secukinumab: prescribing information – dosing, contraindications, interactions, side effects

Paediatric plaque psoriasis

Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy.

Juvenile idiopathic arthritis (JIA)

Enthesitis-related arthritis (ERA)
Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active enthesitis-related arthritis in patients 6 years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy (see section 5.1).

Juvenile psoriatic arthritis (JPsA)
Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active juvenile psoriatic arthritis in patients 6 years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy (see section 5.1).

25.0***
* p<0.05, ** p<0.01, *** p<0.001; versus placebo
All p-values adjusted for multiplicity of testing based on pre-defined hierarchy, except BASDAI 50 and ASDAS-CRP Non-responder imputation used for missing binary endpoint

ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; ASDAS: Ankylosing Spondylitis Disease Activity Score; BSL: baseline

The onset of action of secukinumab 150 mg occurred as early as week 1 for ASAS 20 and week 2 for ASAS 40 (superior to placebo) in AS study 2.

ASAS 20 responses were improved at week 16 in both anti-TNFα-naïve patients (68.2% versus 31.1%; p<0.05) and anti-TNFα-IR patients (50.0% versus 24.1%; p<0.05) for secukinumab 150 mg compared with placebo, respectively.

In AS study 1 and AS study 2, secukinumab-treated patients (150 mg in AS study 2 and both regimens in AS study 1) demonstrated significantly improved signs and symptoms at week 16, with comparable magnitude of response and efficacy maintained up to week 52 in both anti-TNFα-naive and anti-TNFα-IR patients. In AS study 2, among 72 patients initially randomised to secukinumab 150 mg, 61 (84.7%) patients were still on treatment at week 52. Of the 72 patients randomised to secukinumab 150 mg, 45 and 35 had an ASAS 20/40 response, respectively.

In AS study 3, patients treated with secukinumab (150 mg and 300 mg) demonstrated improved signs and symptoms, and had comparable efficacy responses regardless of dose that were superior to placebo at week 16 for the primary endpoint (ASAS 20). Overall, the efficacy response rates for the 300 mg group were consistently greater compared to the 150 mg group for the secondary endpoints.
During the blinded period, the ASAS 20 and ASAS 40 responses were 69.7% and 47.6% for 150 mg and 74.3% and 57.4% for 300 mg at week 52, respectively. The ASAS 20 and ASAS 40 responses were maintained up to week 156 (69.5% and 47.6% for 150 mg versus 74.8% and 55.6% for 300 mg).
Greater response rates favouring 300 mg were also observed for ASAS partial remission (ASAS PR) response at week 16 and were maintained up to week 156. Larger differences in response rates, favouring 300 mg over 150 mg, were observed in anti-TNFα-IR patients (n=36) compared to anti-TNFα-naïve patients (n=114).

Spinal mobility:
Patients treated with secukinumab 150 mg showed improvements in spinal mobility as measured by change from baseline in BASMI at week 16 for both AS study 1 (-0.40 versus -0.12 for placebo;
p=0.0114) and AS study 2 (-0.51 versus -0.22 for placebo; p=0.0533). These improvements were sustained up to week 52.

Physical function and health-related quality of life:
In AS study 1 and study 2, patients treated with secukinumab 150 mg showed improvements in health- related quality of life as measured by AS Quality of Life Questionnaire (ASQoL) (p=0.001) and SF-36 Physical Component Summary (SF-36PCS) (p<0.001). Patients treated with secukinumab 150 mg also showed statistically significant improvements on exploratory endpoints in physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) compared to placebo (-2.15 versus -0.68), and in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) scale compared to placebo (8.10 versus 3.30). These improvements were sustained up to week 52.

