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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
RITUXAN (BLA-103705)
(RITUXIMAB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/02/2021 (SUPPL-5465)
5 Warnings and Precautions
5.1 Infusion-Related ReactionsAdditions and/or revisions underlined:
RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 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 pediatric patients with mature B-cell NHL/B-AL, administer prednisone as part of chemotherapy regimen prior to RITUXAN during induction and as needed for subsequent cycles [see Dosage and Administration (2.2 and 2.8)]. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (greater than or equal to 25,000/mm3) [see Warnings and Precautions (5.7), Adverse Reactions (6.1)].
6 Adverse Reactions
6.1 Clinical Trials ExperienceExtensive changes; please refer to label
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)
RITUXAN is indicated for the treatment of GPA and MPA in pediatric patients 2 years of age and older with GPA and MPA. RITUXAN is not indicated in pediatric patients less than 2 years of age with GPA or MPA.
The use of RITUXAN 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 RITUXAN 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 RITUXAN 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 RITUXAN 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)].
Mature B-Cell NHL/B-AL
The safety and effectiveness of RITUXAN in combination with chemotherapy for the treatment of previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have been established in pediatric patients aged 6 months and older. Use of RITUXAN for this indication is supported by evidence from an adequate and well-controlled study in pediatric patients aged 1 year and older on the basis that the course of advanced disease is expected to be similar between pediatric patients aged 6 months to less than 1 year to that of pediatric patients aged 1 year and older to allow extrapolation of data to younger pediatric patients and use pharmacokinetic modeling [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Patients younger than 3 years had a higher incidence of infections compared to patients 3 years and older [see Adverse Reactions (6.1)].
The safety and effectiveness of RITUXAN in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age.
The safety and effectiveness of RITUXAN have not been established in pediatric patients with CLL.
Rheumatoid Arthritis and Pemphigus Vulgaris
The safety and effectiveness of RITUXAN have not been established in pediatric patients with PV or RA.
RITUXAN 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 GUIDEExtensive changes; please refer to label
06/30/2021 (SUPPL-5464)
8 Use in Specific Populations
8.2 Lactation
(Additions and/or revisions are 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 RITUXAN 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
(Additions and/or revisions are underlined)
RITUXAN 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 RITUXAN.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with RITUXAN and for 12 months after the last dose.
08/28/2020 (SUPPL-5460)
6 Adverse Reactions
6.4 Clinical Trials Experience in Pemphigus Vulgaris (PV)(Extensive changes due to addition of results from Study WA29330 entitled, “A Randomized, Double-Blind, Double-Dummy, Active-Comparator, Multicenter Study to Evaluate the Efficacy and Safety of Rituximab Versus MMF in Patients With Pemphigus Vulgaris.”)
(Additions and/or revisions underlined)
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%) RITUXAN- treated PV patients tested positive for ADA by week 52 (19 patients had treatment-inducted ADA and 1 patient had treatment-enhanced ADA).
01/23/2020 (SUPPL-5461)
5 Warnings and Precautions
5.1 Embryo-Fetal Toxicity(Additions and/or revisions underlined)
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. Advise females of reproductive potential to use effective contraception while receiving RITUXAN and for at least 12 months after the last dose.
8 Use in Specific Populations
17 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.
Advise females of reproductive potential to use effective contraception during treatment with RITUXAN and for at least 12 months after the last dose.
(Additions and/or revisions underlined)
There are no data on the presence of rituximab 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 RITUXAN and for at least 6 months after the last dose.
(Additions and/or revisions underlined)
Contraception
RITUXAN can cause fetal harm when administered to a pregnant woman.
Females
Advise females of reproductive potential to use effective contraception during treatment with RITUXAN and for at least 12 months after the last dose.
11/25/2019 (SUPPL-5459)
6 Adverse Reactions
6.6 Postmarketing Experience(addition underlined)
…
Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).
