Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most common adverse reaction was respiratory tract infections in approximately 14% of patients in the psoriasis and psoriatic arthritis clinical studies.

Tabulated list of adverse reactions

Table 1 provides a list of adverse reactions from psoriasis and psoriatic arthritis clinical studies as well as from post-marketing experience. The adverse reactions are classified by MedDRA System Organ Class and frequency, 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), not known (cannot be estimated from the available data).

Table 1:      List of adverse reactions

System Organ Class                         Frequency               Adverse reactions Infections and infestations                Very common             Respiratory tract infections Uncommon                Herpes simplex infections
Uncommon                Tinea infections
Uncommon                Gastroenteritis
Immune system disorders                    Uncommon                Hypersensitivity Uncommon                Anaphylaxis
Nervous system disorders                   Common                  Headache Gastrointestinal disorders                 Common                  Diarrhoea Skin and subcutaneous tissue               Uncommon                Urticaria disorders                                  Uncommon                Rash Musculoskeletal and connective             Common                  Arthralgia tissue disorders
General disorders and administration       Common                  Injection site reactions site conditions
Investigations                             Common                  Transaminases increased Uncommon                Neutrophil count decreased

Description of selected adverse reactions
Transaminases increased
In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, adverse events of increased transaminases (includes ALT increased, AST increased, hepatic enzyme increased, transaminases increased, liver function test abnormal, hypertransaminasaemia) were reported more frequently in the guselkumab-treated groups (8.6% in the q4w group and 8.3% in the q8w group) than in the placebo group (4.6%). Through 1 year, adverse events of increased transaminases (as above) were reported in 12.9% of patients in the q4w group and 11.7% of patients in the q8w group.

Based on laboratory assessments, most transaminase increases (ALT and AST) were ≤ 3 x upper limit of normal (ULN). Transaminase increases from > 3 to ≤ 5 x ULN and > 5 x ULN were low in frequency, occurring more often in the guselkumab q4w group compared with the guselkumab q8w group (Table 2).
A similar pattern of frequency by severity and by treatment group was observed through the end of the 2- year Phase III psoriatic arthritis clinical study.

Table 2:      Frequency of patients with transaminase increases post-baseline in two Phase III psoriatic arthritis clinical studies

Through week 24a                             Through 1 yearb
Placebo         guselkumab        guselkumab        guselkumab      guselkumab N=370c         100 mg q8w         100 mg q4w        100 mg q8w      100 mg q4w N=373c            N=371c            N=373 c         N=371 c
ALT
>1 to ≤3 x ULN          30.0%             28.2%             35.0%             33.5%            41.2% >3 to ≤ 5 x ULN         1.4%              1.1%              2.7%              1.6%             4.6% >5 x ULN                0.8%              0.8%              1.1%              1.1%             1.1% AST
>1 to ≤3 x ULN          20.0%             18.8%             21.6%             22.8%            27.8% >3 to ≤ 5 x ULN         0.5%              1.6%              1.6%              2.9%             3.8% >5 x ULN                1.1%              0.5%              1.6%              0.5%             1.6% a placebo-controlled period b patients randomised to placebo at baseline and crossed over to guselkumab are not included c number of patients with at least one post-baseline assessment for the specific laboratory test within the time period

In the psoriasis clinical studies, through 1 year, the frequency of transaminase increases (ALT and AST) for the guselkumab q8w dose was similar to that observed for the guselkumab q8w dose in the psoriatic arthritis clinical studies. Through 5 years, the incidence of transaminase elevation did not increase by year of guselkumab treatment. Most transaminase increases were ≤ 3 x ULN.

In most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.

Neutrophil count decreased
In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, the adverse event of decreased neutrophil count was reported more frequently in the guselkumab-treated group (0.9%) than in the placebo group (0%). Through 1 year, the adverse event of decreased neutrophil count was reported in 0.9% of patients treated with guselkumab. In most cases, the decrease in blood neutrophil count was mild, transient, not associated with infection and did not lead to discontinuation of treatment.

Gastroenteritis
In two Phase III psoriasis clinical studies through the placebo-controlled period, gastroenteritis occurred more frequently in the guselkumab-treated group (1.1%) than in the placebo group (0.7%).
Through Week 264, 5.8%of all guselkumab-treated patients reported gastroenteritis. Adverse reactions of gastroenteritis were non-serious and did not lead to discontinuation of guselkumab through Week 264. Gastroenteritis rates observed in psoriatic arthritis clinical studies through the placebo-controlled period were similar to those observed in the psoriasis clinical studies.

Injection site reactions
In two Phase III psoriasis clinical studies through Week 48, 0.7% of guselkumab injections and 0.3% of placebo injections were associated with injection site reactions. Through Week 264, 0.4% of guselkumab injections were associated with injection site reactions. Injection site reactions were generally mild to moderate in severity; none were serious, and one led to discontinuation of guselkumab.

In two Phase III psoriatic arthritis clinical studies through Week 24, the number of subjects that reported 1 or more injection site reactions was low and slightly higher in the guselkumab groups than in the placebo group; 5 (1.3%) subjects in the guselkumab q8w group, 4 (1.1%) subjects in the guselkumab q4w group, and 1 (0.3%) subject in the placebo group. One subject discontinued guselkumab due to an injection site reaction during the placebo-controlled period of the psoriatic arthritis clinical studies. Through 1 year, the proportion of subjects reporting 1 or more injection site reactions was 1.6% and 2.4% in the guselkumab q8w and q4w groups respectively. Overall, the rate of injections associated with injection site reactions observed in psoriatic arthritis clinical studies through the placebo-controlled period was similar to rates observed in the psoriasis clinical studies.

Immunogenicity
The immunogenicity of guselkumab was evaluated using a sensitive and drug-tolerant immunoassay.

In pooled Phase II and Phase III analyses in patients with psoriasis, and psoriatic arthritis, 5% (n=145) of patients treated with guselkumab developed antidrug antibodies in up to 52 weeks of treatment. Of the patients who developed antidrug antibodies, approximately 8% (n=12) had antibodies that were classified as neutralizing, which equates to 0.4% of all patients treated with guselkumab. In pooled Phase III analyses in patients with psoriasis, approximately 15% of patients treated with guselkumab developed antidrug antibodies in up to 264 weeks of treatment. Of the patients who developed antidrug antibodies, approximately 5% had antibodies that were classified as neutralizing, which equates to 0.76% of all patients treated with guselkumab. Antidrug antibodies were not associated with lower efficacy or development of injection-site reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medical 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