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  • CLASSES

    Anti-Rheumtic Monoclonal Antibodies
    B Lymphocyte Stimulator (BLyS) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous and subcutaneous human monoclonal antibody that inhibits B lymphocyte stimulator (BLyS)
    Used with standard therapy for active autoantibody-positive, systemic lupus erythematosus (SLE) and active lupus nephritis
    Infusion reactions possible with IV use; serious hypersensitivity reactions and infections have been reported

    COMMON BRAND NAMES

    Benlysta, Benlysta SC

    HOW SUPPLIED

    Benlysta Intravenous Inj Pwd F/Sol: 120mg, 400mg
    Benlysta SC Subcutaneous Inj Sol: 1mL, 200mg

    DOSAGE & INDICATIONS

    For the treatment of active, autoantibody-positive, systemic lupus erythematosus (SLE) in combination with standard therapy.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV infused over 1 hour every 2 weeks for the first 3 doses, then every 4 weeks thereafter. Consider premedication to attenuate infusion- and hypersensitivity-related reactions. Discontinue the infusion immediately if the patient experiences a serious hypersensitivity reaction. LIMITATION OF USE: Belimumab has not been evaluated and is not recommended in patients with severe active central nervous system lupus or in combination with other biologic products.[43658]

    Children and Adolescents 5 to 17 years

    10 mg/kg/dose IV infused over 1 hour every 2 weeks for the first 3 doses, then every 4 weeks thereafter. Consider premedication to attenuate infusion- and hypersensitivity-related reactions. Discontinue the infusion immediately if the patient experiences a serious hypersensitivity reaction. LIMITATION OF USE: Belimumab has not been evaluated and is not recommended in patients with severe active central nervous system lupus or in combination with other biologic products.[43658]

    Subcutaneous dosage
    Adults

    200 mg subcutaneously once weekly. If transitioning from intravenous to subcutaneous therapy, administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose. LIMITATION OF USE: Belimumab has not been evaluated and is not recommended in patients with severe active central nervous system lupus or in combination with other biologic products.[43658]

    For the treatment of active lupus nephritis in combination with standard therapy.
    Intravenous dosage
    Adults

    10 mg/kg/dose IV infused over 1 hour every 2 weeks for the first 3 doses, then every 4 weeks thereafter. Consider premedication to attenuate infusion- and hypersensitivity-related reactions. Discontinue the infusion immediately if the patient experiences a serious hypersensitivity reaction. LIMITATION OF USE: Belimumab has not been evaluated and is not recommended in patients with severe active central nervous system lupus or in combination with other biologic products.

    Subcutaneous dosage
    Adults

    400 mg (two 200-mg injections) subcutaneously once weekly for 4 doses, then 200 mg subcutaneously once weekly thereafter. A patient may transition from intravenous to subcutaneous therapy any time after receipt of the first 2 intravenous doses. If transitioning from intravenous to subcutaneous therapy, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last intravenous dose. LIMITATION OF USE: Belimumab has not been evaluated and is not recommended in patients with severe active central nervous system lupus or in combination with other biologic products.

    MAXIMUM DOSAGE

    Adults

    10 mg/kg/dose IV; 200 mg/week subcutaneously.

    Geriatric

    10 mg/kg/dose IV; 200 mg/week subcutaneously.

    Adolescents

    10 mg/kg/dose IV; safety and efficacy of subcutaneous administration have not been established.

    Children

    5 to 12 years: 10 mg/kg/dose IV; safety and efficacy of subcutaneous administration have not been established.
    1 to 4 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Only belimumab vials should be used to prepare doses for intravenous administration.
     
    Reconstitution
    Remove drug vial from the refrigerator and allow to stand 10 to 15 minutes to reach room temperature.
    Reconstitute with the appropriate amount of Sterile Water for Injection to a final concentration of belimumab 80 mg/mL; add 1.5 mL of Sterile Water for Injection to the 120 mg-vial or 4.8 mL of Sterile Water for Injection to the 400-mg vial.
    Direct the stream of Sterile Water for Injection toward the side of the vial to minimize foaming. Gently swirl 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, but it may take up to 30 minutes.
    If a mechanical reconstitution device (swirler) is used to reconstitute belimumab, it should not exceed 500 rpm, and the vial swirled for no longer than 30 minutes.
    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.
    Storage: Protect the reconstituted solution from sunlight. If not used immediately, refrigerate at 2 to 8 degrees C (36 to 46 degrees F). The total time from reconstitution to completion of infusion should not exceed 8 hours.[43658]
     