…
09/27/2019 (SUPPL-5457)
5 Warnings and Precautions
5.1 Infusion-Related Reactions(additions and/or revisions are underlined)
RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 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. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.
Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (greater than or equal to 25,000/mm^3).
(additions and/or revisions are underlined)
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.
6 Adverse Reactions
(additions and/or revisions are underlined)
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
Infusion-related reactions
Severe mucocutaneous reactions
Hepatitis B reactivation with fulminant hepatitis
Progressive multifocal leukoencephalopathy
Tumor lysis syndrome
Infections
Cardiovascular adverse reactions
Renal toxicity
Bowel obstruction and perforation
(extensive revisions; please refer to labeling for complete information)
(extensive revisions; please refer to labeling for complete information)
(additions and/or revisions are 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 to RITUXAN in the studies described below with the incidence of antibodies in other studies or to other 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 RITUXAN. 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 RITUXAN. 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%) RITUXAN-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 RITUXAN-treated adult 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).
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. The clinical relevance of anti-rituximab antibody formation in RITUXAN-treated PV patients is unclear.
8 Use in Specific Populations
8.4 Pediatric Use(additions and/or revisions are underlined)
RITUXAN is indicated for the treatment of GPA and MPA in pediatric patients 2 years of age and older with GPA and MPA. RITUXAN is not indicated in pediatric patients less than 2 years of age with GPA or MPA.
The use of RITUXAN 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 RITUXAN 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 RITUXAN 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 RITUXAN 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.
The safety and effectiveness of RITUXAN have not been established in pediatric patients with NHL, CLL, PV, or RA.
Rituxan 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.
(extensive revisions; please refer to labeling for complete information)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(additions and/or revisions are underlined)
What is RITUXAN?
RITUXAN 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.
People with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) ages 2 years and above: with glucocorticoids, to treat GPA and MPA.
Adults with Pemphigus Vulgaris (PV): to treat moderate to severe PV.
RITUXAN is not indicated in children less than 2 years of age with GPA or MPA or in children with conditions other than GPA or MPA.
…
What are the possible side effects of RITUXAN? RITUXAN can cause serious side effects, including:
See “What is the most important information I should know about RITUXAN?”
Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have:
kidney failure and the need for dialysis treatment
abnormal heart rhythm
TLS can happen within 12 to 24 hours after an infusion of RITUXAN. Your healthcare provider may do blood tests to check you for TLS. Your healthcare provider may give you medicine to help prevent TLS. Tell your healthcare provider right away if you have any of the following signs or symptoms of TLS:
nausea o diarrhea
vomiting o lack of energy
Serious infections. Serious infections can happen during and after treatment with RITUXAN, and can lead to death. RITUXAN can increase your risk of getting infections and can lower the ability of your immune system to fight infections. Types of serious infections that can happen with RITUXAN include bacterial, fungal, and viral infections. After receiving RITUXAN, some people have developed low levels of certain antibodies in their blood for a long period of time (longer than 11 months). Some of these people with low antibody levels developed infections. People with serious infections should not receive RITUXAN. Tell your healthcare provider right away if you have any symptoms of infection:
Fever
cold symptoms, such as runny nose or sore throat that do not go away
flu symptoms, such as cough, tiredness, and body aches
earache or headache
pain during urination
cold sores in the mouth or throat
cuts, scrapes or incisions that are red, warm, swollen or painful
Heart problems. RITUXAN may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with RITUXAN if you have symptoms of heart problems or have a history of heart problems. Tell your healthcare provider right away if you have chest pain or irregular heartbeats during treatment with RITUXAN.
Kidney problems, especially if you are receiving RITUXAN for NHL. RITUXAN can cause severe kidney problems that lead to death. Your healthcare provider should do blood tests to check how well your kidneys are working.
Stomach and Serious bowel problems that can sometimes lead to death. Bowel problems, including blockage or tears in the bowel can happen if you receive RITUXAN with chemotherapy medicines. Tell your healthcare provider right away if you have any severe stomach-area (abdomen) pain or repeated vomiting during treatment with RITUXAN.
