Drug Safety-related Labeling Changes (SrLC)

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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.

BENLYSTA (BLA-125370)

(BELIMUMAB)

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

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06/20/2025 (SUPPL-85)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of BENLYSTA have been established for the treatment of active SLE and active lupus nephritis in pediatric patients 5 years of age and older who are receiving standard therapy.

The safety and effectiveness of BENLYSTA have not been established in pediatric patients less than 5 years of age.

Intravenous Use

Use of BENLYSTA intravenously in pediatric patients 5 years of age and older with active SLE is supported by evidence from pharmacokinetic (PK), safety, and efficacy results from a pediatric trial (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENLYSTA plus standard therapy from the Phase 3 intravenous studies in adults with active SLE (Trials 2 and 3). In Trial 6, the proportion of pediatric subjects achieving an SRI-4 response was higher in subjects receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric subjects receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with placebo plus standard therapy [see Clinical Studies (14.4)]. Pharmacokinetics were evaluated in a total of 53 pediatric subjects (Trial 6) and were consistent with the adult population with active SLE [see Clinical Pharmacology (12.3)].

Use of BENLYSTA intravenously in pediatric patients 5 years of age and older with active lupus nephritis is based on the extrapolation of efficacy from the intravenous trial (Trial 5) in adults (n = 224) with active lupus nephritis, and supported by pharmacokinetic data from intravenous studies in adults (n = 224) with active lupus nephritis and from pediatric subjects (n = 53) with active SLE (Trial 6). Estimated belimumab exposures for pediatric patients were comparable to adults with active lupus nephritis [see Clinical Pharmacology (12.3)].

Subcutaneous Use

Use of BENLYSTA, administered subcutaneously in pediatric patients 5 years of age and older who weigh at least 15 kg with active SLE, is supported by evidence from an open-label pharmacokinetic trial (subcutaneous administration of BENLYSTA in pediatric subjects with active SLE) and Trial 6 (a pharmacokinetic, efficacy, and safety trial of intravenous dosing in pediatric subjects with active SLE). The pharmacokinetics of belimumab, following subcutaneous administration in pediatric patients, are estimated to be comparable to adults who receive BENLYSTA subcutaneously and pediatric patients who receive BENLYSTA intravenously [see Clinical Pharmacology (12.3)].

Use of BENLYSTA, administered subcutaneously in pediatric patients 5 years of age and older who weigh at least 15 kg with active lupus nephritis, is based on the extrapolation of efficacy from the intravenous trial in adults (n = 224) with active lupus nephritis (Trial 5), and is supported by pharmacokinetic data derived from the same adult trial (Trial 5), a pharmacokinetic, efficacy, and safety intravenous trial in pediatric subjects with active SLE (n = 53) (Trial 6), and an open-label subcutaneous trial in pediatric subjects with active SLE (n = 25). Belimumab exposures for pediatric patients with active lupus nephritis following subcutaneous administration are estimated to be comparable to adults with active lupus nephritis who receive BENLYSTA intravenously [see Clinical Pharmacology (12.3)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

How will I receive BENLYSTA?

When given in a vein (intravenously)

. . .

BENLYSTA may be prescribed as a single-dose autoinjector or as a single-dose prefilled syringe.

The single-dose autoinjector is for use in adults and children 5 years of age and older.
The single-dose prefilled syringe is for use in adults 18 years of age and older.

. . .

05/16/2024 (SUPPL-81)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of BENLYSTA have been established for the treatment of SLE and lupus nephritis in pediatric patients 5 to less than 18 years of age.

…

Subcutaneous Use

Use of BENLYSTA, administered subcutaneously in pediatric patients (5 to less than 18 years of age and weighing at least 15 kg) with SLE, is supported by evidence from an open-label pharmacokinetic trial (subcutaneous administration of BENLYSTA in pediatric patients with SLE) and Trial 6 (a pharmacokinetic, efficacy, and safety study of intravenous dosing in pediatric patients with SLE). The pharmacokinetics of belimumab, following subcutaneous administration in pediatric patients, are estimated to be similar to adults who receive BENLYSTA subcutaneously and pediatric patients who receive BENLYSTA intravenously [see Clinical Pharmacology (12.3)].

The safety and effectiveness of the subcutaneous administration of BENLYSTA, in pediatric patients less than 18 years of age with active lupus nephritis, have not been established

The safety and effectiveness of BENLYSTA have not been established in pediatric patients less than 5 years of age.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is BENLYSTA?

BENLYSTA is a prescription medicine used to treat:
- adults and children 5 years of age and older with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines, and
- adults and children 5 years of age and older with active lupus nephritis (lupus-related kidney inflammation), who are receiving other lupus medicines.
BENLYSTA contains belimumab which is in a group of medicines called monoclonal antibodies. Lupus is a disease of the immune system (the body system that fights infection). When given together with other medicines for lupus, BENLYSTA decreases lupus disease activity more than other lupus medicines alone.
It is not known if BENLYSTA is safe and effective in people with severe active central nervous system lupus.
It is not known if BENLYSTA, given under the skin (subcutaneously), is safe and effective for use in:
- children less than 5 years of age or less than 33 pounds (15 kg) with SLE.
- children less than 18 years of age with active lupus nephritis.
  It is not known if BENLYSTA, given in a vein (intravenously), is safe and effective for use in children less than 5 years of age.
  …
  How will I receive BENLYSTA?
  …
  When given under the skin (subcutaneously)
  …

BENLYSTA may be prescribed as a single-dose autoinjector or as a single-dose prefilled syringe.
- The single-dose autoinjector is for use in adults and children 5 to less than 18 years of age.
- The single-dose prefilled syringe is for use in adults 18 years of age and older.
  …
For children less than 10 years of age, BENLYSTA must be given by a healthcare provider or a trained caregiver.
…
Use BENLYSTA on the same day each week or the same day every 2 weeks, as your healthcare provider tells you.
…

02/09/2024 (SUPPL-82)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

Additions and/or revisions underlined:

…

Progressive Multifocal Leukoencephalopathy (PML)

Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with suspected PML, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued.