    Preparation
    Once reconstituted, the belimumab injection in the vial must be further diluted to prepare the IV infusion.
    Belimumab is NOT compatible with dextrose-containing solutions. Dilute belimumab in 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or Lactated Ringer's Injection only, to a total volume of 250 mL. For patients weighing 40 kg or less, 100 mL may be used as long as the concentration in the infusion bag does not exceed 4 mg/mL. From the infusion bag or bottle, withdraw and discard a volume equal to the volume of the reconstituted solution of belimumab required for the patient's dose. Then add the reconstituted solution of belimumab to the infusion bag or bottle. Gently invert the bag or bottle to mix the solution.
    Discard any unused belimumab solution that remains in the vials.
    Storage: Once diluted, the infusion may be stored at 2 to 8 degrees C (36 to 46 degrees F) or room temperature. The total time from reconstitution to completion of infusion should not exceed 8 hours.[43658]
     
    IV Infusion
    Administer belimumab by intravenous infusion only; do not give as an IV push or bolus.
    Only healthcare providers prepared to manage anaphylaxis should administer belimumab by infusion.
    Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.
    Infuse over 1 hour; administration may be slowed or interrupted if infusion reaction occurs.
    Do not administer belimumab concomitantly in the same IV line with other agents.[43658]

    Subcutaneous Administration

    Only belimumab prefilled syringes or autoinjectors should be used for subcutaneous administration.
    The first belimumab subcutaneous injection should be under the supervision of a healthcare professional. Patients may self-administer belimumab using the prefilled syringe or autoinjector after proper training.
    Preparation
    Remove prefilled syringe or autoinjector from the refrigerator and allow 30 minutes to reach room temperature. Do not warm in any other way.
    Inspect syringe or autoinjector prior to administration; belimumab should be clear to opalescent and colorless to pale yellow. Small air bubbles, however, are expected and acceptable.
    Do not use the autoinjector or prefilled syringe if dropped on a hard surface.
    Storage of unopened prefilled syringes or autoinjectors: Protect from light and store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) until time of use. Prefilled syringe or autoinjector may be stored outside the refrigerator for up to 12 hours if protected from light. Do not use or place back in the refrigerator if left out for more than 12 hours. Do not freeze and do not use if the injection has been frozen. Do not shake. Avoid exposure to heat.[43658]
     
    Administration
    Subcutaneous administration sites include the abdomen and thigh. Do not inject within 2 inches of the umbilicus. Do not administer where the skin is tender, bruised, erythematous, or hard.
    For the prefilled syringe, insert the entire needle into the pinched area of the skin at a slight 45-degree angle using a dart-like motion. Push the plunger all the way down until all the solution is injected. While keeping your hold on the syringe, slowly move your thumb back, allowing the plunger to rise. The needle will automatically rise into the needle guard.
    For the autoinjector, position the autoinjector straight over the injection site at a 90-degree angle. Make sure the gold needle guard is flat on the skin. To start the injection, firmly press the autoinjector down onto the injection site and hold in place. A "click" will be heard at the start of the injection. Continue to hold the autoinjector down until you see that the purple indicator has stopped moving. A second "click" may be heard. The injection may take up to 15 seconds to complete. When the injection is complete, lift the injector from the injection site.
    Dispose of any used prefilled syringes or autoinjectors immediately after use.
    Rotate sites of injection with each dose. When a 400-mg dose is administered at the same site, the 2 individual 200-mg injections should be administered at least 5 cm (approximately 2 inches) apart.
    Missed dose: If a dose is missed, administer as soon as possible. Thereafter, the patient can resume dosing on their usual day of administration or start a new weekly schedule from the day that the missed dose was administered. Do not give 2 doses on the same day.[43658]

    STORAGE

    Benlysta:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container
    Benlysta SC:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions, requires an experienced clinician, risk of serious hypersensitivity reactions or anaphylaxis