Your healthcare provider will stop treatment with RITUXAN if you have severe, serious or life-threatening side effects.
The most common side effects of RITUXAN include:
infusion-related reactions (see “What is the most important information I should know about RITUXAN?”)
infections (may include fever, chills)
body aches
tiredness
nausea
In adult patients with GPA or MPA the most common side effects of RITUXAN also include:
low white and red blood cells
swelling
diarrhea
muscle spasms
Other side effects with RITUXAN include:
aching joints during or within hours of receiving an infusion
more frequent upper respiratory tract infection
These are not all of the possible side effects with RITUXAN.
01/25/2019 (SUPPL-5454)
Boxed Warning
WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY(Additions and/or revisions are underlined)
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.
…
5 Warnings and Precautions
5.1 Infusion-Related Reactions(Subsection title has been revised; additions and/or revisions are underlined)
RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30?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 and PV patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RITUXAN.
6 Adverse Reactions
6 ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Infusion-related reactions
…
6.1 Clinical Trials Experience in Lymphoid Malignancies
(Additions and/or revisions are underlined)
…
The most common adverse reactions of RITUXAN (incidence ?25%) observed in clinical trials of patients with NHL were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia.
The most common adverse reactions of RITUXAN (incidence ?25%) observed in clinical trials of patients with CLL were: infusion-related reactions and neutropenia.
Infusion-Related Reactions
In the majority of patients with NHL, infusion-related reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first RITUXAN infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the RITUXAN infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [see Warnings and Precautions (5.1)]. In patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of RITUXAN at Cycle 2, the incidence of Grade 3-4 infusion reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]).
…
CLL
The data below reflect exposure to RITUXAN in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 11 (NCT00281918) or Study 12 (NCT00090051). The age range was 30?83 years and 71% were men. Detailed safety data collection in Study 11 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions.
Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea.
In Study 11, the following Grade 3 and 4 adverse reactions occurred more frequently in
R-FC-treated patients compared to FC-treated patients: infusion-related reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%).
In Study 12, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion-related reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs.?1%). Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity.
6.2 Clinical Trials Experience in Rheumatoid Arthritis
(Additions and/or revisions are underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice.
The data presented below reflect the experience in 2578 RA patients treated with RITUXAN in controlled and long-term studies1 with a total exposure of 5014 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.
…
Infusion-Related Reactions
In the RITUXAN RA pooled placebo-controlled studies, 32% of RITUXAN-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, RITUXAN 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 RITUXAN-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 RITUXAN or placebo decreased to 9% and 11%, 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 rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion-related reactions decreased with subsequent courses of RITUXAN. The administration of intravenous glucocorticoids prior to RITUXAN infusions reduced the incidence and severity of such reactions, however, there was no clear benefitfrom the administration of oral glucocorticoids for the prevention of acute infusion-related reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to RITUXAN infusions.
…
6.3 Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)
(Additions and/or revisions are underlined)
Infusion-Related Reactions
Infusion-related reactions in GPA/MPA Study 1 were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with RITUXAN, 12% experienced at least one infusion-related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the 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 pre-medicated 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.
….
The safety profile was consistent with the safety profile for RITUXAN 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 (<4%). One patient had two serious IRRs, two IRRs led to a dose modification, and no IRRs were severe, fatal, or led to withdrawal from the study.
Infections
In GPA/MPA Study 2, 30/57 (53%) patients in the non-U.S.-licensed rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis.
Long-term, Observational Study with RITUXAN 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 RITUXAN (mean of 8 infusions [range 1-28]) for up to 4 years, according to
physician standard practice and discretion. Majority of patients received doses ranging from 500 mg to 1000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for RITUXAN in RA and GPA and MPA.