Non-radiographic axial spondyloarthritis (nr-axSpA)
The safety and efficacy of secukinumab were assessed in 555 patients in one randomised, double-blind, placebo-controlled phase III study (PREVENT), consisting of a 2-year core phase and a 2-year extension phase, in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) fulfilling the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA) with no radiographic evidence of changes in the sacroiliac joints that would meet the modified New York criteria for ankylosing spondylitis (AS). Patients enrolled had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, a Visual Analogue Scale (VAS) for total back pain of ≥40 (on a scale of 0-100 mm), despite current or previous non-steroidal anti-inflammatory drug (NSAID) therapy and increased C-reactive protein (CRP) and/or evidence of sacroiliitis on Magnetic Resonance Imaging (MRI). Patients in this study had a diagnosis of axSpA for a mean of 2.1 to 3.0 years and 54% of the study participants were female.

In the PREVENT study, 9.7% of patients were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients).

In the PREVENT study, 9.9% and 14.8% of patients used concomitant MTX or sulfasalazine, respectively. In the double-blind period, patients received either placebo or secukinumab for 52 weeks.
Patients randomised to secukinumab received 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4 followed by the same dose every month, or a once monthly injection of secukinumab 150 mg. The

primary endpoint was at least 40% improvement in Assessment of SpondyloArthritis International Society (ASAS 40) at Week 16 in anti-TNFα-naive patients.

Signs and symptoms:
In the PREVENT study, treatment with secukinumab 150 mg resulted in significant improvements in the measures of disease activity compared to placebo at week 16. These measures include ASAS 40, ASAS 5/6, BASDAI score, BASDAI 50, high-sensitivity CRP (hsCRP), ASAS 20 and ASAS partial remission response compared to placebo (Table 13). Responses were maintained up to week 52.

Table 13
Clinical response in the PREVENT study at week 16

Outcome (p-value versus placebo)
Placebo
150 mg1
Number of anti-TNFα-naive patients randomised
ASAS 40 response, %

Cosentyx is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Cosentyx is indicated.

Posology

Paediatric plaque psoriasis (adolescents and children from the age of 6 years)
The recommended dose is based on body weight (Table 1) and administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Table 1
Recommended dose for paediatric plaque psoriasis

Body weight at time of dosing
Recommended dose
<25 kg
75 mg
25 to <50 kg
75 mg
≥50 kg
150 mg (*may be increased to 300 mg)
*Some patients may derive additional benefit from the higher dose.

Juvenile idiopathic arthritis (JIA)

Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA)
The recommended dose is based on body weight (Table 2) and administered by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg.

Table 2
Recommended dose for juvenile idiopathic arthritis

Body weight at time of dosing
Recommended dose
<50 kg
75 mg
≥50 kg
150 mg

Cosentyx may be available in other strengths and/or presentations depending on the individual treatment needs.

For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response by 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks.

The safety and efficacy of Cosentyx in children with plaque psoriasis and in the juvenile idiopathic arthritis (JIA) categories of ERA and JPsA below the age of 6 years have not been established.

The safety and efficacy of Cosentyx in children below the age of 18 years in other indications have not yet been established. No data are available.

Special populations

Renal impairment / hepatic impairment
Cosentyx has not been studied in these patient populations. No dose recommendations can be made.

Method of administration

Cosentyx is to be administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The syringe must not be shaken.

After proper training in subcutaneous injection technique, patients may self-inject Cosentyx or be injected by a caregiver if a physician determines that this is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients or caregivers should be instructed to inject the full amount of Cosentyx according to the instructions provided in the package leaflet.
Comprehensive instructions for administration are given in the package leaflet.

Cosentyx is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Cosentyx is indicated.

Posology

Adult plaque psoriasis
The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, a maintenance dose of 300 mg every 2 weeks may provide additional benefit for patients with a body weight of 90 kg or higher. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Paediatric plaque psoriasis (adolescents and children from the age of 6 years)
The recommended dose is based on body weight (Table 1) and administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Table 1
Recommended dose for paediatric plaque psoriasis

Body weight at time of dosing
Recommended dose
<25 kg
75 mg
25 to <50 kg
75 mg
≥50 kg
150 mg (*may be increased to 300 mg)
*Some patients may derive additional benefit from the higher dose.

The 150 mg and 300 mg solution for injection in pre-filled syringe and in pre-filled pen are not indicated for administration to paediatric patients with a weight <50 kg. Cosentyx may be available in other strengths and/or presentations depending on the individual treatment needs.

