Belimumab is a human monoclonal antibody that inhibits B lymphocyte stimulator protein (BLyS). Inhibition of BLyS inhibits the survival of B cells including autoreactive B cells and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. Belimumab is indicated as an adjunct to standard therapy for the treatment of active systemic lupus erythematosus (SLE) and active lupus nephritis in adult and pediatric patients 5 years and older. Standard SLE therapy includes corticosteroids, antimalarials, NSAIDs, and/or immunosuppressants (e.g., azathioprine, mycophenolate, or methotrexate). NICE guidelines recommend that belimumab only be used as add-on therapy if the patient has a Safety of Estrogen in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of 10 or more despite standard treatment; continued belimumab treatment beyond 6 months is only recommended if the SELENA-SLEDAI score is reduced by 4 points or more. Intravenous use of belimumab is associated with infusion-related reactions, and the symptoms of these reactions may overlap with those noted with hypersensitivity reactions. Serious and sometimes fatal hypersensitivity reactions and infections have been reported in patients receiving biologic immunosuppressive agents, including both intravenous and subcutaneous belimumab.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Vials are intended for intravenous use only (not subcutaneous use).
Reconstitution of Vial
-Remove drug vial from the refrigerator and allow 10 to 15 minutes for it to reach room temperature.
-Use a 21- or 25- gauge needle to pierce the vial stopper for reconstitution and dilution.
-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
-add 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 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 vial 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.
Preparation of the IV infusion
-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, a 100 mL bag or bottle of the above listed diluents may be used as long as the infusion concentration does not exceed 4 mg/mL.
--From a 250 mL (or 100 mL) 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. Do NOT shake.
-Discard any unused belimumab solution that remains in the vials.
-Storage: Once diluted, the IV 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.
IV Infusion Administration
-Administer belimumab by intravenous infusion only; do not give as an IV push or bolus.
-Only health care 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.
Subcutaneous Administration
-Use only belimumab prefilled syringes or autoinjectors for subcutaneous administration (not vials).
-The first belimumab subcutaneous injection should be under the supervision of a health care professional. Patients may self-administer belimumab using the prefilled syringe or autoinjector after proper training.
-Both the prefilled syringe and autoinjector come with 'Instructions for Use'.
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 it is dropped on a hard surface.
-Do NOT shake.
-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.
Subcutaneous 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: Do not remove the needle cap until just prior to injection. 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: Do not remove the ring cap until just prior to injection. 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.
-Properly 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.
Patients receiving immunosuppressive agents such as belimumab may develop an infection, which can be serious and fatal. Overall, the incidence of serious infections in controlled trials was similar in patients receiving belimumab vs. placebo, whereas fatal infections occurred more frequently in patients receiving belimumab. However, data from 1 clinical trial found the incidence of serious infections increased when belimumab was administered in combination with another biologic therapy (rituximab). Caution is advised if belimumab is administered in combination with other biologic therapies. Additionally, consider the risks and benefits of belimumab therapy in patients with severe or chronic infection. Instruct patients to report the development of any signs or symptoms of an infection and consider interrupting belimumab treatment in patients who develop a new infection; treat as clinically indicated. Belimumab may cause leukopenia, which increases the risk of infection. Leukopenia was noted in 4% of 674 patients who received belimumab 10 mg/kg and in 2% of placebo recipients. In systemic lupus erythematosus (SLE) controlled clinical trials of belimumab administered intravenously, the overall incidence of infections was 71% in patients treated with belimumab as compared to 67% in those who received placebo. Upper respiratory tract infection, urinary tract infection, naso-pharyngitis, sinusitis, bronchitis, and influenza were reported in greater than 5% of belimumab-treated patients. The incidence of serious infections and fatal infections were 6% and 0.3%, respectively, in the belimumab-treated group and 5.2% and 0.1%, respectively, in the placebo-treated group. Pneumonia, urinary tract infections, cellulitis, and bronchitis were the most frequently reported serious infections. Among 674 patients who were administered belimumab 10 mg/kg, pharyngitis was noted in 5%, naso-pharyngitis in 9%, bronchitis in 9%, cystitis in 4%, and viral gastroenteritis in 3%. In a clinical trial involving adults patients with lupus nephritis, the overall incidence of infections was 82% with intravenous belimumab and 76% with placebo. The incidences of serious and fatal infections were 14% and 0.9%, respectively, with intravenous belimumab and 17% and 0.9%, respectively, with placebo. In a postmarketing safety trial in adults patients with SLE, the incidence of serious infection was 3.7% with intravenous belimumab 10 mg/kg and 4.1% with placebo. The incidences of fatal infections and all-cause mortality were 0.45% and 0.5%, respectively, with belimumab and 0.15% and 0.4%, respectively, with placebo. In a 104-week clinical trial of adults with SLE, the incidence of serious infections were higher in patients treated with belimumab plus rituximab (9%) than in those receiving belimumab plus placebo (2.8%) or belimumab plus standard therapy (5.3%). In the SLE controlled trials of subcutaneous belimumab, the overall incidence of infections was 55% in patients treated with belimumab compared to 57% in those receiving placebo. Serious infections were reported in 4.1% with belimumab and 5.4% with placebo. The most commonly reported infections with subcutaneous belimumab were similar to those reported with intravenous belimumab. Fatal infections occurred in 0.5% of belimumab patients; no cases of fatal infection with placebo. Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), some fatal, have been reported in patients with SLE 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. In patients with suspected PML, immunosuppressant therapy, including belimumab, must be suspended until PML has been excluded. If PML is confirmed, treatment must be discontinued.
