BENLYSTA (belimumab) for injection

BENLYSTA (belimumab) for injection

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BENLYSTA (belimumab) for injection

Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a murine cell (NS0) expression system.

Intravenous Infusion

BENLYSTA (belimumab) for injection is a sterile, white to off-white, preservative-free, lyophilized powder in a single-dose vial for reconstitution and dilution prior to intravenous infusion. BENLYSTA for injection is supplied as 120 mg per vial and 400 mg per vial and requires reconstitution with Sterile Water for Injection, USP (1.5 mL and 4.8 mL, respectively) to obtain a concentration of 80 mg/mL. After reconstitution, each vial allows for withdrawal of 1.5 mL (120 mg) or 5 mL (400 mg). Each mL delivers 80 mg belimumab, citric acid (0.16 mg), polysorbate 80 (0.4 mg), sodium citrate (2.7 mg), and sucrose (80 mg), with a pH of 6.5.

The vial stoppers are not made with natural rubber latex.

Subcutaneous Injection

BENLYSTA (belimumab) injection is a sterile, preservative-free, clear to opalescent, and colorless to pale yellow solution for subcutaneous use. It is supplied in a 1-mL single-dose prefilled autoinjector with a fixed 27-gauge, half-inch needle or in a 1-mL single-dose prefilled syringe with a fixed 27-gauge, half-inch needle with a needle guard. Each 1 mL delivers 200 mg belimumab, L-arginine hydrochloride (5.3 mg), L-histidine (0.65 mg), L-histidine monohydrochloride (1.2 mg), polysorbate 80 (0.1 mg), and sodium chloride (6.7 mg), with a pH of 6.0.

The autoinjectors and prefilled syringes are not made with natural rubber latex.

Indications and usage

BENLYSTA is a B-lymphocyte stimulator (BLyS)-specific inhibitor indicated for the treatment of:

  • patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy;
  • adult patients with active lupus nephritis who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics. Use of BENLYSTA is not recommended in these situations.

Mechanism of Action

BENLYSTA is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. BENLYSTA does not bind B cells directly, but by binding BLyS, BENLYSTA inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Dosage and administration

Recommended Intravenous Dosage Regimen — Adults with SLE or Lupus Nephritis and Pediatric Patients with SLE

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

Recommended Subcutaneous Dosage Regimen — Adult Patients with SLE

  • The recommended dosage is 200 mg once weekly given as a subcutaneous injection in the abdomen or thigh. Subcutaneous dosing is not based on weight.
  • If transitioning from intravenous therapy with BENLYSTA to subcutaneous administration, administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose.

Recommended Subcutaneous Dosage Regimen — Adult Patients with Lupus Nephritis

  • In patients initiating therapy with BENLYSTA for active lupus nephritis, the recommended dosage regimen is a 400-mg dose (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. The dose is given via subcutaneous injection in the abdomen or thigh.
  • A patient with lupus nephritis may transition from intravenous therapy with BENLYSTA to subcutaneous therapy any time after the patient completes the first 2 intravenous doses.

Contraindications

  • BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

Adverse reactions

Common adverse reactions in adults (≥5%): nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous administration).

Adverse reactions in pediatric patients aged 5 years and older were consistent with those observed in adults.

Warnings and precautions

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.

Hypersensitivity Reactions, including Anaphylaxis: 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.

Infusion Reactions: 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.

Depression and Suicidality: 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)

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Immunization: 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. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

Drug interactions

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

Use in specific populations

Pregnancy: 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.

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.

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 Bcell reduction and other immune dysfunction

Lactation: 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.

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: Intravenous administration of BENLYSTA in patients with SLE is indicated in children aged 5 years and older.

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.

Geriatric Use: Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects. Use with caution in elderly 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.

Overdosage

There is limited experience with overdosage of belimumab. Adverse reactions reported in association with cases of overdose have been consistent with those expected for belimumab.

Two doses of up to 20 mg/kg have been given intravenously to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

Storage

Intravenous Infusion: Refrigerate vials at 36°F to 46°F (2°C to 8°C). Store vials in the original carton until use to protect from light. Do not freeze. Avoid exposure to heat.

Subcutaneous Injection

Prior to Dispensing: Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat.

Following Dispensing: Refrigerate prefilled autoinjectors and prefilled syringes at 36°F to 46°F (2°C to 8°C). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Avoid exposure to heat.

BENLYSTA may be stored outside of the refrigerator up to 86°F (30°C) for up to 12 hours if protected from sunlight. Do not use and do not place back in refrigerator if left out for more than 12 hours.

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