02/15/2023 (SUPPL-79)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypersensitivity Reactions, including Anaphylaxis

(Additions and/or revisions underlined)

Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Adverse Reactions (6.1)]. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to a week following the most recent infusion.

Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

…

Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion-related reactions in all cases. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response or infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions or infusion- related reaction.

BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis and infusion-related reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion-related reactions. In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. With intravenous administration, the infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.2)].

5.3 Depression and Suicidality

(Additions and/or revisions underlined)

In controlled clinical trials, depression and suicidality were reported in patients receiving BENLYSTA [see Adverse Reactions (6.1)]…

5.4 Malignancy

(Additions and/or revisions underlined)

There is an increased risk of malignancies with the use of immunosuppressants. The impact of treatment with BENLYSTA on the development of malignancies is not known [see Adverse Reactions (6.1)].

Consider the individual benefit-risk in patients with known risk factors for the development or reoccurrence of malignancy prior to prescribing BENLYSTA. In patients who develop malignancies, consider the risk and benefit of continued treatment with BENLYSTA.

5.5 Immunization

(Additions and/or revisions underlined)

Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations.

5.6 Concomitant Use with Other Biologic Therapies

(Additions and/or revisions underlined)

Available data do not support the safety and efficacy of concomitant use of BENLYSTA with rituximab in patients with SLE. An increased incidence of serious infections and post-injection systemic reactions in patients receiving BENLYSTA concomitantly with rituximab compared to patients receiving BENLYSTA alone has been observed [see Adverse Reactions (6.1)]. The safety and efficacy of BENLYSTA concomitantly with other biologic therapies, including B- cell-targeted therapies, have not been established. Caution should be exercised if BENLYSTA is administered in combination with other biologic therapies [see Warnings and Precautions (5)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label for complete information)

8 Use in Specific Populations

8.1 Pregnancy

Pregnancy Exposure Registry

(Additions and/or revisions underlined)

There is a pregnancy exposure registry that evaluates pregnancy outcomes in women with lupus exposed to BENLYSTA during pregnancy. Healthcare professionals are encouraged to refer patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/benlysta-belimumab/.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness of BENLYSTA have been established for the treatment of SLE and lupus nephritis in pediatric patients 5 to 17 years old.

Use of BENLYSTA in pediatric patients with SLE is supported by evidence from pharmacokinetic (PK) and efficacy results from a pediatric study (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENYLSTA plus standard therapy from the Phase 3 intravenous studies in adults with SLE. A randomized, double-blind, placebo-controlled, PK, efficacy, and safety study (Trial 6) to evaluate intravenously administered BENLYSTA 10 mg/kg plus standard therapy compared with placebo plus standard therapy over 52 weeks was conducted in 93 pediatric patients with SLE. The proportion of pediatric patients achieving an SRI-4 response was higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric patients receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with placebo plus standard therapy [see Clinical Studies (14.3)]. Pharmacokinetics were evaluated in a total of 53 pediatric patients with SLE and were consistent with the adult population with SLE [see Clinical Pharmacology (12.3)].

Use of BENLYSTA in pediatric patients with active lupus nephritis is based on the extrapolation of efficacy from the intravenous study in adults (n = 224) with active lupus nephritis, and supported by pharmacokinetic data from intravenous studies in adults (n = 224) with active lupus nephritis and from pediatric patients (n = 53) with SLE. Estimated belimumab exposures for pediatric patients were comparable to adults with active lupus nephritis [see Clinical Pharmacology (12.3)].

The safety and effectiveness of intravenous administration of BENLYSTA have not been established in pediatric patients younger than 5 years of age.

The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). It is important that the patient’s overall health be assessed at each visit and any questions resulting from the patient’s reading of the Medication Guide and Instructions for Use be discussed.

For patients receiving BENLYSTA, give patients the Medication Guide for BENLYSTA.

Serious Infections

(Additions and/or revisions underlined)

Inform patients that BENLYSTA may decrease their ability to fight infections, and that serious infections, including some fatal ones, occurred in patients receiving BENLYSTA in clinical trials. Instruct patients to tell their healthcare provider if they develop signs or symptoms of an infection. [see Warnings and Precautions (5.1)].

Progressive Multifocal Leukoencephalopathy

Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions/Anaphylaxis

(Additions and/or revisions underlined)

Educate patients on the signs and symptoms of hypersensitivity reactions and infusion-related reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA. Inform patients about possible delayed reactions that may include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling that may occur after administration of BENLYSTA and advise them to contact their healthcare provider [see Warnings and Precautions (5.2)].

Depression and Suicidality

(Additions and/or revisions underlined)

Instruct patients (and caregivers if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes [see Warnings and Precautions (5.3)].

Immunizations

(Additions and/or revisions underlined)

Inform patients that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see Warnings and Precautions (5.65)].

Pregnancy Registry

(Additions and/or revisions underlined)

Inform patients that there is a pregnancy registry to evaluate fetal outcomes of pregnant women with lupus exposed to BENLYSTA [see Use in Specific Populations (8.1)].

07/26/2022 (SUPPL-78)

5 Warnings and Precautions

5.2 Hypersensitivity Reactions, including Anaphylaxis

Additions and/or revisions underlined

Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Adverse Reactions (6.1)].

…

Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion-related reactions in all cases. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response or infusion-related In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy.

…

Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur.

5.3 Depression and Suicidality

Additions and/or revisions underlined

In controlled clinical trials, depression and suicidality were reported in patients receiving BENLYSTA [see Adverse Reactions (6.1)].

…

5.4 Malignancy

Additions and/or revisions underlined

There is an increased risk of malignancies with the use of immunosuppressants. The impact of treatment with BENLYSTA on the development of malignancies is not known [see Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and/or revisions, please refer to label for complete information.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

Safety and effectiveness of BENLYSTA have been established for the treatment of SLE and lupus nephritis in pediatric patients 5 to 17 years old.

The safety and effectiveness of intravenous administration of BENLYSTA have not been established in pediatric patients younger than 5 years of age.

The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.

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

MEDICATION GUIDE

Additions and/or revisions underlined

…

What is BENLYSTA?

