Drug Safety-related Labeling Changes (SrLC)

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TRUXIMA (BLA-761088)

(RITUXIMAB-ABBS)

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

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06/09/2025 (SUPPL-32)

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:

. . .

Rheumatoid Arthritis and Pemphigus Vulgaris

The safety and effectiveness of TRUXIMA have not been established in pediatric patients with 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:

. . .

TRUXIMA is a prescription medicine used to treat:

. . .

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

. . .

02/04/2022 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

B-Cell Malignancies

The data described below reflect exposure to rituximab in 3092 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=2427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 patients with another indication. Most NHL patients received rituximab …

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

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 TRUXIMA 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

Newly added information:

Pregnancy Testing

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

8.4 Pediatric Use

Additions and/or revisions underlined:

Rheumatoid Arthritis

The safety and effective of rituximab products have not been established in pediatric patients with RA.

Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA)…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Before you receive TRUXIMA, tell your healthcare provider about all of your medical conditions, including if you:

Females who are able to become pregnant:

• Your healthcare provider should do a pregnancy test to see if you are pregnant before starting TRUXIMA.

• You should use effective birth control (contraception) during treatment with TRUXIMA and for 12 months after your last dose of TRUXIMA. Talk to your healthcare provider about effective birth control.

• Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with TRUXIMA.

05/29/2020 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

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

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

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 TRUXIMA and for at least 6 months after the last dose.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

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 TRUXIMA and for at least 12 months after the last dose.

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) and Use in Specific Populations (8.1)].

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

Lactation

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

Other

Provides for revisions to the Prescribing Information and Medication Guide of Truxima, to incorporate changes made to the labeling for US-licensed Rituxan in January 2020.

12/18/2019 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

(Newly added subsection) 

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.

Immunization

(Newly added information)

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

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.

Infusion-Related Reaction

(Newly added information)

For RA, GPA and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.

Progressive Multifocal Leukoencephalopathy (PML)

(Additions underlined)

JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab.

Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists

(Newly added subsection) 

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 TRUXIMA 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

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

(Newly added subsection; see label for complete information)

Clinical Trials Experience in Rheumatoid Arthritis

(Newly added subsection; see label for complete information)

Immunogenicity

(Newly added information)

A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving rituximab. Anti-rituximab antibody positivity was not associated with increased rates of infusion-related reactions or other adverse events. Upon further treatment, the proportions of patients with infusion-related reactions were similar between anti-rituximab antibody positive  and negative patients, and most reactions were mild to moderate. Four anti- rituximab antibody positive patients had serious infusion-related reactions, and the temporal relationship between anti-rituximab  antibody positivity and infusion-related reaction was variable. 

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

Postmarketing Experience

(Additions underlined)

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

7 Drug Interactions

(Additions underlined)

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.

8 Use in Specific Populations

Geriatric Use

(Newly added subsections) 

Rheumatoid Arthritis

Among the 2578 patients in global RA studies completed to date, 12% were 65-75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and  younger patients. The rates of serious adverse reactions, including serious infections, malignancies,  and cardiovascular events were higher in older patients.

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

Of the 99 rituximab-treated GPA and MPA patients in GPA/MPA Study 1, 36 (36%) were 65 years old and over, while  8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients  that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from  younger subjects.

In GPA/MPA Study 2, 30 (26%) of the enrolled patients were at least 65 years old, of which 12 patients were exposed to non-U.S.-licensed rituximab and 18 were exposed to azathioprine. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

Pediatric Use

(Additions 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.

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

Medication Guide

(Additions underlined)

TRUXIMA is a prescription medicine used to treat adults with:

• 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.

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

 (MPA): with glucocorticoids, to treat GPA and MPA.

TRUIXMA is not indicated for treatment of children.

 

TRUXIMA can cause serious side effects, including: 

Kidney problems, especially if you are receiving TRUXIMA for NHL. TRUXIMA can cause severe kidney

problems that lead to death. Your healthcare provider should do blood tests to check how well your kidneys

are working.

05/23/2019 (SUPPL-1)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions, please refer to label for more information)

8 Use in Specific Populations

8.5 Geriatric Use

(additions underlined)

 

 

Diffuse Large B-Cell NHL

Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis.

…

05/23/2019 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions, please refer to label for more information)

8 Use in Specific Populations

8.5 Geriatric Use

(additions underlined)

…

Chronic Lymphocytic Leukemia

 

Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older; of these, 100 rituximab-treated patients (15%) were 70 years of age or older.

 

In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 11 or in CLL Study 12; 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 12 . 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 11, the dose intensity of rituximab was similar in older and younger patients, however in CLL Study 12 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 11); 56% vs. 39% (CLL Study 12)], febrile neutropenia [16% vs. 6% (NHL Study 10 (NCT00719472))], anemia [5% vs. 2% (CLL Study 11); 21% vs. 10% (CLL Study 12)], thrombocytopenia [19% vs. 8% (CLL Study 12)], pancytopenia [7% vs. 2% (CLL Study 11); 7% vs. 2% (CLL Study 12)] and infections [30% vs. 14% (CLL Study 12)].