Infusion-related reactions are associated with the administration of belimumab; close patient monitoring is recommended, as hypersensitivity reactions may present as infusion reactions. If the patient develops an infusion reaction, the infusion rate may be slowed or interrupted. However, if a serious hypersensitivity reaction occurs, then the infusion must be discontinued immediately. Consider premedication to attenuate such responses; insufficient evidence exists to determine whether premedication diminishes the frequency or severity of infusion reactions. The most common infusion reactions, occurring in 3% or more of patients receiving belimumab during clinical trials, were headache, nausea, and skin reactions. Among 674 patients who received 10 mg/kg, 15% had nausea, and 5% had migraine. In controlled clinical trials, same-day infusion reactions were reported in 17% (251/1458) of belimumab-treated patients and in 15% (99/675) of those treated with placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving belimumab and in 0.4% of patients receiving placebo; these included bradycardia, myalgia, headache, rash, urticaria, and hypotension.
Belimumab may cause diarrhea and nausea. Among 674 patients who received 10 mg/kg, 12% had diarrhea as compared with 9% of patients who received placebo, and 15% had nausea as compared with 12% who received placebo. Nausea (3% or more) has also been reported as one of the symptoms of belimumab-related infusion reactions; if additional symptoms are present, carefully evaluate the patient for the presence of an infusion-related reaction.
Hypersensitivity reactions, including anaphylaxis and death, have been associated with belimumab use. If a patient experiences a serious reaction, belimumab administration must be discontinued immediately and the patient treated accordingly. In controlled clinical trials of intravenous belimumab, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving belimumab and 11% (76/675) of those receiving placebo. Manifestations of these reactions, including anaphylaxis (0.6%) or anaphylactic shock, hypotension, angioedema, urticaria or other rash (unspecified), pruritus, and dyspnea were reported in 0.6% of treated patients during premarketing clinical trials. The more common infusion or hypersensitivity type reactions (3% or more of patients) included skin reactions (rash, urticaria, pruritus). In the controlled trial of subcutaneous belimumab, systemic hypersensitivity reactions were similar to those reported in the intravenous trials. Acute hypersensitivity reactions generally occur within hours of the infusion; however, delay in the onset of hypersensitivity reactions has been observed. Non-acute hypersensitivity reactions (e.g., rash, nausea, fatigue, myalgia, headache, and facial edema) have been reported and typically occur up to a week after the most recent infusion. Hypersensitivity reactions may occur in patients who have previously tolerated belimumab infusions. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions. However, the manufacturer recommends premedication prior to intravenous infusion. Infusion reactions are also associated with belimumab administration and may have similar signs and symptoms as those associated with hypersensitivity reactions. Advise patients and caregivers of the signs and symptoms of hypersensitivity and to seek immediate medical help if such symptoms occur. Monitor all patients during and for an appropriate period of time after belimumab administration.