Hidradenitis suppurativa (HS)
The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing. Based on clinical response, the maintenance dose can be increased to 300 mg every 2 weeks. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Psoriatic arthritis
For patients with concomitant moderate to severe plaque psoriasis, please refer to adult plaque psoriasis recommendation.

For patients who are anti-TNFα inadequate responders (IR), the recommended dose is 300 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

For other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg.

Axial spondyloarthritis (axSpA)
Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Each 300 mg dose is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Non-radiographic axial spondyloarthritis (nr-axSpA)
The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing.

Juvenile idiopathic arthritis (JIA)

Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA)
The recommended dose is based on body weight (Table 2) and administered by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg.

Table 2
Recommended dose for juvenile idiopathic arthritis

Body weight at time of dosing
Recommended dose
<50 kg
75 mg
≥50 kg
150 mg

The 150 mg and 300 mg solution for injection in pre-filled syringe and in pre-filled pen are not indicated for administration to paediatric patients with a weight <50 kg. Cosentyx may be available in other strengths and/or presentations depending on the individual treatment needs.

For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response by 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Special populations

Elderly patients (aged 65 years and over)
No dose adjustment is required (see section 5.2).

Renal impairment / hepatic impairment
Cosentyx has not been studied in these patient populations. No dose recommendations can be made.

Paediatric population
The safety and efficacy of Cosentyx in children with plaque psoriasis and in the juvenile idiopathic arthritis (JIA) categories of ERA and JPsA below the age of 6 years have not been established.

The safety and efficacy of Cosentyx in children below the age of 18 years in other indications have not yet been established. No data are available.

Method of administration

Cosentyx is to be administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The syringe or the pen must not be shaken.

After proper training in subcutaneous injection technique, patients may self-inject Cosentyx or be injected by a caregiver if a physician determines that this is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients or caregivers should be instructed to inject the full amount of Cosentyx according to the instructions provided in the package leaflet.
Comprehensive instructions for administration are given in the package leaflet.

Cosentyx is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Cosentyx is indicated.

Posology

Adult plaque psoriasis
The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, a maintenance dose of 300 mg every 2 weeks may provide additional benefit for patients with a body weight of 90 kg or higher. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

Paediatric plaque psoriasis (adolescents and children from the age of 6 years)
The recommended dose is based on body weight (Table 1) and administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

Table 1
Recommended dose for paediatric plaque psoriasis

Body weight at time of dosing
Recommended dose
<25 kg
75 mg
25 to <50 kg
75 mg
≥50 kg
150 mg (*may be increased to 300 mg)
*Some patients may derive additional benefit from the higher dose.

Cosentyx may be available in other strengths and/or presentations depending on the individual treatment needs.

Hidradenitis suppurativa (HS)
The recommended dose is 300 mg of secukinumab by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing. Based on clinical response, the maintenance dose can be increased to 300 mg every 2 weeks. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

Psoriatic arthritis
For patients with concomitant moderate to severe plaque psoriasis, please refer to adult plaque psoriasis recommendation.

For patients who are anti-TNFα inadequate responders (IR), the recommended dose is 300 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

For other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg.

Axial spondyloarthritis (axSpA)
Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)
The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing. Based on clinical response, the dose can be increased to 300 mg. Each 300 mg dose is given as two subcutaneous injections of 150 mg.

Non-radiographic axial spondyloarthritis (nr-axSpA)
The recommended dose is 150 mg by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dosing.

Juvenile idiopathic arthritis (JIA)

Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA)
The recommended dose is based on body weight (Table 2) and administered by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing. Each 75 mg dose is given as one subcutaneous injection of 75 mg. Each 150 mg dose is given as one subcutaneous injection of 150 mg.

Table 2
Recommended dose for juvenile idiopathic arthritis

Body weight at time of dosing
Recommended dose
<50 kg
75 mg
≥50 kg
150 mg

Cosentyx may be available in other strengths and/or presentations depending on the individual treatment needs.