6.4 Clinical Trials Experience in Pemphigus Vulgaris (PV)
(Additions and/or revisions are underlined)
Infusion-Related Reactions
Infusion-related reactions were the most commonly reported adverse drug reactions (58%, 22 patients). All infusion-related reactions were mild to moderate (Grade 1 or 2) except one Grade 3 serious infusion-related reaction (arthralgia) associated with the Month 12 maintenance infusion. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA and MPA patients.
6.5 Immunogenicity
(Additions and/or revisions are underlined)
…
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 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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Infusion-Related Reactions
Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions including urticaria, hypotension, angioedema, sudden cough, breathing problems, weakness, dizziness, palpitations, or chest pain.
(Additions and/or revisions are underlined)
What is the most important information I should know about RITUXAN? RITUXAN can cause serious side effects that can lead to death, including:
Infusion-related reactions. Infusion-related reactions are very common side effects of RITUXAN treatment. Serious infusion-related reactions can happen during your infusion or within 24 hours after your infusion of RITUXAN. Your healthcare provider should give you medicines before your infusion of RITUXAN to decrease your chance of having a severe infusion-related reaction.
…
The most common side effects of RITUXAN include:
infusion-related reactions (see “What is the most important information I should know about RITUXAN?”)
10/18/2018 (SUPPL-5451)
6 Adverse Reactions
6.3 Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)(Additions and/or revisions are underlined)
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 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 RITUXAN in RA and GPA and MPA.
Infusion 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 (<4%). One patient had two serious IRRs, two IRRs led to a dose modification, and no IRRs were severe, fatal, or led to withdrawal from the study.
Infections
In GPA/MPA Study 2, 30/57 (53%) patients in the non-U.S.-licensed rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis.
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis
Of the 99 RITUXAN-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.
06/07/2018 (SUPPL-5450)
5 Warnings and Precautions
Additions and/or revisions underlined:
5.1 Infusion Reactions
… For RA and PV patients …
5.12 Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA, MPA, and PV
… has not been studied in GPA or MPA or PV patients exhibiting peripheral …
6 Adverse Reactions
Newly added subsection:
6.4 Clinical Trials Experience in Pemphigus Vulgaris (PV)
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 practice.
A non-U.S.-approved rituximab product in combination with short-term prednisone was compared to that of prednisone monotherapy in a randomized, controlled, multicenter open-label study of 90 patients (74 Pemphigus Vulgaris [PV] patients and 16 Pemphigus Foliaceus [PF] patients). Safety results for the PV patient population during the 24-month treatment period are described below.
The safety profile of the non-U.S.-approved rituximab product in patients with PV was consistent with that observed in patients with RITUXAN-treated RA and GPA and MPA.
Adverse reactions presented below in Table 4 were adverse events which occurred at a rate greater than or equal to 5% among PV patients treated with a non-U.S.-approved rituximab product and with at least 2% absolute difference in incidence between the group treated with a non-U.S.-approved rituximab product and the prednisone monotherapy group up to Month 24. No patients in the group treated with a non-U.S.-approved rituximab product 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 ?5% Among PV Patients treated with a non- U.S.-approved rituximab product and with at Least 2% Absolute Difference in Incidence Between the Group treated with a non-U.S.-approved rituximab product with Short-term Prednisone and the Group Treated with Prednisone Monotherapy in the Clinical Study Up to Month 24 Newly added table; please refer to label for complete information.
Infusion reactions were the most commonly reported adverse drug reactions (58%, 22 patients). All infusion reactions were mild to moderate (Grade 1 or 2) except one Grade 3 serious infusion reaction (arthralgia) associated with the Month 12 maintenance infusion. The proportion of patients experiencing an infusion reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion reactions. Symptoms of infusion reactions were similar in type and severity to those seen in RA and GPA and MPA patients.
Fourteen patients (37%) in the group treated with a non-U.S.-approved rituximab product experienced treatment-related infections compared to 15 patients (42%) in the prednisone group. The most common infections in the group treated with a non-U.S.-approved rituximab product were herpes simplex, herpes zoster, bronchitis, urinary tract infection, fungal infection, and conjunctivitis. Three patients (8%) in the group treated with a non-U.S.-approved rituximab product 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).