    Belimumab use carries a risk of serious hypersensitivity reactions or anaphylaxis. The drug is contraindicated in patients who have had anaphylaxis with belimumab. Administration of belimumab requires an experienced clinician prepared to manage anaphylaxis and infusion-related reactions. Consider premedication to attenuate such responses. Monitor all patients during and for an appropriate period of time after belimumab administration. If serious hypersensitivity reactions develop during belimumab administration, discontinue the infusion immediately and treat accordingly. The infusion rate may be slowed or interrupted should an infusion reaction develop. It is important to note that hypersensitivity reactions may present as infusion reactions. While most hypersensitivity reactions have occurred acutely, some appear 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. Adverse events associated with the infusion may also occur. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving belimumab and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions 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. 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. Advise patients and caregivers of the signs and symptoms of hypersensitivity and to seek immediate medical help if symptoms develop.

    Immunosuppression, infection, progressive multifocal leukoencephalopathy

    Serious infections, including fatal infections, have been reported in patients receiving immunosuppressive therapy, including belimumab. Consider risks and benefits of belimumab prior to initiating therapy in patients with a chronic or severe infection. Consider interrupting belimumab therapy in patients who develop a new infection while on therapy; monitor these patients closely. While the overall incidence of serious infections was similar between belimumab and place in clinical trials, the incidence of fatal infections was higher with belimumab. The most frequently reported serious infections were pneumonia, urinary tract infections, cellulitis, and bronchitis. In clinical trials, fatal infections occurred in 0.3% to 0.9% of belimumab patients and 0% to 0.9% of placebo patients. Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents. Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), some fatal, have been reported in patients with systemic lupus erythematosus receiving immunosuppressants, including belimumab. Immunosuppression and impaired immune function are risk factors for PML. Consider a diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms. Consult a neurologist or other appropriate specialist as warranted. Consider discontinuation of immunosuppressant therapy, including belimumab, in patients with confirmed PML.[43658]

    Depression, psychiatric event, suicidal ideation

    Use belimumab therapy cautiously in patients with a history of depression or other psychiatric disorders. Prior to initiating belimumab therapy, prescribers should consider patient's medical history and psychiatric status to assess for risk of depression and suicide. Advise all patients and, if applicable, their caregivers to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other changes in moods or behaviors. Psychiatric events, related primarily to depression-related events, insomnia, and anxiety, were reported more frequently with belimumab than with placebo during clinical trials. Serious events, including suicide and suicidal ideation or behavior, were reported. In intravenous belimumab clinical trials, 2 suicides (0.1%) were reported with belimumab (one with 10 mg/kg and one with 1 mg/kg). Among patients who develop a psychiatric event or symptoms, the potential risks and benefits of continued belimumab therapy should be assessed.[43658]

    Vaccination

    Vaccination with live vaccines should not be given for 30 days before or concurrently with belimumab, 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 belimumab or on the effect of belimumab on new immunizations. Because of its mechanism of action, belimumab may interfere with the response to immunizations. The risks and benefits should also be considered prior to administering live or live-attenuated vaccines to an infant exposed to belimumab in utero.

    New primary malignancy

    The impact of treatment with belimumab on the development of a new primary malignancy is not known. In the controlled clinical trials in adults with systemic lupus erythematosus (SLE), malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving intravenous belimumab and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% and 0.3% of patients receiving intravenous belimumab and placebo, respectively. Similar data was observed in SLE clinical trials of subcutaneous belimumab. The mechanism of action of belimumab could increase the risk for the development of malignancies.

    Black patients

    Some data suggest that Black patients may have a reduced clinical response to belimumab. Exploratory subgroup analyses of 2 intravenous dosing trials revealed the SLE Responder Index-4 (SRI-4) response rates were lower for Black patients receiving belimumab plus standard therapy compared to Black patients receiving placebo plus standard therapy (44% for placebo, 31% for belimumab 1 mg/kg, 36% for belimumab 10 mg/kg). In another intravenous dosing trial utilizing the modified SLEDAI-2K scoring for proteinuria, the SLE responder rate (SRI-S2K) at week 52 was higher in Black patients receiving belimumab 10 mg/kg plus standard therapy compared to those receiving placebo plus standard therapy (49% vs. 42%); the difference was not statistically significant. In a subcutaneous dosing study, the SRI-4 response was slightly higher for Black patients receiving belimumab therapy compared to those receiving placebo (45% vs. 39%); however, the treatment difference was not as large as that observed in the overall population (61% for belimumab and 48% for placebo in the overall population). The safety profile of belimumab in Black patients is consistent with the safety profile in the overall population.[43658]

