Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile in adults

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 from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study 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 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, rash disorders
Uncommon                 Angioedema


Musculoskeletal and connective     Common                  Pain in extremity tissue disorders

General disorders and              Common                  Infusion or injection -related systemic administration site conditions                             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.

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.

For information on infections observed in paediatric patients with SLE see Paediatric population section below.

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.

Gastrointestinal disorders: 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.

Paediatric population

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 section 4.4).
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.
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)