Additions and/or revisions underlined:
… The clinical relevance of anti-rituximab antibody formation in RITUXAN-treated patients is unclear.
Using a new ELISA assay, a total of 19/34 (56%) patients with PV, who were treated with a non- U.S.-approved rituximab product, tested positive for anti-rituximab antibodies by 18 months. The clinical relevance of anti-rituximab antibody formation in RITUXAN-treated PV patients is unclear.
04/03/2018 (SUPPL-5453)
5 Warnings and Precautions
5.11 Embryo-Fetal Toxicity(Newly added subsection)
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 risk to a fetus. Females of childbearing potential should use effective contraception while receiving RITUXAN and for 12 months following the last dose of RITUXAN.
(Additions and/or revisions are underlined)
…
RITUXAN is not recommended for use in patients with severe, active infections.
(Additions and/or revisions are underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience in Lymphoid Malignancies(Additions and/or revisions are underlined)
…
The data described below reflect exposure to RITUXAN in 2783 patients, with exposures ranging from a single infusion up to 2 years. RITUXAN 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, and 676 patients with CLL. Most NHL patients received RITUXAN as an infusion of 375 mg/m2 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.
CLL patients received RITUXAN 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of RITUXAN-based therapy.
The most common adverse reactions of RITUXAN (incidence ?25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia.
The most common adverse reactions of RITUXAN (incidence ?25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia.
(Additions and/or revisions are 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 to RITUXAN in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
an ELISA assay, anti-rituximab antibody was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent RITUXAN. 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 RITUXAN. 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 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 reactions, and the temporal relationship between anti-rituximab antibody positivity and infusion reaction was variable.
A total of 23/99 (23%) RITUXAN-treated patients with GPA and MPA tested positive for anti- rituximab antibodies by 18 months. The clinical relevance of anti-rituximab antibody formation in RITUXAN-treated patients is unclear.
(Additions and/or revisions are underlined)
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Infusion reactions
Severe mucocutaneous reactions
Hepatitis B reactivation with fulminant hepatitis
Progressive multifocal leukoencephalopathy
Tumor lysis syndrome
Infections
Cardiovascular adverse reactions
Renal toxicity
Bowel obstruction and perforation
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion)
Risk Summary
Based on human data, RITUXAN can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to RITUXAN 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.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
There are no data on the presence of rituximab 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. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of RITUXAN due to the potential for serious adverse reactions in breastfed infants.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Rituximab can cause fetal harm
Contraception
Females
Females of childbearing potential should use effective contraception while receiving RITUXAN and for 12 months following treatment.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
The safety and effectiveness of RITUXAN in pediatric patients have not been established.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Newly added subsections; additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Infusion Reactions
Inform patients about the signs and symptoms of infusion reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion reactions including urticaria, hypotension, angioedema, sudden cough, breathing problems, weakness, dizziness, palpitations, or chest pain.
Severe Mucocutaneous Reactions
Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules.
Hepatitis B Virus Reactivation
Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.
Progressive Multifocal Leukoencephalopathy (PML)
Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems.
Tumor Lysis Syndrome (TLS)
Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the increased risk of infections during and after treatment with RITUXAN.
Cardiovascular Adverse Reactions
Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats.
Renal Toxicity
Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function.
Bowel Obstruction and Perforation
Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting.
Embryo-Fetal Toxicity
Advise a pregnant woman of the potential risk to a fetus. Advise female patients that rituximab can cause fetal harm if taken during pregnancy and to use effective contraception during treatment with RITUXAN and for at least 12 months after the last dose of RITUXAN. Advise patients to inform their healthcare provider of a known or suspected pregnancy.
Lactation
Advise women not to breastfeed during treatment with RITUXAN and for 6 months after the last dose.
(Medication Guide Format has been revised; please refer to label)