Benlysta

Important Administration Information

BENLYSTA may be administered intravenously or subcutaneously [see Dosage and Administration ( 2.2, 2.3)]. Vials are intended for intravenous use only (not for subcutaneous use) and autoinjectors and prefilled syringes are intended for subcutaneous use only (not for intravenous use).

Recommended Intravenous Dosage for Adult and Pediatric Patients with SLE or Lupus Nephritis

Dosage

BENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus.

The recommended intravenous dosage is 10 mg/kg at 2‑week intervals for the first 3 doses and at 4‑week intervals thereafter. Reconstitute, dilute, and administer as an intravenous infusion over a period of 1 hour. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Contraindications , Warnings and Precautions ].

Precautions Prior to Intravenous Use

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis [see Warnings and Precautions ].

Prior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions [see Warnings and Precautions , Adverse Reactions ].

Preparation of Intravenous Solutions

BENLYSTA for intravenous use is provided as a lyophilized powder in a single‑dose vial and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows. Use of a 21- to 25-gauge needle is recommended when piercing the vial stopper for reconstitution and dilution.

Reconstitution Instructions for Intravenous Use:

1.

Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.

2.

Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain a concentration of 80 mg/mL belimumab.

3.

Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.

4.

Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.

5.

The stream of sterile water should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.

6.

If a mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.

7.

Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.

Dilution Instructions for Intravenous Use:

1.

Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringer’s Injection, USP to a volume of 250 mL for intravenous infusion. To prepare the intravenous infusion solution for patients whose body weight is less than or equal to 40 kg, a 100 mL bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection may be used such that the resulting belimumab concentration in the infusion bag does not exceed 4 mg/mL. From a 250‑mL (or 100‑mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection, withdraw and discard a volume equal to the volume of the reconstituted solution of BENLYSTA required for the patient’s dose. Then add the required volume of the reconstituted solution of BENLYSTA into the intravenous infusion solution in the infusion bag or bottle. Gently invert the bag or bottle to mix the intravenous infusion solution. Any unused solution in the vials must be discarded.

2.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.

3.

The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 36°F to 46°F (2°C to 8°C). Solutions of BENLYSTA diluted in normal saline, half-normal saline, or Lactated Ringer’s Injection may be stored at 36°F to 46°F (2°C to 8°C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed 8 hours.

4.

No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.

Administration Instructions for Intravenous Use

1.

The diluted solution of BENLYSTA should be administered by intravenous infusion over a period of 1 hour.

2.

BENLYSTA should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of BENLYSTA with other agents.

Recommended Subcutaneous Dosage

The recommended dosages of BENLYSTA, when administered subcutaneously, are provided in Table 1. When administered subcutaneously, BENLYSTA should be administered in the patient’s abdomen or thigh. For patients less than 10 years of age, BENLYSTA must be administered by a healthcare professional or trained caregiver.

Transitioning from Intravenous to Subcutaneous Administration

SLE: Administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose.

Lupus Nephritis: A patient with lupus nephritis may transition from intravenous therapy with BENLYSTA to subcutaneous therapy after the patient completes the first 2 intravenous doses. If transitioning, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last intravenous dose.

Administration Instructions for Subcutaneous Injection

1.

It is recommended that the first subcutaneous injection of BENLYSTA should be under the supervision of a healthcare professional. The healthcare provider should provide proper training in subcutaneous technique and education about signs and symptoms of hypersensitivity reactions [see Warning and Precautions ]. A patient may self-inject or the patient caregiver may administer BENLYSTA subcutaneously after the healthcare provider determines it is appropriate.

2.

Instruct the patient or patient caregiver to follow the directions for administration provided in the Instructions for Use.

3.

Instruct the patient or patient caregiver to remove the autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for 30 minutes prior to the subcutaneous injection. Do not warm BENLYSTA in any other way.

4.

Prior to administration, instruct the patient or patient caregiver to visually inspect the window of the autoinjector or the prefilled syringe for particulate matter or discoloration. BENLYSTA should be clear to opalescent and colorless to pale yellow. Do not use BENLYSTA if the product exhibits discoloration or particulate matter. Instruct the patient not to use the BENLYSTA autoinjector or prefilled syringe if dropped on a hard surface.

5.

When injecting in the same body region, advise the patient or patient caregiver to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When a 400-mg dose is administered at the same site, it is recommended that the 2 individual 200-mg injections be administered at least 5 cm (approximately 2 inches) apart.

6.

Instruct the patient or patient caregiver to administer BENLYSTA, preferably on the same day each week or the same day of alternate weeks, as appropriate.

7.

If a dose is missed, instruct the patient to administer a dose as soon as the patient remembers. Thereafter, the patient can resume dosing on their usual day of administration or start a new schedule from the day that the missed dose was administered.

Pregnancy

Pregnancy Exposure Registry

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/.

Risk Summary

Available 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 (see Clinical Considerations). 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 (see Clinical Considerations). 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 (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 (see Data). 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 [see Clinical Pharmacology ].

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, miscarriage, and intrauterine growth restriction. Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal autoantibodies 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 [see Warnings and Precautions ].

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, 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 area under the curve [AUC] basis with maternal animal 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. Immunoglobulin G (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.

Lactation

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.

Females and Males of Reproductive Potential

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.

Pediatric Use

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.

Intravenous Use

Use of BENLYSTA intravenously 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 ]. Pharmacokinetics were evaluated in a total of 53 pediatric patients with SLE and were consistent with the adult population with SLE [see Clinical Pharmacology ].

Use of intravenous administration 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 ].

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 ].

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.

Geriatric Use

Clinical studies of BENLYSTA did not include sufficient numbers of subjects, 65 years of age or older, to determine whether they respond differently from younger subjects. Use with caution in geriatric patients.

Renal Impairment

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

Hepatic Impairment

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.

Racial Groups

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 ].

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 ].

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 ].

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 ].

Serious Infections

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 [see Adverse Reactions ].

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 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.

Hypersensitivity Reactions, including Anaphylaxis

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

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

Depression and Suicidality

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

Malignancy

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 ].

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.

Immunization

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.

Concomitant Use with Other Biologic Therapies

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 ]. 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 ].