For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response by 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Special populations

Elderly patients (aged 65 years and over)
No dose adjustment is required (see section 5.2).

Renal impairment / hepatic impairment
Cosentyx has not been studied in these patient populations. No dose recommendations can be made.

Paediatric population
The safety and efficacy of Cosentyx in children with plaque psoriasis and in the juvenile idiopathic arthritis (JIA) categories of ERA and JPsA below the age of 6 years have not been established.

The safety and efficacy of Cosentyx in children below the age of 18 years in other indications have not yet been established. No data are available.

Method of administration

Cosentyx is to be administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The powder for solution for injection must be reconstituted before use.

The reconstitution, dose preparation and administration of the powder for solution for injection is to be done by a healthcare professional. For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the Instructions for Use in the package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important, active infection, e.g. active tuberculosis (see section 4.4).

Summary of the safety profile

The most frequently reported adverse reactions 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 [HS] 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 infestations
Very common
Upper respiratory tract infections
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 system disorders
Uncommon
Neutropenia
Immune system disorders
Rare
Anaphylactic reactions
Angioedema
Nervous system disorders
Common
Headache
Eye disorders
Uncommon
Conjunctivitis
Respiratory, thoracic and mediastinal disorders
Common
Rhinorrhoea
Gastrointestinal disorders
Common
Diarrhoea
Nausea
Uncommon
Inflammatory bowel disease
Skin and subcutaneous tissue disorders
Common
Eczema
Uncommon
Urticaria
Dyshidrotic eczema
Rare
Exfoliative dermatitis2)
Hypersensitivity vasculitis
Not known
Pyoderma gangrenosum
General disorders and administration site conditions
Common
Fatigue
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, 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile

The most frequently reported adverse reactions 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 infestations
Very common
Upper respiratory tract infections
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 system disorders
Uncommon
Neutropenia
Immune system disorders
Rare
Anaphylactic reactions
Angioedema
Nervous system disorders
Common
Headache
Eye disorders
Uncommon
Conjunctivitis
Respiratory, thoracic and mediastinal disorders
Common
Rhinorrhoea
Gastrointestinal disorders
Common
Diarrhoea
Nausea
Uncommon
Inflammatory bowel disease
Skin and subcutaneous tissue disorders
Common
Eczema
Uncommon
Urticaria
Dyshidrotic eczema
Rare
Exfoliative dermatitis2)
Hypersensitivity vasculitis
Not known
Pyoderma gangrenosum
General disorders and administration site conditions
Common
Fatigue
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, 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Secukinumab has the potential to increase the risk of infections. Serious infections have been observed in patients receiving secukinumab in the post-marketing setting. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should not be administered until the infection resolves.

In clinical studies, infections have been observed in patients receiving secukinumab (see section 4.8).
Most of these were mild or moderate upper respiratory tract infections such as nasopharyngitis and did not require treatment discontinuation.

Related to the mechanism of action of secukinumab, non-serious mucocutaneous candida infections were more frequently reported for secukinumab than placebo in the psoriasis clinical studies (3.55 per 100 patient years for secukinumab 300 mg versus 1.00 per 100 patient years for placebo) (see section 4.8).

Tuberculosis

Tuberculosis (active and/or latent reactivation) has been reported in patients treated with secukinumab.
Patients should be evaluated for tuberculosis infection prior to initiating treatment with secukinumab.
Secukinumab should not be given to patients with active tuberculosis (see section 4.3). In patients with latent tuberculosis, anti-tuberculosis therapy should be considered prior to initiation of secukinumab as per clinical guidelines. Patients receiving secukinumab should be monitored for signs and symptoms of active tuberculosis.

Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis)

Cases of new or exacerbations of inflammatory bowel disease have been reported with secukinumab (see section 4.8). Secukinumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, secukinumab should be discontinued and appropriate medical management should be initiated.

Hypersensitivity reactions

Rare cases of anaphylactic reactions and angioedema have been observed in patients receiving secukinumab. If an anaphylactic reaction, angioedema or other serious allergic reactions occur, administration of secukinumab should be discontinued immediately and appropriate therapy initiated.