…

It is not known if BENLYSTA is safe and effective for use in children under 5 years of age when given in a vein (intravenously).
It is not known if BENLYSTA is safe and effective for use in children under 18 years of age when
given under the skin (subcutaneously).
…

12/16/2020 (SUPPL-73)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

(Additions and/or revisions underlined)

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Overall, the incidence of serious infections in controlled trials was similar in patients receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in patients receiving BENLYSTA.

In controlled trials of BENLYSTA administered intravenously in adults with SLE, the incidence of serious infections was 6.0% in patients receiving BENLYSTA compared with 5.2% in patients receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis. Fatal infections occurred in 0.3% of patients receiving BENLYSTA and in 0.1% of patients receiving placebo [see Adverse Reactions (6.1)].

In a controlled trial of active lupus nephritis, adults received BENLYSTA administered intravenously plus standard therapy or placebo plus standard therapy. Serious infections occurred in 14% of patients receiving BENLYSTA and in 17% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving BENLYSTA and in 0.9% (2/224) of patients receiving placebo [see Adverse Reactions (6.1)].

In a postmarketing safety trial of BENLYSTA administered intravenously to adults with SLE, the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Fatal infections occurred in 0.45% of patients receiving BENLYSTA and 0.15% of patients receiving placebo [see Adverse Reactions (6.1)].

In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE, the incidence of serious infections was 4.1% in patients receiving BENLYSTA and 5.4% in patients receiving placebo. Fatal infections occurred in 0.5% of patients receiving BENLYSTA and in none of the patients receiving placebo [see Adverse Reactions (6.2)].

Consider the risk and benefit before initiating treatment with BENLYSTA in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving it and monitor these patients closely.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA.

5.2 Hypersensitivity Reactions, including Anaphylaxis

(Additions and/or revisions underlined)

Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.3)]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE, systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.

BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1)].

Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur.

5.3 Infusion Reactions

(Additions and/or revisions underlined)

In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (?3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.2)]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1), Adverse Reactions (6.1)].

BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely [see Warnings and Precautions (5.2)].

5.4 Depression and Suicidality

(Additions and/or revisions underlined)

In controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, psychiatric events were reported more frequently in patients treated with BENLYSTA (16%) than with placebo (12%) and were related primarily to depression-related events, insomnia, and anxiety. Serious psychiatric events and serious depression were reported in 0.8% and 0.4% of patients receiving BENLYSTA, and 0.4% and 0.1% of patients receiving placebo, respectively. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg) [see Adverse Reactions (6.1)].

In a postmarketing trial of BENLYSTA administered intravenously in adults with SLE, serious psychiatric events and serious depression were reported in 1.0% and 0.3% of patients receiving BENLYSTA, and 0.3% and <0.1% of patients receiving placebo, respectively. The overall incidence of suicidal ideation or behavior or self-injury without suicidal intent was 0.7% of patients receiving BENLYSTA and 0.2% of patients receiving placebo. No suicide was reported in either group [see Adverse Reactions (6.1)].

The intravenous trials above did not exclude patients with a history of psychiatric disorders.

In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE, which excluded patients with a history of psychiatric disorders, psychiatric events were reported less frequently in patients receiving BENLYSTA (6%) compared with those receiving placebo (11%). There were no serious depression-related events or suicides reported in either group [see Adverse Reactions (6.2)].

Assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. Instruct patients receiving BENLYSTA (and caregivers, if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or other mood changes. Consider the risk and benefit of continued treatment with BENLYSTA for patients who develop such symptoms.

5.5 Malignancy

(Additions and/or revisions underlined)

The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE,

malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the intravenous controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. In a controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the data were similar. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

6 Adverse Reactions

6.1 Clinical Trials Experience with Intravenous Administration

(Additions and/or revisions underlined)

Adults

The data described in Table 1 reflect exposure to BENLYSTA administered intravenously plus standard therapy compared with placebo plus standard therapy in 2,133 adult patients with SLE in 3 controlled trials (Trials 1, 2, and 3). Patients received BENLYSTA plus standard therapy at doses of 1 mg/kg (n = 673), 4 mg/kg (n = 111; Trial 1 only), or 10 mg/kg (n = 674), or placebo plus standard therapy (n = 675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks [see Clinical Studies (14.1)]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 intravenous doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended intravenous dose of 10 mg/kg compared with placebo.

…

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Patients with SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Patients Receiving Placebo plus Standard Therapy

…

Infections: In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, the overall incidence of infections was 71% in patients receiving BENLYSTA compared with 67% in patients receiving placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Serious infections occurred in 6.0% of patients receiving BENLYSTA and in 5.2% of patients receiving placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Fatal infections occurred in 0.3% (4/1,458) of patients receiving BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

In a randomized, double-blind, placebo-controlled, 104-week trial of active lupus nephritis in adults receiving BENLYSTA administered intravenously (N = 448), the overall incidence of infections was 82% in patients receiving BENLYSTA compared with 76% in patients receiving placebo. Serious infections occurred in 14% of patients receiving BENLYSTA and in 17% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving BENLYSTA and in 0.9% (2/224) of patients receiving placebo.

In a randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N = 4,003), the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Serious infections leading to discontinuation of treatment occurred in 1.0% of patients receiving BENLYSTA and in 0.9% of patients receiving placebo. Fatal infections occurred in 0.45% (9/2,002) of patients receiving BENLYSTA and in 0.15% (3/2,001) of patients receiving placebo, where the incidence of all-cause mortality was 0.50% (10/2,002) in patients receiving BENLYSTA and 0.40% (8/2,001) in patients receiving placebo.

Depression and Suicidality: In controlled clinical trials of BENLYSTA administered intravenously in adults with SLE (N = 2,133), psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), primarily related to depression-related events (6.3% BENLYSTA; 4.7% placebo), insomnia (6.0% BENLYSTA; 5.3% placebo), and anxiety (3.9% BENLYSTA; 2.8% placebo). Serious psychiatric events were reported in 0.8% (12/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg).

