BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.
Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.
How supplied: BENLYSTA for intravenous use is available as 120 mg in a 5-mL single-dose vial and 400 mg in a 20-mL single-dose vial. BENLYSTA for subcutaneous use is available as a 200 mg/mL single-dose prefilled autoinjector and a 200 mg/mL single-dose prefilled glass syringe.
BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.
WARNINGS AND PRECAUTIONS
There were more deaths reported with BENLYSTA than with placebo during the controlled period of the intravenous 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. Etiologies included infection, cardiovascular disease, and suicide.
In the controlled clinical trial of BENLYSTA administered subcutaneously (N = 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving BENLYSTA). Infection was the most common cause of death.
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving BENLYSTA and monitor these patients closely.
In controlled clinical trials of BENLYSTA administered intravenously, serious infections occurred in 6.0% and 5.2% of patients receiving BENLYSTA and placebo, respectively. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% and 1.0% of patients receiving BENLYSTA and placebo, respectively. Infections resulting in death occurred in 0.3% (4/1,458) and 0.1% (1/675) of patients receiving BENLYSTA and placebo, respectively. In the controlled trials of BENLYSTA administered subcutaneously (N = 836), serious infections occurred in 4.1% and 5.4% of patients receiving BENLYSTA and placebo, respectively.
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.
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 of BENLYSTA administered intravenously, hypersensitivity reactions occurring on the day of the infusion were reported in 13% (191/1,458) and 11% (76/675) of patients receiving BENLYSTA and placebo, respectively. Anaphylaxis was observed in 0.6% (9/1,458) and 0.4% (3/675) of patients receiving BENLYSTA and placebo, respectively. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response. There is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.
Healthcare providers should be aware of the risk of hypersensitivity reactions and be prepared to manage anaphylaxis. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Patients should be monitored during and for an appropriate period of time after the intravenous administration of BENLYSTA, 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 trial of BENLYSTA administered subcutaneously (N = 836), the incidence and severity of systemic hypersensitivity reactions were similar to those observed in the intravenous clinical trials.
In the controlled clinical trials, infusion reactions occurring on the day of the infusion were reported in 17% (251/1,458) and 15% (99/675) of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions occurring in ≥3% of patients receiving BENLYSTA were headache, nausea, and skin reactions.
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 these 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 controlled clinical trials of BENLYSTA administered intravenously, serious psychiatric events were reported in 0.8% and 0.4% of patients receiving BENLYSTA and placebo, respectively. Serious depression was reported in 0.4% and 0.1% of patients receiving BENLYSTA and placebo, respectively. Two suicides were reported in patients receiving BENLYSTA. In the controlled trial of BENLYSTA administered subcutaneously, serious psychiatric events were reported in 0.2% of patients receiving BENLYSTA and in no patients receiving placebo. It is unknown if treatment with BENLYSTA is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.
The impact of treatment with BENLYSTA on the development of malignancies is not known. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.
Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations.
USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE
BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with these therapies.
Adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and placebo respectively and, at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies, were: nausea 15% and 12%; diarrhea 12% and 9%; pyrexia 10% and 8%; nasopharyngitis 9% and 7%; bronchitis 9% and 5%; insomnia 7% and 5%; pain in extremity 6% and 4%; depression 5% and 4%; migraine 5% and 4%; pharyngitis 5% and 3%; cystitis 4% and 3%; leukopenia 4% and 2%; viral gastroenteritis 3% and 1%.
The safety profile observed for BENLYSTA administered subcutaneously was consistent with the known safety profile of BENLYSTA administered intravenously, with the exception of local injection site reactions, which occurred in 6.1% and 2.5% of patients receiving BENLYSTA and placebo, respectively.
OTHER IMPORTANT INFORMATION FOR BENLYSTA
USE IN SPECIFIC POPULATIONS
Pregnancy: There are insufficient data on use of BENLYSTA in pregnant women to establish whether there is drug-associated risk for major birth defects or miscarriage. Following an assessment of benefit versus risk, if prevention is warranted, women of childbearing potential should use effective contraception during treatment and for at least 4 months after the final treatment.
Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.
Lactation: There is no information available on the presence of belimumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BENLYSTA and any potential adverse effects on the breastfed child from BENLYSTA or from the underlying maternal condition.
Black/African American Patients: In controlled clinical trials of BENLYSTA administered intravenously, SLE Responder Index-4 (SRI-4) response rates were lower for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo.
In the controlled trial of BENLYSTA administered subcutaneously, SRI-4 response was slightly higher for black/African American patients receiving BENLYSTA relative to black/African American patients receiving placebo, but the treatment difference was not as great as that observed in the overall population. Use with caution in black/African American patients.
820085R0 July 2017