Latex-sensitive individuals

The removable needle cap of Cosentyx 75 mg solution for injection in pre-filled syringe contains a derivative of natural rubber latex. No natural rubber latex has to date been detected in the removable needle cap. Nevertheless, the use of Cosentyx 75 mg solution for injection in pre-filled syringe in

latex-sensitive individuals has not been studied and there is therefore a potential risk of hypersensitivity reactions which cannot be completely ruled out.

Vaccinations

Live vaccines should not be given concurrently with secukinumab.

Patients receiving secukinumab may receive concurrent inactivated or non-live vaccinations. In a study, after meningococcal and inactivated influenza vaccinations, a similar proportion of healthy volunteers treated with 150 mg of secukinumab and those treated with placebo were able to mount an adequate immune response of at least a 4-fold increase in antibody titres to meningococcal and influenza vaccines. The data suggest that secukinumab does not suppress the humoral immune response to the meningococcal or influenza vaccines.

Prior to initiating therapy with Cosentyx, it is recommended that paediatric patients receive all age-appropriate immunisations as per current immunisation guidelines.

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of secukinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Secukinumab was administered concomitantly with methotrexate (MTX), sulfasalazine and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis). Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab (see also section 4.5).

Hepatitis B reactivation

Hepatitis B virus reactivation can occur in patients treated with secukinumab. In accordance with clinical guidelines for immunosuppressants, testing patients for HBV infection is to be considered before initiating treatment with secukinumab. Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation during secukinumab treatment. If reactivation of HBV occurs while on secukinumab, discontinuation of the treatment should be considered, and patients should be treated according to clinical guidelines.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Secukinumab has the potential to increase the risk of infections. Serious infections have been observed in patients receiving secukinumab in the post-marketing setting. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should not be administered until the infection resolves.

In clinical studies, infections have been observed in patients receiving secukinumab (see section 4.8).
Most of these were mild or moderate upper respiratory tract infections such as nasopharyngitis and did not require treatment discontinuation.

Related to the mechanism of action of secukinumab, non-serious mucocutaneous candida infections were more frequently reported for secukinumab than placebo in the psoriasis clinical studies (3.55 per 100 patient years for secukinumab 300 mg versus 1.00 per 100 patient years for placebo) (see section 4.8).

Tuberculosis

Tuberculosis (active and/or latent reactivation) has been reported in patients treated with secukinumab.
Patients should be evaluated for tuberculosis infection prior to initiating treatment with secukinumab.
Secukinumab should not be given to patients with active tuberculosis (see section 4.3). In patients with latent tuberculosis, anti-tuberculosis therapy should be considered prior to initiation of secukinumab as per clinical guidelines. Patients receiving secukinumab should be monitored for signs and symptoms of active tuberculosis.

Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis)

Cases of new or exacerbations of inflammatory bowel disease have been reported with secukinumab (see section 4.8). Secukinumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, secukinumab should be discontinued and appropriate medical management should be initiated.

Hypersensitivity reactions

Rare cases of anaphylactic reactions and angioedema have been observed in patients receiving secukinumab. If an anaphylactic reaction, angioedema or other serious allergic reactions occur, administration of secukinumab should be discontinued immediately and appropriate therapy initiated.

Latex-sensitive individuals – Cosentyx 150 mg solution for injection in pre-filled syringe and 150 mg solution for injection in pre-filled pen only

The removable needle cap of Cosentyx 150 mg solution for injection in pre-filled syringe and Cosentyx 150 mg solution for injection in pre-filled pen contains a derivative of natural rubber latex.
No natural rubber latex has to date been detected in the removable needle cap. Nevertheless, the use of Cosentyx 150 mg solution for injection in pre-filled syringe and Cosentyx 150 mg solution for injection in pre-filled pen in latex-sensitive individuals has not been studied and there is therefore a potential risk of hypersensitivity reactions which cannot be completely ruled out.

Vaccinations

Live vaccines should not be given concurrently with secukinumab.

