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There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.
In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections ( > 5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1,458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.
Progressive Multifocal Leukoencephalopathy (PML)
Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA.
The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.
Hypersensitivity Reactions, Including Anaphylaxis
Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema, have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Infusion Reactions]. 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.
BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.
In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions ( ≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Hypersensitivity Reactions, Including Anaphylaxis]. 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 [see ADVERSE REACTIONS].
BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.
In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if treatment with BENLYSTA is associated with increased risk for these events.
Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.
Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.
Concomitant Use With Other Biologic Therapies Or Intravenous Cyclophosphamide
BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.
Patient Counseling Information
See the FDA-approved patient labeling (Medication Guide).
Advice For The Patient
Give patients the Medication Guide for BENLYSTA and provide them an opportunity to read it prior to each treatment session. It is important that the patient's overall health be assessed at each infusion visit and any questions resulting from the patient's reading of the Medication Guide be discussed.
Mortality: Advise patients that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see WARNINGS AND PRECAUTIONS].
Serious Infections: Advise patients that BENLYSTA may decrease their ability to fight infections. Ask patients if they have a history of chronic infections and if they are currently on any therapy for an infection [see WARNINGS AND PRECAUTIONS]. Instruct patients to tell their healthcare provider if they develop signs or symptoms of an infection.
Progressive Multifocal Leukoencephalopathy (PML): Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see WARNINGS AND PRECAUTIONS].
Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of hypersensitivity and infusion reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA. Inform patients to tell their healthcare provider about possible reactions that may include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling and may occur after administration of BENLYSTA [see WARNINGS AND PRECAUTIONS].
Depression: Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [see WARNINGS AND PRECAUTIONS].
Immunizations: Inform patients that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see WARNINGS AND PRECAUTIONS].
Pregnancy and Nursing Mothers: Inform patients that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Encourage pregnant patients to enroll in the pregnancy registry for BENLYSTA [see Use In Specific Populations]. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not evaluated.
Effects on male and female fertility have not been directly evaluated in animal studies.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.
Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5, and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24%, and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8%, and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of immunoglobulin M (IgM) in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.
It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.
Safety and effectiveness of BENLYSTA have not been established in children.
Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.
In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects receiving BENLYSTA relative to black subjects receiving placebo [see Clinical Studies]. Use with caution in black/African-American patients.
Last reviewed on RxList: 4/17/2014
This monograph has been modified to include the generic and brand name in many instances.
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