Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety of belimumab in patients with SLE has been evaluated in three pre-registration, placebo-controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo-controlled subcutaneous study, and two post-marketing placebo-controlled intravenous studies; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study.

The data presented in the table below reflect exposure in 674 patients with SLE from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study 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 84% of Benlysta-treated patients and 87% of placebo- treated patients. The most frequently reported adverse reaction (≥5% of patients with SLE treated with Benlysta plus standard of care and at a rate ≥1% greater than placebo) was nasopharyngitis. 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 below 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 <1/1000

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The frequency given is the highest seen with either formulation.

System organ class               Frequency             Adverse reaction(s) 
Infections and infestations1     Very common           Bacterial infections, e.g. bronchitis, urinary tract infection

Common                Gastroenteritis viral, pharyngitis,
nasopharyngitis, viral upper respiratory tract infection

Blood and lymphatic system       Common                Leucopenia disorders
Immune system disorders          Common                Hypersensitivity reactions2 
Uncommon              Anaphylactic reaction

Rare                  Delayed-type, non-acute hypersensitivity reactions
Psychiatric disorders            Common                Depression
Uncommon              Suicidal behaviour, suicidal ideation

Nervous system disorders         Common                Migraine

Gastrointestinal disorders        Common               Diarrhoea, nausea 
Skin and subcutaneous tissue     Common                Injection site reactions3, urticaria, disorders                                              rash


Uncommon              Angioedema
Musculoskeletal and              Common                Pain in extremity connective tissue disorders

General disorders and            Common                Infusion or injection-related administration site conditions                         systemic reactions2, pyrexia 1
See ‘Description of selected adverse reactions’ and section 4.4 ‘Infections’ for further information.
2
‘Hypersensitivity reactions’ covers a group of terms, including anaphylaxis, and can manifest as a range of symptoms including hypotension, angioedema, urticaria or other rash, pruritus, and dyspnoea. ‘Infusion or injection-related systemic reactions’ covers a group of terms and can manifest as a range of symptoms including bradycardia, myalgia, headache, rash, urticaria, pyrexia, hypotension, hypertension, dizziness, and arthralgia. Due to overlap in signs and symptoms, it is not possible to distinguish between hypersensitivity reactions and infusion or injection-related systemic reactions in all cases.
3
Applies to subcutaneous formulation only.

Description of selected adverse reactions

Data presented below are pooled from the three pre-registration intravenous clinical studies (10 mg/kg intravenous dose only) and the subcutaneous clinical study. ‘Infections’ and ‘Psychiatric disorders‘ 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.

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 section 5.1) 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.

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 above 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.

Injection site reactions: 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.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/.
Additionally, you should also report to GSK Israel (il.safety@gsk.com)