Patients receiving secukinumab may receive concurrent inactivated or non-live vaccinations. In a study, after meningococcal and inactivated influenza vaccinations, a similar proportion of healthy volunteers treated with 150 mg of secukinumab and those treated with placebo were able to mount an adequate immune response of at least a 4-fold increase in antibody titres to meningococcal and influenza vaccines. The data suggest that secukinumab does not suppress the humoral immune response to the meningococcal or influenza vaccines.

Prior to initiating therapy with Cosentyx, it is recommended that paediatric patients receive all age-appropriate immunisations as per current immunisation guidelines.

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of secukinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Secukinumab was administered concomitantly with methotrexate (MTX), sulfasalazine and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis). Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab (see also section 4.5).

Hepatitis B reactivation

Hepatitis B virus reactivation can occur in patients treated with secukinumab. In accordance with clinical guidelines for immunosuppresants, testing patients for HBV infection is to be considered before initiating treatment with secukinumab. Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation during secukinumab treatment. If reactivation of HBV occurs while on secukinumab, discontinuation of the treatment should be considered, and patients should be treated according to clinical guidelines.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Secukinumab has the potential to increase the risk of infections. Serious infections have been observed in patients receiving secukinumab in the post-marketing setting. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should not be administered until the infection resolves.

In clinical studies, infections have been observed in patients receiving secukinumab (see section 4.8).
Most of these were mild or moderate upper respiratory tract infections such as nasopharyngitis and did not require treatment discontinuation.

Related to the mechanism of action of secukinumab, non-serious mucocutaneous candida infections were more frequently reported for secukinumab than placebo in the psoriasis clinical studies (3.55 per 100 patient years for secukinumab 300 mg versus 1.00 per 100 patient years for placebo) (see section 4.8).

Tuberculosis

Tuberculosis (active and/or latent reactivation) has been reported in patients treated with secukinumab.
Patients should be evaluated for tuberculosis infection prior to initiating treatment with secukinumab.
Secukinumab should not be given to patients with active tuberculosis (see section 4.3). In patients with latent tuberculosis, anti-tuberculosis therapy should be considered prior to initiation of secukinumab as per clinical guidelines. Patients receiving secukinumab should be monitored for signs and symptoms of active tuberculosis.

Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis)

Cases of new or exacerbations of inflammatory bowel disease have been reported with secukinumab (see section 4.8). Secukinumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, secukinumab should be discontinued and appropriate medical management should be initiated.

Hypersensitivity reactions

Rare cases of anaphylactic reactions and angioedema have been observed in patients receiving secukinumab. If an anaphylactic reaction, angioedema or other serious allergic reactions occur, administration of secukinumab should be discontinued immediately and appropriate therapy initiated.

Vaccinations

Live vaccines should not be given concurrently with secukinumab.

Patients receiving secukinumab may receive concurrent inactivated or non-live vaccinations. In a study, after meningococcal and inactivated influenza vaccinations, a similar proportion of healthy volunteers treated with 150 mg of secukinumab and those treated with placebo were able to mount an adequate immune response of at least a 4-fold increase in antibody titres to meningococcal and influenza vaccines. The data suggest that secukinumab does not suppress the humoral immune response to the meningococcal or influenza vaccines.

Prior to initiating therapy with Cosentyx, it is recommended that paediatric patients receive all age-appropriate immunisations as per current immunisation guidelines.

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of secukinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Secukinumab was administered concomitantly with methotrexate (MTX), sulfasalazine and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis). Caution should be exercised when considering concomitant use of other immunosuppressants and secukinumab (see also section 4.5).

Hepatitis B reactivation

Hepatitis B virus reactivation can occur in patients treated with secukinumab. In accordance with clinical guidelines for immunosuppresants, testing patients for HBV infection is to be considered before initiating treatment with secukinumab. Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation during secukinumab treatment. If reactivation of HBV occurs while on secukinumab, discontinuation of the treatment should be considered, and patients should be treated according to clinical guidelines.

Live vaccines should not be given concurrently with secukinumab (see also section 4.4).

