Benlysta Drug Information

Important Administration Instructions BENLYSTA may be administered intravenously or subcutaneously. 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). Precautions Prior to Intravenous Use BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis.

Prior to intravenous dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.

Recommended Intravenous Dosage, and Preparation and Administration Instructions BENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus. Recommended Dosage and Administration The recommended intravenous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis 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. Do not concomitantly infuse BENLYSTA 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.

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. Preparation of the Intravenous Solution 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. • Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP. • Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP. 3. Direct the stream of sterile water towards 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. 4. If a mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, do not exceed 500 rpm or swirl the vial for more than 30 minutes. 5.

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. Visually inspect parenteral drug products 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.

If the reconstituted solution of BENLYSTA is not used immediately, store, protect from direct sunlight and refrigerate at 36°F to 46°F (2°C to 8°C). Store solutions of BENLYSTA diluted in normal saline, half‑normal saline, or Lactated Ringer’s Injection 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.

Recommended Subcutaneous Dosage, and Preparation and Administration Instructions The recommended subcutaneous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis is provided in Table 1. Administer BENLYSTA subcutaneously in the abdomen or thigh. For patients less than 10 years of age, BENLYSTA must be administered by a healthcare professional or trained caregiver.

Table 1. Recommended Subcutaneous Dosage of BENLYSTA Administration Instructions for Subcutaneous Injection 1. Administer the first subcutaneous injection of BENLYSTA under the supervision of a healthcare provider.

Provide patients or caregivers with proper training on subcutaneous administration and education about signs and symptoms of hypersensitivity reactions. For adults and pediatric patients 10 years of age and older, subsequent subcutaneous BENLYSTA administrations may be performed by the patient or trained caregiver, if determined to be appropriate. For pediatric patients less than 10 years of age, subsequent subcutaneous BENLYSTA administrations must be performed by a healthcare provider or trained caregiver. 2.

Instruct the patient or caregiver to follow the directions for administration provided in the Instructions for Use. 3. Instruct the patient or 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 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 or caregiver 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 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 administering a 400‑mg dose, inject each 200‑mg injection at least 5 cm (approximately 2 inches) apart. 6.

Instruct the patient or 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 or caregiver 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.

Switching from Intravenous to Subcutaneous BENLYSTA Use Active SLE Administer the first subcutaneous BENLYSTA dose 1 to 4 weeks after the last intravenous dose. Active Lupus Nephritis Patients may be switched from intravenous BENLYSTA treatment to subcutaneous BENLYSTA treatment after completing at least 2 intravenous doses.

Clinical Trials Experience

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. 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. In Trials of subjects treated with BENLYSTA plus standard therapy reported an adverse event compared with 92% treated with placebo plus standard therapy.

The most common serious adverse events were serious infections (6% and 5.2% in the groups receiving BENLYSTA and placebo plus standard therapy, respectively), some of which were fatal. The proportion of subjects who discontinued treatment due to any adverse reaction during Trials for subjects receiving BENLYSTA plus standard therapy and 7.1% for subjects receiving placebo plus standard therapy. Table 2.

The most frequent infections (>5% of subjects 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 subjects receiving BENLYSTA and 1.0% of subjects receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis.

In a randomized, double‑blind, placebo‑controlled, 52‑week, postmarketing safety trial of BENLYSTA administered intravenously in adults with active SLE (N = 4,003), the incidence of serious infections was 3.7% in subjects receiving BENLYSTA compared with 4.1% in subjects receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of subjects receiving BENLYSTA and 0.4% of subjects receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension.

The most common infusion reactions (≥3% of subjects receiving BENLYSTA) were headache, nausea, and skin reactions. Two suicides (0.1%) were reported in subjects receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg). No suicide was reported in either group.

The intravenous trials above did not exclude subjects with a history of psychiatric disorders. In the intravenous controlled clinical trials, malignancies, excluding non‑melanoma skin cancers, were observed in of subjects receiving BENLYSTA and placebo, respectively. Intravenous Administration in Black/African-American Subjects with Active SLE The safety of BENLYSTA 10 mg/kg administered intravenously in adults plus standard therapy (n = 331) compared with placebo plus standard therapy (n = 165) in Black subjects with active SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population.

Intravenous Administration in Adult Subjects with Active 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). The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with active 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.

Specific Adverse Reactions in Adult Subjects with Active Lupus Nephritis (Intravenous Administration) Infections: In Trial 5, the overall incidence of infections was 82% in subjects receiving BENLYSTA compared with 76% in subjects receiving placebo. Serious Infections: In Trial 5, serious infections occurred in 14% of subjects receiving BENLYSTA and in 17% of subjects receiving placebo. Intravenous Administration in Pediatric Subjects 5 Years of Age and Older with Active SLE The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric subjects with active SLE (Trial 6).

The adverse reactions observed were consistent with those observed in adults with SLE. Subcutaneous Administration in Adult Subjects with Active SLE The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 adult subjects with active SLE in a controlled trial (Trial 7). In the trial, 81% of subjects treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy.

The proportion of subjects who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of subjects receiving BENLYSTA plus standard therapy and 8.9% of subjects 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 Trial 7, the overall incidence of infections was 55% in subjects receiving BENLYSTA compared with 57% in subjects receiving placebo.

The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. Serious Infections: In Trial 7, the incidence of serious infections was 4.1% in subjects receiving BENLYSTA and 5.4% in subjects receiving placebo. Fatal infections occurred in 0.5% (3/556) of subjects receiving BENLYSTA and in none of the subjects receiving placebo (0/280).

Depression and Suicidality: In Trial 7, which excluded subjects with a history of psychiatric disorders, psychiatric events were reported in 6% of subjects receiving BENLYSTA and 11% of subjects receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of subjects receiving BENLYSTA and in no subjects receiving placebo. There were no serious depression‑related events or suicides reported in either group.

Malignancy: In Trial 7, the reports of malignancies were similar to those reported with BENLYSTA administered intravenously. 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 Subcutaneous BENLYSTA and Intravenous Rituximab in Adult Subjects with Active SLE BENLYSTA administered subcutaneously in combination with intravenous rituximab was studied in a Phase 3, randomized, double‑blind, placebo‑controlled, 104‑week trial in adult subjects with active SLE. In general, adverse reactions were consistent with the known safety profile of BENLYSTA and rituximab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Fatal anaphylaxis. • Stevens‑Johnson syndrome and toxic epidermal necrolysis.

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.

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. 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 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. 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 ) 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 basis with maternal animal intravenous doses up to 150 mg/kg).

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.

Pediatric Use 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. Pharmacokinetics were evaluated in a total of 53 pediatric subjects (Trial 6) and were consistent with the adult population with active SLE.

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. 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.

• BENLYSTA is contraindicated in patients with a prior history of:
• Anaphylaxis with belimumab.
• Stevens-Johnson syndrome or toxic epidermal necrolysis with belimumab. Previous anaphylaxis, Stevens‑Johnson syndrome, or toxic epidermal necrolysis as a reaction to belimumab.

There is limited experience with overdosage of belimumab.