In a randomized, double-blind, placebo-controlled, 52-week, postmarketing safety trial of BENLYSTA administered intravenously in adults with SLE (N = 4,003), serious psychiatric events were reported in 1.0% (20/2,002) of patients receiving BENLYSTA and 0.3% (6/2,001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2,002) of patients receiving BENLYSTA and in <0.1% (1/2,001) receiving placebo. The overall incidence of serious suicidal ideation or behavior or self-injury without suicidal intent was 0.7% (15/2,002) of patients receiving BENLYSTA and 0.2% (5/2,001) of patients receiving placebo. On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (48/1,974) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 2.0% (39/1,988) of patients receiving placebo. No suicide was reported in either group.

The intravenous trials above did not exclude patients with a history of psychiatric disorders.

Black/African-American Patients: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n = 331) compared with placebo plus standard therapy (n = 165) in Black patients with SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population [see Clinical Studies (14.1)].

Lupus Nephritis: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n = 224) compared with placebo plus standard therapy (n = 224) was evaluated in adults with active lupus nephritis for up to 104 weeks (Trial 5) [see Clinical Studies (14.2)]. The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with SLE. Cases of myelosuppression, including febrile neutropenia, leukopenia, and pancytopenia, were observed in subjects who received induction therapy with cyclophosphamide followed by maintenance therapy with azathioprine, or mycophenolate.

Pediatric Patients

The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric patients with SLE (Trial 6). The adverse reactions observed were consistent with those observed in adults [see Clinical Studies (14.3)].

6.2 Clinical Trials Experience with Subcutaneous Administration in Adults

(Additions and/or revisions underlined)

The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 patients with SLE in a controlled trial (Trial 7). In addition to standard therapy, patients received BENLYSTA 200 mg (n = 556) or placebo (n = 280) (2:1 randomization) once weekly for up to 52 weeks [see Clinical Studies (14.4)].

The overall population had a mean age of 39 years (range: 18 to 77), 94% were female, and 60% were White. In the trial, 81% of patients treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of patients receiving BENLYSTA plus standard therapy and 8.9% of patients receiving placebo plus standard therapy.

The safety profile observed for BENLYSTA administered subcutaneously plus standard therapy was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy, with the exception of local injection site reactions.

Infections

In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the overall incidence of infections was 55% in patients receiving BENLYSTA compared with 57% in patients receiving placebo (serious infections: 4.1% with BENLYSTA and 5.4% with placebo). The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously.

Fatal infections occurred in 0.5% (3/556) of patients receiving BENLYSTA and in no patients receiving placebo (0/280).

Depression and Suicidality

In a controlled trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), which excluded patients with a history of psychiatric disorders, psychiatric events were reported in 6% of patients receiving BENLYSTA and 11% of patients receiving placebo. Depression- related events were reported in 2.7% (15/556) of patients receiving BENLYSTA and 3.6% (10/280) of patients receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group. On the C-SSRS, 1.3% (7/554) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of patients receiving placebo.

Injection Site Reactions

In a controlled clinical trial of BENLYSTA administered subcutaneously in adults with SLE (N = 836), the frequency of injection site reactions was 6.1% (34/556) for patients receiving

BENLYSTA plus standard therapy and 2.5% (7/280) for patients receiving placebo plus standard therapy. These injection site reactions (most commonly pain, erythema, hematoma, pruritus, and induration) were mild to moderate in severity. The majority (94%) did not necessitate discontinuation of treatment.

6.4 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is 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 belimumab with the incidence of antibodies in other studies or to other products may be misleading.

In Trials 2 and 3 (intravenous dosing in adults with SLE), anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving

10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. In Trial 4 (intravenous dosing in adult Black patients), anti- belimumab antibodies were detected in 2 of 321 (0.6%) patients receiving BENLYSTA

10 mg/kg during the 52-week, placebo-controlled period. In Trial 5 (intravenous dosing in adults with lupus nephritis), there was no formation of anti-belimumab antibodies in 224 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 104-week, placebo-controlled period. In Trial 6 (intravenous dosing in pediatric patients with SLE), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week, placebo-controlled period. In Trial 7 (subcutaneous dosing in adults with SLE), there was no formation of anti-belimumab antibodies in 556 patients receiving BENLYSTA 200 mg during the 52-week, placebo-controlled period.

The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays.

7 Drug Interactions

(Additions and/or revisions underlined)

Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, cyclophosphamide, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and/or non-steroidal anti-inflammatory drugs (NSAIDs) without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Intravenous administration of BENLYSTA in patients with SLE is indicated in children aged

5 years and older. Determination of efficacy in pediatric patients was based on pharmacokinetic (PK) and efficacy results from a pediatric SLE study (Trial 6), as well as PK exposure and extrapolation of the established efficacy of BENYLSTA plus standard therapy from the Phase 3 intravenous studies in adults with SLE. A randomized, double-blind, placebo-controlled, PK, efficacy, and safety study (Trial 6) to evaluate intravenously administered BENLYSTA 10 mg/kg plus standard therapy compared with placebo plus standard therapy over 52 weeks was conducted in 93 pediatric patients with SLE. The proportion of pediatric patients achieving an SRI-4 response was higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric patients receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with placebo plus standard therapy [see Clinical Studies (14.3)].

The adverse event profile in pediatric patients was consistent with the overall population in the Phase 3 studies in adults [see Adverse Reactions (6.1)].

Pharmacokinetics were evaluated in a total of 53 pediatric patients and were consistent with the adult population [see Clinical Pharmacology (12.3)]. The safety and effectiveness of BENLYSTA have not been established in pediatric patients younger than 5 years of age.

The safety and effectiveness of intravenous administration of BENLYSTA have not been established in pediatric patients with active lupus nephritis younger than 18 years of age.

The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.

8.8 Racial Groups

(Additions and/or revisions underlined)

In Trial 2 and Trial 3 (intravenous dosing), SLE Responder Index-4 (SRI-4) response rates were lower for Black patients receiving BENLYSTA plus standard therapy relative to Black patients receiving placebo plus standard therapy [see Clinical Studies (14.1)].

In Trial 4 (intravenous dosing), a 2:1 randomized, placebo-controlled trial in Black patients, SLE Responder Index (SRI-S2K) response rates were higher for Black patients receiving BENLYSTA plus standard therapy (49%) relative to Black patients receiving placebo plus standard therapy (42%). However, the treatment difference was not statistically significant [see Clinical Studies (14.1)].

