Adverse reactions : תופעות לוואי

 4.8   Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) are upper respiratory tract infections (17.1%) (most frequently nasopharyngitis, rhinitis).


Tabulated list of adverse reactions
Adverse reactions from clinical studies and post-marketing reports (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on 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); and not known (cannot be estimated from the available data).

Over 20,000 patients have been treated with secukinumab in blinded and open-label clinical studies in various indications (plaque psoriasis, psoriatic arthritis, axial spondyloarthritis, hidradenitis suppurativa and other autoimmune conditions), representing 34,908 patient years of exposure. Of these, over 14,000 patients were exposed to secukinumab for at least one year. The safety profile of secukinumab is consistent across all indications.



Table 3          List of adverse reactions in clinical studies1) and post-marketing experience System Organ Class         Frequency          Adverse reaction
Infections           and Very common          Upper respiratory tract infections infestations               Common             Oral herpes
Uncommon           Oral candidiasis
Otitis externa
Lower respiratory tract infections
Tinea pedis
Not known          Mucosal and cutaneous candidiasis (including oesophageal candidiasis)
Blood and lymphatic Uncommon                  Neutropenia system disorders
Immune           system Rare                  Anaphylactic reactions disorders                                     Angioedema
Nervous          system Common                Headache disorders
Eye disorders              Uncommon           Conjunctivitis
Respiratory, thoracic Common                  Rhinorrhoea and          mediastinal disorders
Gastrointestinal           Common             Diarrhoea disorders                                     Nausea
Uncommon           Inflammatory bowel disease
Skin and subcutaneous Common                  Eczema tissue disorders           Uncommon           Urticaria
Dyshidrotic eczema
Rare               Exfoliative dermatitis2)
Hypersensitivity vasculitis
Not known          Pyoderma gangrenosum
General disorders and Common                  Fatigue administration       site conditions
1)
Placebo-controlled clinical studies (phase III) in plaque psoriasis, PsA, AS, nr-axSpA and HS patients exposed to 300 mg, 150 mg, 75 mg or placebo up to 12 weeks (psoriasis) or 16 weeks (PsA, AS, nr- axSpA and HS) treatment duration
2)
Cases were reported in patients with psoriasis diagnosis

Description of selected adverse reactions

Infections
In the placebo-controlled period of clinical studies in plaque psoriasis (a total of 1,382 patients treated with secukinumab and 694 patients treated with placebo for up to 12 weeks), infections were reported in 28.7% of patients treated with secukinumab compared with 18.9% of patients treated with placebo. The majority of infections consisted of non-serious and mild to moderate upper respiratory tract infections, such as nasopharyngitis, which did not necessitate treatment discontinuation. There was an increase in mucosal or cutaneous candidiasis, consistent with the mechanism of action, but the cases were mild or moderate in severity, non-serious, responsive to standard treatment and did not necessitate treatment discontinuation.
Serious infections occurred in 0.14% of patients treated with secukinumab and in 0.3% of patients treated with placebo (see section 4.4).

Over the entire treatment period (a total of 3,430 patients treated with secukinumab for up to 52 weeks for the majority of patients), infections were reported in 47.5% of patients treated with secukinumab (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of patients treated with secukinumab (0.015 per patient-year of follow-up).
Infection rates observed in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non- radiographic axial spondyloarthritis) clinical studies were similar to those observed in the psoriasis studies.

Patients with hidradenitis suppurativa are more susceptible to infections. In the placebo-controlled period of clinical studies in hidradenitis suppurativa (a total of 721 patients treated with secukinumab and 363 patients treated with placebo for up to 16 weeks), infections were numerically higher compared to those observed in the psoriasis studies (30.7% of patients treated with secukinumab compared with 31.7% in patients treated with placebo). Most of these were non-serious, mild or moderate in severity and did not require treatment discontinuation or interruption.

Neutropenia
In psoriasis phase III clinical studies, neutropenia was more frequently observed with secukinumab than with placebo, but most cases were mild, transient and reversible. Neutropenia <1.0-0.5x109/l (CTCAE grade 3) was reported in 18 out of 3,430 (0.5%) patients on secukinumab, with no dose dependence and no temporal relationship to infections in 15 out of 18 cases. There were no reported cases of more severe neutropenia. Non-serious infections with usual response to standard care and not requiring discontinuation of secukinumab were reported in the remaining 3 cases.

The frequency of neutropenia in psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and hidradenitis suppurativa was similar to psoriasis.

Rare cases of neutropenia <0.5x109/l (CTCAE grade 4) were reported.

Immunogenicity
In psoriasis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and hidradenitis suppurativa clinical studies, less than 1% of patients treated with secukinumab developed antibodies to secukinumab up to 52 weeks of treatment. About half of the treatment emergent anti-drug antibodies were neutralising, but this was not associated with loss of efficacy or pharmacokinetic abnormalities.

Paediatric population

Undesirable effects in paediatric patients from the age of 6 years with plaque psoriasis The safety of secukinumab was assessed in two phase III studies in paediatric patients with plaque psoriasis.
The first study (paediatric study 1) was a double-blind, placebo-controlled study of 162 patients from 6 to less than 18 years of age with severe plaque psoriasis. The second study (paediatric study 2) is an open-label study of 84 patients from 6 to less than 18 years of age with moderate to severe plaque psoriasis. The safety profile reported in these two studies was consistent with the safety profile reported in adult plaque psoriasis patients.

Undesirable effects in paediatric patients with JIA
The safety of secukinumab was also assessed in a phase III study in 86 juvenile idiopathic arthritis patients with ERA and JPsA from 2 to less than 18 years of age. The safety profile reported in this study was consistent with the safety profile reported in adult patients.

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 and    to    Novartis     using   the    following    email     address: safetydesk.israel@novartis.com