Drug Safety-related Labeling Changes (SrLC)

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BENLYSTA (BLA-761043)

(BELIMUMAB)

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

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08/21/2026 (SUPPL-39)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

BENLYSTA is contraindicated in patients with a prior history of:

• Anaphylaxis with belimumab [see Warnings and Precautions (5.2)].
• Stevens-Johnson syndrome or toxic epidermal necrolysis with belimumab [see Warnings and Precautions (5.3)].

5 Warnings and Precautions

Newly added subsection:

5.3 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with BENLYSTA. Monitor for and advise patients about signs and symptoms of SJS/TEN during treatment with BENLYSTA. Discontinue BENLYSTA immediately if signs or symptoms suggestive of SJS/TEN occur. Early consultation with a dermatologist or other appropriate specialist is recommended to ensure greater diagnostic accuracy and appropriate management. If the etiology is considered to be associated with BENLYSTA, permanently discontinue and do not reintroduce BENLYSTA [see Contraindications (4)].

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions (5.3)]

. . .

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

• Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.3)].

. . .

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about BENLYSTA?

Immunosuppressive agents, including BENLYSTA can cause serious side effects. Some of these side effects may cause death. The following are serious adverse reactions that have occurred in patients receiving BENLYSTA:

. . .

3. Severe skin reactions. Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur with BENLYSTA. Stop using BENLYSTA right away and tell your healthcare provider if you develop any of the signs and/or symptoms of a severe skin reaction listed below. These may sometimes begin with fever and flu-like symptoms. Your healthcare provider will permanently stop your treatment with BENLYSTA if a severe skin reaction is confirmed:

• painful rash, with reddish non-elevated, target-like or circular patches on the trunk often with central blisters
• widespread skin peeling or blistering
• ulcers often appearing in the eyes, nose, mouth, throat, and genitals

. . .

Do not use BENLYSTA if you:

• are allergic to belimumab or any of the ingredients in BENLYSTA. See the end of this Medication Guide for a complete list of ingredients in BENLYSTA.
• had Stevens-Johnson syndrome or toxic epidermal necrolysis with BENLYSTA.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Advise patients about signs and symptoms of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Instruct patients to stop taking any further doses of BENLYSTA and immediately call their healthcare provider if they experience signs and symptoms suggestive of SJS/TEN [see Warnings and Precautions (5.3)].

. . .

06/20/2025 (SUPPL-34)

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-27)

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-28)

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-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

…

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.

Concomitant Use of Rituximab in Adults: BENLYSTA administered subcutaneously in combination with rituximab was studied in a Phase III, randomized, double-blind, placebo- controlled, 104-week study in adult patients with SLE. Patients were randomized to 1 of the 3 treatment arms: BENLYSTA with a single cycle of rituximab (n = 144); BENLYSTA with placebo (n = 72); BENLYSTA plus standard therapy (n = 76). In general, adverse reactions were consistent with the known safety profile of BENLYSTA and rituximab. When compared with BENLYSTA and placebo or BENLYSTA plus standard therapy, BENLYSTA in combination with rituximab was associated with higher frequency of serious adverse events (13.9%, 19.7%, 22.2%), serious infections (2.8%, 5.3%, 9.0%), and post-injection systemic reactions (9.7%, 5.3%, 13.2%).

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/.

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

17 PATIENT COUNSELING INFORMATION

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-21)

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)].

…

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)].

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)].

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.

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.

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)

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-13)

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.

…

01/17/2020 (SUPPL-8)

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-5)

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-7)

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 …

06/22/2018 (SUPPL-2)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

Available data on use of BENLYSTA … there was no evidence of fetal harm with exposures …

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: … premature birth, miscarriage, and intrauterine growth restriction … Passage of maternal autoantibodies across the placenta …

Data

Animal Data:

… There was no evidence of maternal toxicity, effects on embryofetal and infant survival, or structural abnormalities at exposure approximately 9 times …