In Trial 7 (subcutaneous dosing), SRI-4 response was 45% (26/58) in Black patients receiving BENLYSTA plus standard therapy compared with 39% (13/33) in Black patients receiving placebo plus standard therapy [see Clinical Studies (14.4)].

The safety profile of BENLYSTA in Black patients was consistent with the known safety profile of BENLYSTA administered in the overall population [see Adverse Reactions (6.1)].

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is BENLYSTA?

BENLYSTA is a prescription medicine used to treat patients with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines. BENLYSTA is also used to treat adult patients with active lupus nephritis (lupus-related kidney inflammation) who are receiving other lupus medicines. Both intravenous and subcutaneous dosing of BENLYSTA are approved for adults with SLE and lupus nephritis.

Intravenous dosing of BENLYSTA is approved in children aged 5 years and older with SLE.

BENLYSTA contains belimumab which is in a group of medicines called monoclonal antibodies. Lupus is a disease of the immune system (the body system that fights infection). When given together with other medicines for lupus, BENLYSTA decreases lupus disease activity more than other lupus medicines alone.

It is not known if BENLYSTA is safe and effective in people with severe active central nervous system lupus.

…

When administered subcutaneously (under your skin)

Your healthcare provider will tell you how often you should use BENLYSTA. Use BENLYSTA exactly as your healthcare provider tells you to.
Read the Instructions for Use that comes with BENLYSTA for instructions about the right way to give your injections at home.
BENLYSTA may be prescribed as a single-dose autoinjector or as a single-dose prefilled syringe.
Before you use BENLYSTA, your healthcare provider will show you or your caregiver how to give the injections and review the signs and symptoms of possible allergic reactions.
BENLYSTA is injected under your skin (subcutaneously) of your stomach (abdomen) or thigh.
Use BENLYSTA once a week on the same day each week. If you have lupus nephritis, one dose may be 2 injections.

If you miss your dose of BENLYSTA on your planned day, inject a dose as soon as you remember.

Then, inject your next dose at your regularly scheduled time or continue weekly dosing based on the new day injected. In case you are not sure when to inject BENLYSTA, call your healthcare provider.

…

09/24/2020 (SUPPL-71)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

(Additions and/or revisions underlined)

Serious and sometimes fatal infections have been reported in patients receiving

immunosuppressive agents, including BENLYSTA. Overall, the incidence of serious infections in controlled trials was similar in patients receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in patients receiving BENLYSTA.

In controlled trials of BENLYSTA administered intravenously in adults, the incidence of serious infections was 6.0% in patients receiving BENLYSTA compared with 5.2% in patients receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis. Fatal infections occurred in 0.3% of patients receiving BENLYSTA and in 0.1% of patients receiving placebo [see Adverse Reactions (6.1)].

In a postmarketing safety trial of BENLYSTA administered intravenously, the incidence of serious infections was 3.7% in patients receiving BENLYSTA compared with 4.1% in patients receiving placebo. Fatal infections occurred in 0.45% of patients receiving BENLYSTA and 0.15% of patients receiving placebo [see Adverse Reactions (6.1)].

In a controlled trial of BENLYSTA administered subcutaneously in adults, the incidence of serious infections was 4.1% in patients receiving BENLYSTA and 5.4% in patients receiving placebo. Fatal infections occurred in 0.5% of patients receiving BENLYSTA and in none of the patients receiving placebo [see Adverse Reactions (6.2)].

5.2 Hypersensitivity Reactions, including Anaphylaxis

(Additions and/or revisions underlined)

In a controlled trial of BENLYSTA administered subcutaneously in adults, systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.

Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur.

5.3 Infusion Reactions

(Additions and/or revisions underlined)

In the controlled clinical trials of BENLYSTA administered intravenously in adults, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (greater than or equal to 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.2)]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1), Adverse Reactions (6.1)].

5.4 Depression and Suicidality

(Additions and/or revisions underlined)

In controlled clinical trials of BENLYSTA administered intravenously in adults, psychiatric events were reported more frequently in patients treated with BENLYSTA (16%) than with placebo (12%) and were related primarily to depression-related events, insomnia, and anxiety. Serious psychiatric events and serious depression were reported in 0.8% and 0.4% of patients receiving BENLYSTA, and 0.4% and 0.1% of patients receiving placebo, respectively. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg) [see Adverse Reactions (6.1)].

In a postmarketing trial of BENLYSTA administered intravenously, serious psychiatric events and serious depression were reported in 1.0% and 0.3% of patients receiving BENLYSTA, and 0.3% and <0.1% of patients receiving placebo, respectively. The overall incidence of suicidal ideation or behavior or self-injury without suicidal intent was 0.7% of patients receiving BENLYSTA and 0.2% of patients receiving placebo. No suicide was reported in either group [see Adverse Reactions (6.1)].

The intravenous trials above did not exclude patients with a history of psychiatric disorders.

In a controlled trial of BENLYSTA administered subcutaneously in adults, which excluded patients with a history of psychiatric disorders, psychiatric events were reported less frequently in patients receiving BENLYSTA (6%) compared with those receiving placebo (11%). There were no serious depression-related events or suicides reported in either group [see Adverse Reactions (6.2)].

6 Adverse Reactions

6.1 Clinical Trials Experience with Intravenous Administration

(Extensive changes; please refer to label)

6.2 Clinical Trials Experience with Subcutaneous Administration in Adults

(Additions and/or revisions underlined)

Infections

In a controlled trial of BENLYSTA administered subcutaneously in adults (N = 836), the overall incidence of infections was 55% in patients receiving BENLYSTA compared with 57% in patients receiving placebo (serious infections: 4.1% with BENLYSTA and 5.4% with placebo). The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. Fatal infections occurred in 0.5% (3/556) of patients receiving BENLYSTA and in no patients receiving placebo (0/280).

Depression and Suicidality

In a controlled trial of BENLYSTA administered subcutaneously in adults (N = 836), which

excluded patients with a history of psychiatric disorders, psychiatric events were reported in 6% of patients receiving BENLYSTA and 11% of patients receiving placebo. Depression-related events were reported in 2.7% (15/556) of patients receiving BENLYSTA and 3.6% (10/280) of patients receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression- related events or suicides reported in either group. On the C-SSRS, 1.3% (7/554) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of patients receiving placebo.

