Drug Safety-related Labeling Changes (SrLC)

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RUXIENCE (BLA-761103)

(RITUXIMAB-PVVR)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/28/2026 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Treatment of Pediatric Patients with GPA/MPA (GPA/MPA Study 4)

An open-label, single-arm study (NCT01750697) was conducted in 25 pediatric patients 6 years to 17 years of age with active GPA or MPA. The overall study period consisted of a 6-month remission induction phase and a minimum 12-month follow up phase, up to 54 months. During the remission induction phase, patients received rituximab or non-U.S.-licensed rituximab. During the follow up phase, rituximab or non-U.S.-licensed rituximab were given at the discretion of the investigator (17 out of 25 patients received this additional treatment). Concomitant treatment with other immunosuppressive therapy was permitted [see Clinical Studies (14.7)].

The safety profile in pediatric GPA and MPA patients was consistent in type, nature and severity with the known safety profile of rituximab in adult patients with RA, GPA and MPA, and PV.

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 rituximab [see Warnings and Precautions (5.1)].

Serious Infections

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.

6.2 Immunogenicity

Additions and/or revisions underlined:

...

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

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

RUXIENCE is indicated for the treatment of GPA and MPA in pediatric patients 2 years of age and older with GPA and MPA. RUXIENCE is not indicated in pediatric patients less than 2 years of age with GPA or MPA.

The use of RUXIENCE for the treatment of pediatric patients with GPA and MPA 6 years of age and older is supported by evidence from adequate and well-controlled studies of rituximab in adults with GPA and MPA; a trial in pediatric patients 6 years of age and older with active GPA and MPA; and population pharmacokinetic (PK) analyses showing similar drug exposure levels in adults and pediatric patients 6 years to 17 years of age. The use of RUXIENCE for the treatment of pediatric patients with GPA and MPA ages 2 to less than 6 years of age is supported by PK modeling in patients 2 years of age and older and safety data from pediatric patients less than 6 years of age treated with rituximab.

The pediatric trial was a multicenter, open-label, single-arm study (GPA/MPA Study 4) to evaluate the safety, PK and exploratory efficacy of rituximab or non-U.S.-licensed rituximab in 25 pediatric patients (6 patients 6 years to less than 12 years of age and 19 patients 12 years to 17 years of age) with active GPA and MPA over a 6-month remission induction phase and minimum 12-month follow up phase, up to 54 months [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.7)].

The safety and effectiveness of RUXIENCE have not been established in pediatric patients with CLL. Rheumatoid Arthritis and Pemphigus Vulgaris

The safety and effectiveness of RUXIENCE have not been established in pediatric patients with PV or RA.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

06/09/2025 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

Additions and/or revisions underlined:

. . .

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.

. . .

 

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

Subsection title revised

Additions and/or revisions underlined:

. . .

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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

 

6.2 Immunogenicity

Additions and/or revisions underlined:

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

. . .

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

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of RUXIENCE have not been established in pediatric patients with NHL, CLL, PV or RA

. . .

 

8.5 Geriatric Use

Additions and/or revisions underlined:

. . .

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

RUXIENCE is a prescription medicine used to treat:

. . .

• Adults with Pemphigus Vulgaris (PV): to treat moderate to severe PV

. . .

10/16/2023 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and revisions underlined:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

RUXIENCE is given by infusion through your central catheter or through a needle placed in a vein (intravenous infusion), in your arm.

11/15/2021 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Immunization

Additions and/or revisions underlined: 

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.

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

Additions and/or revisions underlined: 

Limited data are available on the safety of the use of biologic agents or disease modifying antirheumatic drugs (DMARDs) other than methotrexate in RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA 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

Newly added section: 

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 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Immunogenicity

Additions and/or revisions underlined: 

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other rituximab products may be misleading.

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.

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined: 

Risk Summary

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.

8.3 Females and Males of Reproductive Potential

Rituximab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RUXIENCE.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for 12 months after the last dose.

8.4 Pediatric Use

Additions and/or revisions underlined: 

The safety and effectiveness of rituximab products have not been established in pediatric patients with NHL, CLL 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.

8.5 Geriatric Use

Additions and/or revisions underlined: 

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined: 

What is RUXIENCE?

RUXIENCE is a prescription medicine used to treat:

• Adults with Non-Hodgkin’s Lymphoma (NHL): alone or with other chemotherapy medicines.

• Adults with Chronic Lymphocytic Leukemia (CLL): with the chemotherapy medicines fludarabine and cyclophosphamide.

• Adults with Rheumatoid Arthritis (RA): with another prescription medicine called methotrexate, to reduce the signs and symptoms of moderate to severe active RA in adults, after treatment with at least one other medicine called a Tumor Necrosis Factor (TNF) antagonist has been used and did not work well enough.

05/26/2020 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Infusion-Related Reactions

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

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.

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 at least 12 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

‘Clinically significant’ replaces ‘serious’ in the first sentence of the section.

6.1 Clinical Trials Experience in Lymphoid Malignancies

DLBCL

Additions and/or revisions underlined:

… 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

In all instances in this section, Study 1 replaces Study 11 and Study 2 replaces Study 12.

6.2 Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis and Microscopic Polyangiitis (MPA).

Additions and/or revisions underlined:

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 …

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 (14.6)], 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 …

Additions and/or revisions underlined:

6.3 Immunogenicity

A total of 23/99 (23%) rituximab-treated adult patients with GPA and MPA developed anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximab- treated adult patients is unclear.

6.4 Postmarketing Experience

• Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).

8 Use in Specific Populations

Additions and/or revisions underlined:

8.2 Lactation

Risk Summary

There are no data on the presence of rituximab products in human milk, the effect on the breastfed child, or the effect on milk production. However, rituximab is detected in the milk of lactating cynomolgus monkeys and IgG is present in human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RUXIENCE and for at least 6 months after the last dose.

8.3 Females and Males of Reproductive Potential

Contraception

Rituximab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for at least 12 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of rituximab products have not been established in pediatric patients with NHL or CLL.

8.5 Geriatric Use

Chronic Lymphocytic Leukemia

Additions and/or revisions underlined:

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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-Fetal Toxicity

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

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

This product’s label may have been updated. For current full prescribing information, please visit www.RUXIENCE.com.

MEDICATION GUIDE

Additions and/or revisions underlined:

What is RUXIENCE?

RUXIENCE is not indicated for treatment of children.

What are the possible side effects of RUXIENCE?

RUXIENCE can cause serious side effects, including:

See “What is the most important information I should know about RUXIENCE?”

In adult patients with GPA or MPA the most common side effects of RUXIENCE also include: …

Other

Provides for updates to the labeling to align with certain September 2019 revisions to the labeling of US-licensed Rituxan.