Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

The most frequent adverse reactions are neutropenia (14.2%), upper respiratory infections (7.1%), increased ALT (6.8%), urinary tract infections (5.7%), and injection site erythema (5.3%). The most common serious adverse reactions are infections (2.9%) (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions listed in the table have been reported in controlled clinical studies. The frequency of adverse reactions listed below is defined using the following convention: 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); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Adverse reactions

System Organ Class                    Frequency                         Adverse reaction Infections and infestations           Common                            Upper respiratory tract infection Urinary tract infection
Nasopharyngitis
Oral herpes
Uncommon                          Pneumonia
Cellulitis
Diverticulitis
Blood and lymphatic system            Very common                       Neutropenia disorders
Common                            Thrombocytopenia

Leukopenia

Metabolism and nutrition              Common                            Hypercholesterolemia disorders
Hypertriglyceridemia
Gastrointestinal disorders            Rare                              Gastrointestinal perforation Hepatobiliary disorders               Common                            Transaminases increased General disorders and                 Common                            Injection site erythema administration site conditions                                          Injection site pruritus 
Description of selected adverse reactions
Infections
In the placebo-controlled population, the rates of infections were 84.5, 81.0, and 75.1 events per 100 patient-years, in the 200 mg and 150 mg sarilumab+ DMARDs and placebo + DMARDs groups respectively. The most commonly reported infections (5% to 7% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. The rates of serious infections were 4.3, 3.0, and 3.1 events per 100 patient-years, in the 200 mg, 150 mg sarilumab+ DMARDs, and placebo + DMARDs groups, respectively.
In the sarilumab+DMARDs long-term safety population, the rates of infections and serious infection were 57.3 and 3.4 events per 100-patient years, respectively.

The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported (see section 4.4).

The overall rates of infections and serious infections in the sarilumab monotherapy population were consistent with rates in the sarilumab+ DMARDs population.

Gastrointestinal perforation
Gastrointestinal perforation was reported in patients with and without diverticulitis. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medicinal products (NSAIDs), corticosteroids, or methotrexate. The contribution of these concomitant medications relative to sarilumab in the development of gastrointestinal perforations is not known (see section 4.4).


Hypersensitivity reactions
In the placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with sarilumab (0.9% in 200 mg group, 0.5% in 150 mg group) than placebo (0.2%). The rates of discontinuations due to hypersensitivity in the sarilumab+ DMARDs long-term safety population and the sarilumab monotherapy population were consistent with the placebo-controlled population. In the placebo-controlled population, 0.2% of the patients treated with sarilumab 200 mg every two weeks (q2w) + DMARD reported serious adverse reactions of hypersensitivity reactions, and none from sarilumab 150 mg q2w + DMARD group.

Injection site reactions
In the placebo-controlled population, injection site reactions were reported in 9.5%, 8%, and 1.4% of patients receiving sarilumab 200 mg, 150 mg, and placebo respectively. These injection site reactions (including erythema and pruritus) were mild to moderate in severity for the majority of patients (99.5%, 100%, and 100%, for sarilumab 200 mg, 150 mg, and placebo respectively). Two patients on sarilumab (0.2%) discontinued treatment due to injection site reactions.

Laboratory abnormalities
To allow for a direct comparison of frequency of laboratory abnormalities between placebo and active treatment, data from weeks 0-12 were used as this was prior to patients being permitted to switch from placebo to sarilumab.

Neutrophil count
Decreases in neutrophil counts below 1 x 109/L occurred in 6.4% and 3.6% of patients in the 200 mg and 150 mg sarilumab+ DMARDs group, respectively, compared to no patients in the placebo + DMARDs group. Decreases in neutrophil counts below 0.5 x 109/L occurred in 0.8% and 0.6% of patients in the 200 mg and 150 mg sarilumab+ DMARDs groups, respectively. In patients experiencing a decrease in absolute neutrophil count (ANC), modification of treatment regimen such as interruption of sarilumab or reduction in dose resulted in an increase or normalisation of ANC (see section 4.2).

Decrease in ANC was not associated with higher incidence of infections, including serious infections.

In the sarilumab+ DMARDs long-term safety population and the sarilumab monotherapy population, the observations on neutrophil counts were consistent with those seen in the placebo-controlled population (see section 4.4).

Platelet count

Decreases in platelet counts below 100 x 103/µL occurred in 1.2% and 0.6% of patients on 200 mg and 150 mg sarilumab+ DMARDs, respectively, compared to no patients on placebo + DMARDs.

In the sarilumab+ DMARDs long-term safety population and the sarilumab monotherapy population, the observations on platelet counts were consistent with those seen in the placebo-controlled population.

There were no bleeding events associated with decreases in platelet count.

Liver enzymes
Liver enzyme abnormalities are summarised in Table 3. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of treatment or reduction in dose, resulted in decrease or normalisation of liver enzymes (see section 4.2). These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency (see section 4.4).

Table 3: Incidence of liver enzyme abnormalities in controlled clinical studies 
Placebo +         Sarilumab            Sarilumab              Sarilumab DMARD              150 mg +             200 mg +         monotherapy any Dose N = 661           DMARD                DMARD                  N = 467 N = 660              N = 661
AST
>3 x ULN –                  0%               1.2%                 1.1%                     1.1% 5 x ULN
>5 x ULN                    0%               0.6%                 0.2%                      0% ALT
>3 x ULN –                 0.6%              3.2%                 2.4%                     1.9% 5 x ULN
>5 x ULN                    0%               1.1%                 0.8%                     0.2% 
Lipids
Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of sarilumab+ DMARDs in the placebo-controlled population. At week 4 the mean LDL increased by 14 mg/dL; mean triglycerides increased by 23 mg/dL; and mean HDL increased by 3 mg/dL. After week 4 no additional increases were observed. There were no meaningful differences between doses.

In the sarilumab+ DMARDs long-term safety population and the sarilumab monotherapy population, the observations in lipid parameters were consistent with those seen in the placebo-controlled population.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity with sarilumab.

In the placebo-controlled population, 4.0%, 5.6%, and 2.0% of patients treated with sarilumab 200 mg + DMARDs, sarilumab 150 mg + DMARDs and placebo + DMARDs respectively, exhibited a positive response in the anti-drug antibody (ADA) assay. Positive responses in the neutralising antibody (NAb) assay were detected in 1.0%, 1.6%, and 0.2% of patients on sarilumab 200 mg, sarilumab150 mg, and placebo respectively.

In the sarilumab monotherapy population, observations were consistent with the sarilumab + DMARDs population.

Anti Drug Antibody (ADA) formation may affect pharmacokinetics of sarilumab. No correlation was observed between ADA development and either loss of efficacy or adverse reactions.


The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used and testing conditions. For these reasons, comparison of the incidence of antibodies to sarilumab with the incidence of antibodies to other products may be misleading.

Malignancies
In the placebo-controlled population, malignancies occurred at the same rate in patients receiving either sarilumab+ DMARDs or placebo + DMARDs (1.0 events per 100 patient-years).

In the sarilumab+ DMARDs long-term safety population and the sarilumab monotherapy population, the rates of malignancies were consistent with the rate observed in the placebo-controlled population (see section 4.4).

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