Injection Site Reactions

In a controlled clinical trial of BENLYSTA administered subcutaneously in adults (N = 836), the frequency of injection site reactions was 6.1% (34/556) for patients receiving BENLYSTA plus standard therapy and 2.5% (7/280) for patients receiving placebo plus standard therapy.

6.4 Immunogenicity

(Additions and/or revisions underlined)

In Trials 2 and 3 (intravenous dosing in adults), anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. In Trial 4 (intravenous dosing in adult Black patients), anti- belimumab antibodies were detected in 2 of 321 (0.6%) patients receiving BENLYSTA10 mg/kg during the 52-week, placebo-controlled period. In Trial 5 (intravenous dosing in pediatric patients), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week, placebo-controlled period.

8 Use in Specific Populations

8.8 Racial Groups

(Additions and/or revisions underlined)

In Trial 6 (subcutaneous dosing), SRI-4 response was 45% (26/58) in Black patients receiving BENLYSTA plus standard therapy compared with 39% (13/33) in Black patients receiving placebo plus standard therapy [see Clinical Studies (14.2)].

The safety profile of BENLYSTA in Black patients was consistent with the known safety profile of BENLYSTA administered in the overall population [see Adverse Reactions (6.1)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

For patients receiving BENLYSTA, give patients the Medication Guide for BENLYSTA.

Serious Infections

Advise patients that BENLYSTA may decrease their ability to fight infections, and that serious

infections, including some fatal ones, occurred in patients receiving BENLYSTA in clinical trials.

01/17/2020 (SUPPL-68)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience with Intravenous Administration

(additions underlined)

…

Black/African-American Patients: The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n = 331) compared with placebo plus standard therapy

(n = 165) in black patients (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population.

…

6.4 Immunogenicity

(additions underlined)

… In Trial 4 (intravenous dosing in adult black patients), anti- belimumab antibodies were detected in 2 of 321 (0.6%) patients receiving BENLYSTA 10 mg/kg during the 52-week, placebo-controlled period. In Trial 5 (intravenous dosing in pediatric patients), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week, placebo-controlled period. In Trial 6 (subcutaneous dosing in adults), there was no formation of anti-belimumab antibodies in 556 patients receiving BENLYSTA 200 mg during the 52-week, placebo-controlled period.

…

8 Use in Specific Populations

8.8 Racial Groups

(additions and revisions underlined)

…

In Trial 4 (intravenous dosing), a 2:1 randomized, placebo-controlled trial in black patients, SLE Responder Index (SRI-S2K) response rates were higher for black patients receiving BENLYSTA plus standard therapy (49%) relative to black patients receiving placebo plus standard therapy (42%). However, the treatment difference was not statistically significant .

In Trial 6 (subcutaneous dosing), SRI-4 response was 45% (26/58) in black patients receiving BENLYSTA plus standard therapy compared with 39% (13/33) in black patients receiving placebo plus standard therapy .

The safety profile of BENLYSTA in black patients was consistent with the known safety profile of BENLYSTA administered in the overall population.

09/13/2019 (SUPPL-67)

Approved Drug Label (PDF)

5 Warnings and Precautions

Depression and Suicidality

Change in section title. Additions and/or revisions underlined:

In controlled clinical studies, psychiatric disorders (depression, suicidal ideation and behavior) have been reported more frequently in patients receiving BENLYSTA. Physicians should assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. Patients receiving BENLYSTA (and caregivers if applicable) should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or other mood changes. The risk and benefit of continued treatment with BENLYSTA should be assessed for patients who develop such symptoms.

In controlled clinical trials of BENLYSTA administered intravenously in adults (N = 2,133), psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA; 4.7% placebo), insomnia (6.0% BENLYSTA; 5.3% placebo), and anxiety (3.9% BENLYSTA; 2.8% placebo). Serious psychiatric events were reported in 0.8% (12/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg).

In a randomized, double-blind, placebo-controlled, postmarketing study of BENLYSTA 10 mg/kg administered intravenously (N = 4,003), serious psychiatric events were reported in 1.0% (20/2,002) of patients receiving BENLYSTA and 0.3% (6/2,001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2,002) of patients receiving BENLYSTA and in <0.1% (1/2,001) receiving placebo. The overall incidence of serious suicidal ideation or behavior or self-injury without suicidal intent was 0.7% (15/2,002) of patients receiving BENLYSTA and 0.2% (5/2,001) of patients receiving placebo. On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (48/1,974) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 2.0% (39/1,988) of patients receiving placebo. No suicide was reported in either group.

The intravenous studies above did not exclude patients with a history of psychiatric disorders.

In a controlled trial of BENLYSTA 200 mg administered subcutaneously in adults (N = 836), which excluded patients with a history of psychiatric disorders, psychiatric events were reported in 6% of patients receiving BENLYSTA and 11% of patients receiving placebo. Depression- related events were reported in 2.7% (15/556) of patients receiving BENLYSTA and 3.6% (10/280) of patients receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group. On the C-SSRS, 1.3% (7/554) of patients receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of patients receiving placebo.

6 Adverse Reactions

Additions and/or revisions underlined:

The following have been observed with BENLYSTA and are discussed in detail in the Warnings and Precautions section:

· Mortality

· Serious Infections

· Hypersensitivity Reactions, including Anaphylaxis

· Infusion Reactions

· Depression and Suicidality

· Malignancy

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Depression and Suicidality

Instruct patients (and caregivers if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

04/26/2019 (SUPPL-64)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Mortality

There were more deaths reported with BENLYSTA than with placebo during the controlled period of the intravenous clinical trials in adults.

In the controlled trial of BENLYSTA administered subcutaneously in adults (N = 836) …

5.2 Serious Infections

5.3 Hypersensitivity Reactions, including Anaphylaxis

In the controlled clinical trials of BENLYSTA administered intravenously in adults …

In the controlled trial of BENLYSTA administered subcutaneously in adults …

5.4 Infusion Reactions

In the controlled clinical trials of BENLYSTA administered intravenously in adults …

5.5 Depression

In the controlled clinical trials of BENLYSTA administered intravenously in adults …

In the controlled trial of BENLYSTA administered subcutaneously in adults …

5.6 Malignancy

In the controlled clinical trials of BENLYSTA administered intravenously in adults …

6 Adverse Reactions

Additions and/or revisions underlined:

6.1 Clinical Trials Experience

Adults

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg plus standard therapy and at an incidence at least 1% greater than that observed with placebo plus standard therapy in 3 controlled studies (Trials 1, 2, and 3).