In a study in adult subjects with plaque psoriasis, no interaction was observed between secukinumab and midazolam (CYP3A4 substrate).

No interaction was seen when secukinumab was administered concomitantly with methotrexate (MTX) and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and axial spondyloarthritis).

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception during treatment and for at least 20 weeks after treatment.

Pregnancy

There are no adequate data from the use of secukinumab in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Cosentyx during pregnancy.

Breast-feeding

It is not known whether secukinumab is excreted in human milk. Immunoglobulins are excreted in human milk and it is not known if secukinumab is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from secukinumab, a decision on whether to discontinue breast-feeding during treatment and up to 20 weeks after treatment or to discontinue therapy with Cosentyx must be made taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman.

Fertility

The effect of secukinumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

Cosentyx has no or negligible influence on the ability to drive and use machines.

Doses up to 30 mg/kg (approximately 2000 to 3000 mg) have been administered intravenously in clinical studies without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10

Mechanism of action

Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.

IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis. Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis.

Pharmacodynamic effects

Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis.

In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.

Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation.

Clinical efficacy and safety

Adult plaque psoriasis
The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE].
The efficacy and safety of secukinumab 150 mg and 300 mg were evaluated versus either placebo or

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10

Mechanism of action

Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.

IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, hidradenitis suppurativa, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. IL-17A is also upregulated in hidradenitis suppurativa lesions and increased IL-17A serum levels have been observed in affected patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis.
Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis.

Pharmacodynamic effects

Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab- bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis.

In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.

Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation.

Clinical efficacy and safety

Adult plaque psoriasis
The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE].

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10

Mechanism of action

Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.

IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, hidradenitis suppurativa, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. IL-17A is also upregulated in hidradenitis suppurativa lesions and increased IL-17A serum levels have been observed in affected patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis.
Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis.

Pharmacodynamic effects

Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis.

In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.

Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation.

Clinical efficacy and safety

Adult plaque psoriasis
The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE].

Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar.

Paediatric population

Plaque psoriasis
In a pool of the two paediatric studies, patients with moderate to severe plaque psoriasis (6 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing ≥25 and <50 kg had a mean ± SD steady-state trough concentration of 19.8±6.96 µg/ml (n=24) after 75 mg of secukinumab and patients weighing ≥50 kg had mean ±SD trough concentration of 27.3±10.1 µg/ml (n=36) after 150 mg of secukinumab. The mean ± SD steady-state trough concentration in patients weighing <25 kg (n=8) was 32.6±10.8 µg/ml at week 24 after 75 mg dose.

Juvenile idiopathic arthritis
In a paediatric study, ERA and JPsA patients (2 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing <50 kg, and weighing ≥50 kg had a mean ± SD steady-state trough concentration of 25.2±5.45 µg/ml (n=10) and 27.9±9.57 µg/ml (n=19), respectively.

Adult population

Absorption
Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose.

Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 µg/ml or 27.3±9.5 µg/ml, respectively, between 5 and 6 days post dose.

After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis.

Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar.

Absorption

Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose.

Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 µg/ml or 27.3±9.5 µg/ml, respectively, between 5 and 6 days post dose.

After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis.

On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 µg/ml and 55.2 µg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens.

Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance.

Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated.

The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model.

Following a single subcutaneous injection of 300 mg solution for injection in pre-filled syringe in plaque psoriasis patients, secukinumab systemic exposure was similar to what was observed previously with two injections of 150 mg.

Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar.

Absorption

Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose.

Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 µg/ml or 27.3±9.5 µg/ml, respectively, between 5 and 6 days post dose.

After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis.

On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 µg/ml and 55.2 µg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens.

Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance.

Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated.

The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model.

Following subcutaneous administration of 300 mg at weeks 0, 1, 2, 3 and 4 followed by 300 mg every 2 weeks, the mean ± SD steady-state secukinumab trough concentration at week 16 was approximately 55.1±26.7 µg/ml and 58.1±30.1 µg/ml in HS study 1 and HS study 2, respectively.

Distribution