    Infants, neonates, pregnancy

    Limited data on use of belimumab during human pregnancy, either from observational studies, published case reports, or postmarketing surveillance, are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. 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 fetus. There are also risks to the mother and fetus associated with the underlying maternal condition, systemic lupus erythematosus (SLE). There is 1 case report published of belimumab use throughout pregnancy in a mother with SLE; use led to well-controlled SLE in the mother, but with the presence of mild Ebstein's anomaly of the heart in the baby. During animal studies, no evidence of embryotoxicity or fetal malformations were noted when monkeys were exposed to approximately 9 times (based on intravenous administration) and 20 times (based on subcutaneous administration) the maximum recommended human dose (MRHD). Belimumab-related findings in monkey fetuses and/or infant monkeys included reduction in B-cell counts, reductions in the density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, and altered IgG and IgM titers. These findings were reversible within 3 to 12 months after the drug was discontinued. Based on these data, the immune system of neonates or infants of treated mothers may be adversely affected; the risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to belimumab in utero. Monitor an infant of a belimumab-treated mother for B-cell reduction and other immune dysfunction after birth. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to belimumab; information about the registry can be obtained at pregnancyregistry.gsk.com/belimumab.html or by calling 1-877-681-6296.

    Contraception requirements, reproductive risk

    Discuss the potential reproductive risk of belimumab and contraception requirements in females of childbearing potential. After an assessment of benefit versus risk, if prevention of pregnancy is warranted, females should use effective contraception during treatment and for at least 4 months after the final treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant.

    Breast-feeding

    No information is available on the presence of belimumab in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production. Maternal antibodies are known to be present in human milk; if belimumab is transferred into the milk of a breast-feeding mother, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant are unknown. Belimumab was detected in the milk of cynomolgus monkeys; however, due to species-specific differences in lactation physiology, these animal data may not predict drug concentrations in human milk. The lack of clinical data in humans precludes clear determination of the risk of belimumab to a breast-feeding infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[43658]

    Geriatric

    Use with caution in geriatric patients. Clinical studies did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger patients; most patients were 18 to 45 years of age.[43658]

    ADVERSE REACTIONS

    Severe

    infection / Delayed / 6.0-6.0
    suicidal ideation / Delayed / 1.3-2.4
    angioedema / Rapid / 0.6-0.6
    anaphylactic shock / Rapid / 0.6-0.6
    bradycardia / Rapid / 0.5-0.5
    new primary malignancy / Delayed / 0.2-0.4
    leukoencephalopathy / Delayed / Incidence not known

    Moderate

    infusion-related reactions / Rapid / 17.0-17.0
    depression / Delayed / 2.7-6.3
    migraine / Early / 5.0-5.0
    antibody formation / Delayed / 0-4.8
    cystitis / Delayed / 4.0-4.0
    leukopenia / Delayed / 4.0-4.0
    hypotension / Rapid / 0.6-0.6
    dyspnea / Early / 0.6-0.6
    edema / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    erythema / Early / Incidence not known

    Mild

    nausea / Early / 15.0-15.0
    diarrhea / Early / 12.0-12.0
    fever / Early / 10.0-10.0
    pharyngitis / Delayed / 5.0-9.0
    injection site reaction / Rapid / 6.1-6.1
    insomnia / Early / 6.0-6.0
    anxiety / Delayed / 3.9-3.9
    myalgia / Early / 0.5-0.5
    influenza / Delayed / 5.0
    sinusitis / Delayed / 5.0
    headache / Early / 3.0
    pruritus / Rapid / 3.0
    rash / Early / 3.0
    urticaria / Rapid / 3.0
    fatigue / Early / Incidence not known

    DRUG INTERACTIONS

    Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including belimumab. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclophosphamide: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as intravenous cyclophosphamide. Therefore, belimumab use is not recommended in combination with intravenous cyclophosphamide. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Live Vaccines: (Major) Live vaccines should not be given for 30 days before or concurrently with belimumab, as clinical safety has not been established. Because of its mechanism of action, belimumab may interfere with the response to immunizations. No data are available on the secondary transmission of infection from persons receiving live vaccines. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ocrelizumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as ocrelizumab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Ofatumumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as ofatumumab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Rituximab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including rituximab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Rituximab; Hyaluronidase: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including rituximab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tumor Necrosis Factor modifiers: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Therefore, belimumab use is not recommended in combination with TNF blockers. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.