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Patients Treated with …

Addition of the following:

Pediatric Patients

The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric patients (Trial 4). The adverse reactions observed were consistent with those observed in adults.

Additions and/or revisions underlined:

6.2 Clinical Trials Experience with Subcutaneous Administration in Adults

6.4 Immunogenicity

In Trials 2 and 3 (intravenous dosing in adults) …

In Trial 4 (intravenous dosing in pediatric patients), there was no formation of anti-belimumab antibodies in 53 patients receiving BENLYSTA 10 mg/kg plus standard therapy during the 52-week placebo-controlled period. In Trial 5 (subcutaneous dosing in adults), there was no formation of anti-belimumab antibodies in 556 patients receiving BENLYSTA200 mg.

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

Intravenous administration of BENLYSTA is indicated in children aged 5 years and older. Determination of efficacy in pediatric patients was based on pharmacokinetic (PK) and efficacy results from a pediatric SLE study (Trial 4), as well as PK exposure and extrapolation of the established efficacy of BENYLSTA plus standard therapy from the Phase 3 intravenous studies in adults. A randomized, double-blind, placebo-controlled, PK, efficacy, and safety study

(Trial 4) to evaluate intravenously administered BENLYSTA 10 mg/kg plus standard therapy compared with placebo plus standard therapy over 52 weeks was conducted in 93 pediatric patients with SLE. The proportion of pediatric patients achieving an SRI-4 response was higher in patients receiving BENLYSTA plus standard therapy compared with placebo plus standard therapy. Pediatric patients receiving BENLYSTA plus standard therapy also had a lower risk of experiencing a severe flare compared with the placebo group.

The adverse event profile in pediatric patients was consistent with the overall population in the Phase 3 studies in adults.

Pharmacokinetics were evaluated in a total of 53 pediatric patients and were consistent with the adult population. The safety and effectiveness of BENLYSTA have not been established in pediatric patients younger than 5 years of age.

The safety and effectiveness of subcutaneous administration of BENLYSTA have not been established in pediatric patients younger than 18 years of age.

06/22/2018 (SUPPL-62)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Mortality

There were more deaths reported with BENLYSTA than with placebo during the controlled period of the intravenous clinical trials. Out of 2,133 patients … cardiovascular disease, and suicide.

In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving BENLYSTA). Infection was the most common cause of death.

5.2 Serious Infections

… In the controlled clinical trials of BENLYSTA administered intravenously, the overall incidence …

and in 0.1% (1/675) of patients receiving placebo.

In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), the overall incidence of infections was 55% in patients treated with BENLYSTA compared with 57% in patients who received placebo (serious infections: 4.1% with BENLYSTA and 5.4% with placebo). The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously.

5.3 Hypersensitivity Reactions, including Anaphylaxis

… In the controlled clinical trials of BENLYSTA administered intravenously, hypersensitivity …

BENLYSTA for intravenous use should be administered … and for an appropriate period of time after intravenous administration of BENLYSTA.

In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.

Patients receiving BENLYSTA should be informed of the signs and symptoms …

5.4 Infusion Reactions

In the controlled clinical trials of BENLYSTA administered intravenously, adverse events …

BENLYSTA for intravenous use should be administered …

5.5 Depression

In the controlled clinical trials of BENLYSTA administered intravenously, psychiatric events … in patients receiving BENLYSTA.

In the controlled trial of BENLYSTA administered subcutaneously (N equals 836), psychiatric events were reported in 6% of patients treated with BENLYSTA and in 11% of patients who received placebo. Depression-related events were reported in 2.7% of patients receiving BENLYSTA and 3.6% of patients receiving placebo. Serious psychiatric events were reported in 0.2% of patients receiving BENLYSTA and in no patients receiving placebo. There were no serious depression- related events or suicides reported in either group.

5.6 Malignancy

In the controlled clinical trials of BENLYSTA administered intravenously, malignancies (including non-melanoma skin cancers) were reported in 0.4% … In the intravenous controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed … In the controlled clinical trial of BENLYSTA administered subcutaneously (N equals 836), the data were similar. The mechanism of action …

6 Adverse Reactions

6.1 Clinical Trials Experience with Intravenous Administration

Numerous changes made to this subsection, having to deal with intravenous use and the addition of the term “plus standard therapy”; please refer to label for complete information.

6.2 Clinical Trials Experience with Subcutaneous Administration

Newly added subsection:

The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 patients in a controlled trial (Trial 4). In addition to standard therapy, patients received BENLYSTA 200 mg (n equals 556) or placebo (n equals 280) (2:1 randomization) once weekly for up to 52 weeks.

The overall population had a mean age of 39 years (range: 18 to 77), 94% were female, and 60% were white. In the trial, 81% of patients treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of patients receiving BENLYSTA plus standard therapy and 8.9% of patients receiving placebo plus standard therapy.

Injection Site Reactions

In the clinical study for BENLYSTA administered subcutaneously, the frequency of injection site reactions was 6.1% (34/556) for patients receiving BENLYSTA plus standard therapy and 2.5% (7/280) for patients receiving placebo plus standard therapy. These injection site reactions (most commonly pain, erythema, hematoma, pruritus, and induration) were mild to moderate in severity. The majority (94%) did not necessitate discontinuation of treatment.