Psychiatric adverse events such as suicidal ideation, depression, anxiety, and insomnia may occur with belimumab. In clinical trials, 2 suicides (0.1%) were reported in patients receiving intravenous belimumab. 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 caregivers, if applicable, to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other changes in moods or behaviors. In controlled clinical trials of intravenous belimumab, psychiatric adverse events reported more commonly with belimumab and at rates higher than with placebo included depression-related events (6.3%), serious depression (0.3 to 0.4%), insomnia (6%), and anxiety (3.9%). Serious psychiatric events occurred at an incidence of 0.4% in patients treated with placebo compared to 0.8% in patients treated with belimumab. Suicidal ideation or behavior was reported by 2.4% of belimumab patients and 2% of placebo patients, based on the Columbia-Suicide-Severity Rating Scale (C-SSRS). Patients with a history of psychiatric disorders were not excluded from the belimumab intravenous studies. In the controlled trials of belimumab administered subcutaneously, which excluded patients with a history psychiatric disorders, psychiatric events were reported in 6% of those receiving belimumab and 11% in the placebo group. Depression-related events were reported in 2.7% of patients receiving belimumab and 3.6% in the placebo group. Serious psychiatric events were reported in 0.2% of patients receiving belimumab and in 0% patients receiving placebo. No serious depression-related events or suicides were reported in either group. Based on the C-SSRS, suicidal ideation or behavior was reported in 1.3% of belimumab patients and 0.7% placebo patients.
Belimumab receipt leads to antibody formation against belimumab. Anti-belimumab antibodies were detected in 4 of 563 (0.7%) systemic lupus erythematosus (SLE) patients receiving intravenous belimumab 10 mg/kg and in 27 of 559 (4.8%) patients receiving belimumab 1 mg/kg intravenously (IV). The reported frequency for the group receiving 10 mg/kg IV may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. The clinical relevance of the presence of anti-belimumab antibodies is not known, but 3 patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions were life-threatening. In addition to anti-belimumab antibodies, neutralizing antibodies were detected in 3 patients receiving 1 mg/kg. In an intravenous dosing trial in adult Black patients, belimumab antibodies were detected in 2 of 321 (0.6%) patients receiving belimumab 10 mg/kg IV; the results were consistent with data from the known safety profile of the drug given IV along with standard therapy in the overall population. No belimumab antibodies were detected among 556 patients enrolled in the subcutaneous trial. In addition, no belimumab antibodies were detected in 224 lupus nephritis patients that received intravenous belimumab therapy during a 104-week trial. The detection of antibodies is dependent on the sensitivity and specificity of the assay, and the incidence of positive antibodies may be influenced by assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, the incidence of antibody formation to belimumab cannot be directly compared to other products.
Among 674 belimumab recipients, 10% had fever as compared with 8% of placebo recipients. Fever may be a sign of an infection.
The impact of belimumab treatment on the development of new primary malignancy is not known, but the mechanism of action of belimumab could increase the risk for the development of malignancies. In controlled clinical trials of intravenous belimumab, malignancies (including non-melanoma skin cancer) were reported in 0.4% of patients in both belimumab-treated and placebo-treated groups. Malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) of patients receiving belimumab vs. 0.3% (2/675) of patients receiving placebo. Data were similar with controlled clinical trials of belimumab administered subcutaneously.
In the clinical study for belimumab administered subcutaneously, an injection site reaction was reported in 6.1% of patients receiving belimumab plus standard therapy and in 2.5% of those receiving placebo plus standard therapy. Most commonly reported injection site reactions included pain, erythema, hematoma, pruritus, and induration. Reactions were mild to moderate in severity and the majority (94%) did not necessitate treatment discontinuation.
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.
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. 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. In patients with suspected PML, immunosuppressant therapy, including belimumab, must be suspended until PML has been excluded. If PML is confirmed, treatment must be discontinued.
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 ideation or thoughts, or other changes in moods or behaviors. Among patients who develop a psychiatric event or symptoms, the potential risks and benefits of continued belimumab therapy should be assessed.
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.
There is an increased risk of new primary malignancy associated with the use of immunosuppressants; however, the impact of treatment with belimumab on the development of malignancies is not known. Consider the individual benefit-risk in patients with risk factors for or in those who develop malignancy during treatment.
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.
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 https://mothertobaby.org/ongoing-study/benlysta-belimumab/ or by calling 1-877-311-8972.
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.
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.
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.
For the treatment of active systemic lupus erythematosus (SLE) in combination with standard therapy:
NOTE: Belimumab has not been evaluated and is not recommended for use in patients with severe active central nervous system lupus.
NOTE: Caution is recommended if belimumab is given in combination with other biologic products, as available data do NOT support the safety and efficacy of concomitant use. An increased incidence of serious infections and post-injection systemic reactions have been observed during concurrent use with rituximab.
