Benlysta Adverse Reactions

Summary of the safety profile in adults: The safety of belimumab in patients with SLE has been evaluated in 3 pre-registration placebo-controlled intravenous studies, 1 placebo-controlled subcutaneous study, and one post-marketing placebo-controlled intravenous study; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study.
The data presented in the following table reflect exposure in 674 patients with SLE administered Benlysta intravenously (10 mg/kg over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg once weekly up to 52 weeks). The safety data presented include data beyond Week 52 in some patients with SLE. The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlysta intravenously (10 mg/kg for up to 104 weeks). Data from post-marketing reports are also included.
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products.
Adverse reactions were reported in 87% of Benlysta-treated patients and 90% of placebo-treated patients. The most frequently reported adverse reactions (≥5% of patients with SLE treated with Benlysta plus standard of care and at a rate ≥1% greater than placebo) were viral upper respiratory tract infections, bronchitis, and diarrhoea. The proportion of patients who discontinued treatment due to adverse reactions was 7% for Benlysta-treated patients and 8% for placebo-treated patients.
The most frequently reported adverse reactions (>5% of patients with active lupus nephritis treated with Benlysta plus standard of care) were upper respiratory tract infection, urinary tract infection, and herpes zoster. The proportion of patients who discontinued treatment due to adverse reactions was 12.9% for Benlysta-treated patients and 12.9% for placebo-treated patients.
Tabulated list of adverse reactions: Adverse reactions are listed as follows by MedDRA system organ class and by frequency. The frequency categories used are: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1,000 to <1/100; Rare ≥1/10,000 to <1/1,000.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The frequency given is the highest seen with either formulation. (See Table 8.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Data presented as follows are pooled from the intravenous clinical studies (10 mg/kg intravenous dose only) and the subcutaneous clinical study. Infections and Psychiatric disorders as follows also include data from a post-marketing study.
Infusion or injection-related systemic reactions and hypersensitivity: Infusion or injection-related systemic reactions and hypersensitivity were generally observed on the day of administration, but acute hypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
The incidence of infusion reactions and hypersensitivity reactions after intravenous administration occurring within 3 days of an infusion was 12% in the group receiving Benlysta and 10% in the group receiving placebo, with 1.2% and 0.3%, respectively, requiring permanent treatment discontinuation.
Solution for injection: The incidence of post-injection systemic reactions and hypersensitivity reactions occurring within 3 days of subcutaneous administration was 7% in the group receiving Benlysta and 9% in the group receiving placebo. Clinically significant hypersensitivity reactions associated with Benlysta administered subcutaneously and requiring permanent treatment discontinuation were reported in 0.2% of patients receiving Benlysta and in no patients receiving placebo.
Infections: The overall incidence of infections in intravenous and subcutaneous pre-registration SLE studies was 63% in both groups receiving Benlysta or placebo. Infections occurring in at least 3% of patients receiving Benlysta and at least 1% more frequently than patients receiving placebo were viral upper respiratory tract infection, bronchitis, and urinary tract infection bacterial. Serious infections occurred in 5% of patients in both groups receiving Benlysta or placebo; serious opportunistic infections accounted for 0.4% and 0% of these, respectively. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving Benlysta and 1.5% of patients receiving placebo. Some infections were severe or fatal.
In the lupus nephritis study, patients were receiving a background of standard therapy (see Pharmacology: Pharmacodynamics under Actions) and the overall incidence of infections was 82% in patients receiving Benlysta compared with 76% in patients receiving placebo. Serious infections occurred in 13.8% of patients receiving Benlysta and in 17.0% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving Benlysta and in 0.9% (2/224) of patients receiving placebo.
In a randomised, double-blind, 52-week, post-marketing safety SLE study (BEL115467) which assessed mortality and specific adverse events in adults, serious infections occurred in 3.7% of patients receiving Benlysta (10 mg/kg intravenously) vs 4.1% of patients receiving placebo. However, fatal infections (e.g. pneumonia and sepsis) occurred in 0.45% (9/2002) of Benlysta-treated patients vs 0.15% (3/2001) of patients receiving placebo, while the incidence of all-cause mortality was 0.50% (10/2002) vs 0.40% (8/2001), respectively. Most fatal infections were observed during the first 20 weeks of treatment with Benlysta.
Powder for concentrate for solution for infusion: For information on infections observed in paediatric patients with SLE, see Paediatric population as follows.
Psychiatric disorders: In the pre-registration intravenous SLE clinical studies, serious psychiatric events were reported in 1.2% (8/674) of patients receiving Benlysta 10 mg/kg and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.6% (4/674) of patients receiving Benlysta 10 mg/kg and 0.3% (2/675) of patients receiving placebo. There were two suicides in Benlysta-treated patients (including one receiving 1 mg/kg Benlysta).
In a post-marketing SLE study, serious psychiatric events were reported in 1.0% (20/2002) of patients receiving Benlysta and 0.3% (6/2001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2002) of patients receiving Benlysta and <0.1% (1/2001) of patients receiving placebo. The overall incidence of serious suicidal ideation or behaviour or self-injury without suicidal intent was 0.7% (15/2002) in patients receiving Benlysta and 0.2% (5/2001) in the placebo group. No suicide was reported in either group.
The intravenous SLE studies did not exclude patients with a history of psychiatric disorders.
In the subcutaneous SLE clinical study, which excluded patients with a history of psychiatric disorders, serious psychiatric events were reported in 0.2% (1/556) of patients receiving Benlysta and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group.
Leucopenia: The incidence of leucopenia reported in patients with SLE as an adverse event was 3% in the group receiving Benlysta and 2% in the group receiving placebo.
Gastrointestinal disorders: Powder for concentrate for solution for infusion: Obese patients [Body mass index (BMI) >30 kg/m²] with SLE treated with intravenously administered Benlysta reported higher rates of nausea, vomiting and diarrhoea relative to placebo, and compared with normal-weight patients (BMI ≥18.5 to ≤30 kg/m²). None of these gastrointestinal events in obese patients were serious.
Injection site reactions: Solution for injection: In the subcutaneous SLE study, the frequency of injection site reactions was 6.1% (34/556) and 2.5% (7/280) for patients receiving Benlysta and placebo, respectively. These injection site reactions (most commonly pain, erythema, hematoma, pruritus and induration) were mild to moderate in severity. The majority did not necessitate drug discontinuation.
Paediatric population: Powder for concentrate for solution for infusion: The adverse reaction profile in paediatric patients is based on 52-week safety data from a placebo-controlled study in which 53 patients (6 to 17 years of age) with SLE received Benlysta (10 mg/kg intravenously on Days 0, 14, 28, and then every 28 days, on a background of concomitant treatments). No new safety signals were observed in the paediatric population 12 years of age and above (n=43). Safety data in children younger than 12 years of age (n=10) are limited.
Infections: 5- to 11-year-old group: Infections were reported in 8/10 patients receiving Benlysta and 3/3 patients receiving placebo, and serious infections were reported in 1/10 patients receiving Benlysta and 2/3 patients receiving placebo (see Precautions).
12- to 17-year-old group: Infections were reported in 22/43 patients receiving Benlysta and 25/37 patients receiving placebo, and serious infections were reported in 3/43 patients receiving Benlysta and 3/37 patients receiving placebo. In the open-label extension phase there was one fatal infection in a patient receiving Benlysta.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.