6.4 Immunogenicity

Addition of the following:

Additions and/or revisions underlined:

In Trials 2 and 3 (intravenous dosing), anti-belimumab antibodies were detected … none of the reactions was life-threatening. In Trial 4 (subcutaneous dosing), there was no formation of anti-belimumab antibodies in 556 patients receiving BENLYSTA 200 mg during the 52-week placebo-controlled

period. The clinical relevance of the presence …

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

Available data on use of BENLYSTA in pregnant women … In an animal combined embryo-fetal and pre- and post-natal development study with monkeys that received belimumab by intravenous administration, there was no evidence of fetal harm with exposures approximately 9 times (based on intravenous administration) and 20 times (based on subcutaneous administration) the exposure at the maximum recommended human dose …

Data

Animal Data

… There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD of 200 mg subcutaneously (on an AUC basis with maternal animal intravenous doses up to

150 mg/kg). Belimumab-related findings …

8.6 Renal Impairment

Newly created subsection:

The safety and efficacy of BENLYSTA were evaluated in studies that included patients with SLE who had mild (creatinine clearance [CrCl] greater than or equal to 60 and less than 90 mL/min), moderate (CrCl greater than or equal to 30 and less than 60 mL/min), or severe (CrCl greater than or equal to 15 and less than 30 mL/min) renal impairment. No dosage adjustment is recommended in patients with renal impairment.

8.7 Hepatic Impairment

Newly created subsection:

No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. No dosage adjustment is recommended in patients with hepatic impairment.

8.8 Racial Groups

Additions and/or revisions underlined

In Trial 2 and Trial 3 (intravenous dosing), SLE Responder Index-4 (SRI-4) response rates were lower for black patients receiving BENLYSTA plus standard therapy relative to black patients receiving placebo plus standard therapy. In Trial 4 (subcutaneous dosing), SRI-4 response was slightly higher for black patients receiving BENLYSTA plus standard therapy relative to black patients receiving placebo plus standard therapy, but the treatment difference was not as large as that observed in the overall population and no definitive conclusion can be drawn from this subgroup analysis. Caution should be used when considering treatment with BENLYSTA in black/African-American patients.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

For patients receiving BENLYSTA, give patients the Medication Guide.

Hypersensitivity Reactions/Anaphylaxis and Infusion Reactions

Educate patients on the signs and symptoms of hypersensitivity reactions and infusion reactions … Inform patients to tell their healthcare provider about possible delayed reactions …

12/02/2016 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serious Infections

(additions and/or revisions are underlined)

Physicians should exercise caution when considering the use of BENLYSTA in patients with severe or chronic infections.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

...The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively), some of which were fatal.

8 Use in Specific Populations

8.1 Pregnancy

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Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BENLYSTA during pregnancy. Healthcare professionals are encouraged to register patients by calling 1-877-681-6296.

Risk Summary

Limited data on use of BENLYSTA in pregnant women, from observational studies, published case reports, and postmarketing surveillance, are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with SLE. Monoclonal antibodies, such as belimumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero-exposed infant. In an animal combined embryo-fetal and pre- and post-natal development study with monkeys that received belimumab by intravenous administration, there was no evidence of embryotoxicity or fetal malformations with exposures approximately 9 times the exposure at the maximum recommended human dose (MRHD). Belimumab-related findings in monkey fetuses and/or infants included reductions of B-cell counts, reductions in the density of lymphoid tissue B- lymphocytes in the spleen and lymph nodes, and altered IgG and IgM titers. The no-adverse- effect-level (NOAEL) was not identified for these findings; however, they were reversible within 3 to 12 months after the drug was discontinued. Based on animal data and the mechanism of action of belimumab, the immune system in infants of treated mothers may be adversely affected. It is unknown, based on available data whether immune effects, if identified, are reversible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with SLE are at increased risk of adverse pregnancy outcomes, including worsening of the underlying disease, premature birth, spontaneous abortion, and intrauterine growth restriction. Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal anti-phospholipid antibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block.

Fetal/Neonatal Adverse Reactions: Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to BENLYSTA in utero. Monitor an infant of a treated mother for B- cell reduction and other immune dysfunction.

Data

Animal Data: In a combined embryo-fetal and pre- and post-natal development study, pregnant cynomolgus monkeys received belimumab at intravenous doses of 0, 5, or 150 mg/kg every 2 weeks from confirmation of pregnancy at Gestation Days (GD) 20 to 22, throughout the period of organogenesis (up to approximately GD 50), and continuing to either the day of scheduled cesarean section (GD 150 [late third trimester]) or the day of parturition. There was no evidence of maternal toxicity, embryotoxicity, or teratogenicity at exposure approximately 9 times the exposure at the MRHD of 10 mg/kg intravenously (on an AUC basis with maternal intravenous doses up to 150 mg/kg). Belimumab-related findings in mothers included reductions of immature and mature B-cell counts and in fetuses and/or infants included reductions of immature and mature B-cell counts, reductions in the density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, reduced spleen weights, increased IgG titers, and reduced IgM titers. B-cell counts in infant monkeys exposed to belimumab in utero recovered by 3 months of age and in mothers after 1 year. IgG and IgM levels in infant monkeys recovered by 6 months of age and the reductions in B-lymphocytes in the lymph nodes and spleen were reversed by 1 year of age. Belimumab crossed the placenta, as it was detected in fetal cord blood and amniotic fluid on GD 150.

8.2 Lactation

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Risk Summary

No information is available on the presence of belimumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Belimumab was detected in the milk of cynomolgus monkeys; however, due to species-specific differences in lactation physiology, animal data may not predict drug levels in human milk. Maternal IgG is known to be present in human milk. If belimumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to belimumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of BENLYSTA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BENLYSTA, and any potential adverse effects on the breastfed child from BENLYSTA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Contraception

Following an assessment of benefit versus risk, if prevention of pregnancy is warranted, females of reproductive potential should use effective contraception during treatment and for at least 4 months after the final treatment.

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

17 PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Pregnancy Registry

Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to BENLYSTA.

Pregnancy

Inform female patients of reproductive potential that BENLYSTA may impact the immune system in infants of treated mothers and to inform their prescriber of a known or suspected pregnancy.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

are pregnant or plan to become pregnant. It is not known if BENLYSTA will you’re your unborn baby. Females who are able to become pregnant should talk to their healthcare provider about whether or not they will use birth control (contraception) and receive BENLYSTA. If BENLYSTA is recommended, you should use an effective method of birth control while receiving BENLYSTA and for at least 4 months after the final dose of BENLYSTA. Tell your healthcare provider right away if you become pregnant during your treatment with BENLYSTA or if you think you may be pregnant.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.