    PREGNANCY AND LACTATION

    Pregnancy

    Limited data on use of belimumab during human pregnancy, either from observational studies, published case reports, or postmarketing surveillance, are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. 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 fetus. There are also risks to the mother and fetus associated with the underlying maternal condition, systemic lupus erythematosus (SLE). There is 1 case report published of belimumab use throughout pregnancy in a mother with SLE; use led to well-controlled SLE in the mother, but with the presence of mild Ebstein's anomaly of the heart in the baby. During animal studies, no evidence of embryotoxicity or fetal malformations were noted when monkeys were exposed to approximately 9 times (based on intravenous administration) and 20 times (based on subcutaneous administration) the maximum recommended human dose (MRHD). Belimumab-related findings in monkey fetuses and/or infant monkeys included reduction in B-cell counts, reductions in the density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, and altered IgG and IgM titers. These findings were reversible within 3 to 12 months after the drug was discontinued. Based on these data, the immune system of neonates or infants of treated mothers may be adversely affected; the risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to belimumab in utero. Monitor an infant of a belimumab-treated mother for B-cell reduction and other immune dysfunction after birth. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to belimumab; information about the registry can be obtained at pregnancyregistry.gsk.com/belimumab.html or by calling 1-877-681-6296.

    MECHANISM OF ACTION

    Belimumab inhibits B lymphocyte stimulator (BLyS), which is a B-cell survival factor. Normally, the soluble BLyS binds to its receptors on B cells and allows B cell survival. Belimumab binds BLyS and prevents it from binding to its receptors on B cells. Thus, the survival of B cells including autoreactive B cells is inhibited by belimumab. Further, the differentiation of B cells into immunoglobulin-producing plasma cells is reduced.
     
    Receipt of belimumab infusions for 52 weeks to patients with systemic lupus erythematosus (SLE) significantly reduced circulating CD19+, CD20+, naive, and activated B cells, plasmacytoid cells, and the SLE B-cell subset. Reductions in naive and the SLE B-cell subset were observed as early as week 8 and were sustained to week 52. Memory cells increased initially and slowly declined toward baseline concentrations by week 52. The clinical relevance of these effects on B cells has not been established. Receipt of belimumab also led to reductions in IgG and anti-dsDNA and to increases in complement (C3 and C4) as early as week 8 and were sustained through week 52. The clinical relevance of normalizing these biomarkers has not been definitively established.

    PHARMACOKINETICS

    Belimumab is administered by intravenous infusion or subcutaneous injection. Volume of distribution in adults is 5 L. Systemic clearance is approximately 204 to 215 mL/day, and terminal half-life is 18.3 to 19.4 days.[43658]
     
    Affected cytochrome P450 (CYP450) enzymes and drug transporters: Unknown

    Intravenous Route

    Cmax and AUC were 313 mcg/mL and 3,083 mcg/mL x day, respectively, and the distribution half-life was 1.8 days after receipt of a 10 mg/kg IV infusion in adult patients.[43658]

    Subcutaneous Route

    After subcutaneous administration of 200 mg belimumab in SLE patients, the time to maximum concentration was 2.6 days. The bioavailability is approximately 74%. With weekly administration, there were minor fluctuations around the average concentration with the minimum concentration being only slightly below the average concentration (104 mcg/mL). Cmax and AUC were 108 mcg/mL and 726 mcg/mL x day, respectively, with a distribution half-life of 1.1 days. Population pharmacokinetic modeling and simulation of the subcutaneous belimumab 400 mg weekly loading dose predicted an average belimumab concentration of 78 mcg/mL during the first 12-weeks, which is similar to the estimated concentration of 89 mcg/mL for intravenous administration. The loading dose of 400 mg weekly results in steady-state concentrations from week 2 of dosing. In adults with lupus nephritis, average steady-state concentrations with subcutaneous belimumab 200 mg once weekly are predicted to be similar to observed concentrations with belimumab 10 mg/kg intravenously every 4 weeks.[43658]