery P, et al. Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study. J Rheumatol. 2012;39(12):2238-2246.

    • van Vollenhoven RF, Emery P, Bingham CO, et al. Presented at: European League Against Rheumatism Conference; June 12-15, 2013; Madrid, Spain. Poster SAT0131.

      van Vollenhoven RF, Emery P, Bingham CO, et al. Presented at: European League Against Rheumatism Conference; June 12-15, 2013; Madrid, Spain. Poster SAT0131.

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      Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.

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      Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-1780.

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      Brogan P, Cleary G, Kasapcopur O, et al. Presented at the European League Against Rheumatism Annual European Congress of Rheumatology 2018; June 13-16, 2018; Amsterdam, Netherlands. Poster OP0332.

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      Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicenter, parallel-group, open-label randomized trial. Lancet. 2017;389(10083):2031-2040.

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    • Data on file, REFLEX 2-Year Clinical Study Report. Genentech USA, Inc. and Biogen.

      Data on file, REFLEX 2-Year Clinical Study Report. Genentech USA, Inc. and Biogen.

    • Data on file, Genentech, Inc. 

      Data on file, Genentech, Inc. 

    • Genentech Analysis of SHA Claims and Managed Markets Insight & Technology (MMIT) Data.

      Genentech Analysis of SHA Claims and Managed Markets Insight & Technology (MMIT) Data.

    • DRG and IMS Xponent Data.

      DRG and IMS Xponent Data.