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.
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.
Subcutaneous dosage:
Adults: 200 mg subcutaneously once weekly. If transitioning from IV to subcutaneous therapy, administer the first subcutaneous dose 1 to 4 weeks after the last IV dose.
For the treatment of active lupus nephritis in combination with standard therapy:
NOTE: Belimumab has not been evaluated and is not recommended for use in patients with severe active central nervous system lupus.
NOTE: Caution is recommended if belimumab is given in combination with other biologic products, as available data do NOT support the safety and efficacy of concomitant use. An increased incidence of serious infections and post-injection systemic reactions have been observed during concurrent use with rituximab.
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.
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.
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 (IV) to subcutaneous therapy any time after receipt of the first 2 IV doses. If transitioning from IV to subcutaneous therapy, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last IV dose.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Adalimumab: (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.
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.
Bacillus Calmette-Guerin Vaccine, BCG: (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.
Certolizumab pegol: (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.
Chikungunya Vaccine, Live: (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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Etanercept: (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.
Golimumab: (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.
Infliximab: (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.
Intranasal Influenza Vaccine: (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.
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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (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.
Measles/Mumps/Rubella Vaccines, MMR: (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.
Rotavirus Vaccine: (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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (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.
Smallpox Vaccine, Vaccinia Vaccine: (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.
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.
Typhoid Vaccine: (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.
Varicella-Zoster Virus Vaccine, Live: (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.
Yellow Fever Vaccine, Live: (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.
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.
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.
Affected cytochrome P450 (CYP450) enzymes and drug transporters: Unknown
-Route-Specific Pharmacokinetics
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.
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.
-Special Populations
Hepatic Impairment
No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetic parameters of belimumab. Baseline ALT and AST concentrations did not significantly influence the pharmacokinetic parameters of belimumab.
Renal Impairment
Belimumab was studied in a limited number of patients with SLE who had mild (CrCl 60 to 89 mL/minute), moderate (CrCl 30 to 59 mL/minute), or severe (CrCl 15 to 29 mL/minute) renal impairment: 770 patients with mild renal impairment, 261 patients with moderate renal impairment, and 14 patients with severe renal impairment received belimumab intravenously; 121 patients with mild renal impairment and 30 patients with moderate renal impairment received belimumab subcutaneously. Among patients with lupus nephritis who received intravenous belimumab 10 mg/kg on days 0, 14, 28, and then every 28 days up to 104 weeks, initial belimumab exposures were lower compared to patients with SLE due to the additional clearance associated with proteinuria. Patients with higher proteinuria had lower belimumab exposures. After proteinuria decreased to 1 gram/gram or less with treatment, belimumab clearance and exposure were similar to that seen with SLE patients who received intravenous belimumab 10 mg/kg. Based on the available data, no dose adjustment in patients with proteinuria is needed.
Pediatrics
Belimumab exposure is similar between pediatric and adults patients after intravenous administration.
Children and Adolescents 12 to 17 years
Mean Cmax, Cmin, Cavg, and AUC were 317 mcg/mL, 52 mcg/mL, 112 mcg/mL, and 3,126 mcg/mL x day, respectively, in patients 12 to 17 years.
Children 5 to 11 years
Mean Cmax, Cmin, Cavg, and AUC were 305 mcg/mL, 42 mcg/mL, 92 mcg/mL, and 2,569 mcg/mL x day, respectively, in patients 5 to 11 years.
Geriatric
Limited pharmacokinetic data are available for elderly patients, as less than 2% of the patients included in the pharmacokinetic analysis were 65 years of age or older. Most (70%) patients in the study population were between 18 and 45 years of age, and age did not significantly influence the pharmacokinetic parameters of belimumab.
Gender Differences
Gender did not significantly influence the pharmacokinetic parameters of belimumab; however, 94% and 85% of the intravenous and subcutaneous dosing study population was female.
Ethnic Differences
Race did not significantly influence the pharmacokinetic parameters of belimumab. The racial distribution for 3 of the 4 intravenous trials was 53% White/Caucasian, 16% Asian, 16% Alaska native/American Indian, and 14% Black/African American. Trial 4 only enrolled only Black patients to study intravenous use. In the subcutaneous administration trial, the racial distribution was 61% White, 20% Asian, 11% Black, and 6% Alaska native/American Indian.
Obesity
Body weight and body mass index (BMI) had no clinically relevant effect on the pharmacokinetics of belimumab administered subcutaneously in adults.