No cases of overdose have been reported in clinical studies.
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.
Clinically important, active infection.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Trehalose dihydrate
L-histidine
L-histidine hydrochloride monohydrate
L-methionine
Polysorbate 80
Water for injections
Solution for injection in pre-filled syringe (injection)
Solution for injection in pre-filled pen (SensoReady pen)
The solution is clear and colourless to slightly yellow.
Summary of the safety profile
A total of 6,804 patients have been treated with Cosentyx in blinded and open-label clinical studies in various indications (plaque psoriasis, psoriatic arthritis, ankylosing spondylitis and other autoimmune conditions). Of these, 3,671 patients were exposed to Cosentyx for at least one year, representing 6,450 patient years of exposure.
Adverse reactions in plaque psoriasis
Four placebo-controlled phase III studies in plaque psoriasis were pooled to evaluate the safety of Cosentyx in comparison to placebo up to 12 weeks after treatment initiation. In total, 2,076 patients were evaluated (692 patients on 150 mg, 690 patients on 300 mg and 694 patients on placebo).
The most frequently reported adverse drug reactions (ADRs) were upper respiratory tract infections (most frequently nasopharyngitis, rhinitis). Most of the reactions were mild or moderate in severity.
Adverse reactions in psoriatic arthritis
Cosentyx was studied in two placebo-controlled psoriatic arthritis studies with 1,003 patients (703 patients on Cosentyx and 300 patients on placebo) for a total exposure of 1,061 patient-years of study exposure (median duration of exposure for secukinumab-treated patients: 456 days in PsA Study 1 and 245 days in PsA Study 2). The safety profile observed in patients with psoriatic arthritis treated with Cosentyx is consistent with the safety profile in psoriasis.
Adverse reactions in ankylosing spondylitis
Cosentyx was studied in two placebo-controlled ankylosing spondylitis studies with 590 patients (394 patients on Cosentyx and 196 patients on placebo) for a total of 755 patient-years of study exposure (median duration of exposure for secukinumab-treated patients: 469 days in AS Study 1 and 460 days in AS Study 2). The safety profile observed in patients with ankylosing spondylitis treated with Cosentyx is consistent with the safety profile in psoriasis.
Tabulated list of adverse reactions
ADRs from psoriasis, psoriatic arthritis and ankylosing spondylitis clinical studies as well as from post-marketing experience (Table 1) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug 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).
Table 1 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 | |
|
Tinea pedis | ||
|
Otitis externa | ||
|
Not known |
Mucosal and cutaneous candidiasis (including oesophageal candidiasis) | |
|
Blood and lymphatic system disorders |
Uncommon |
Neutropenia |
|
Immune system disorders |
Rare |
Anaphylactic reactions |
|
Eye disorders |
Uncommon |
Conjunctivitis |
|
Respiratory, thoracic and mediastinal disorders |
Common |
Rhinorrhoea |
|
Gastrointestinal disorders |
Common |
Diarrhoea |
|
Skin and subcutaneous disorders |
Uncommon |
Urticaria |
|
1) Placebo-controlled clinical studies (phase III) in plaque psoriasis, PsA and AS patients exposed to 300 mg, 150 mg, 75 mg or placebo up to 12 weeks (psoriasis) or 16 weeks (PsA and AS) treatment duration | ||
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 Cosentyx and 694 patients treated with placebo for up to 12 weeks), infections were reported in 28.7% of patients treated with Cosentyx 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 Cosentyx and in 0.3% of patients treated with placebo.
Over the entire treatment period (a total of 3,430 patients treated with Cosentyx for up to 52 weeks for the majority of patients), infections were reported in 47.5% of patients treated with Cosentyx (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of patients treated with Cosentyx (0.015 per patient-year of follow-up).
Infection rates observed in psoriatic arthritis and ankylosing spondylitis clinical studies were similar to those observed in the psoriasis studies.
Neutropenia
In psoriasis phase 3 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 Cosentyx were reported in the remaining 3 cases.
The frequency of neutropenia in psoriatic arthritis and ankylosing spondylitis is similar to psoriasis.
Rare cases of neutropenia <0.5x109/l (CTCAE Grade 4) were reported.
Hypersensitivity reactions
Immunogenicity
In psoriasis, psoriatic arthritis and ankylosing spondylitis clinical studies, less than 1% of patients treated with Cosentyx 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.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Non-clinical data revealed no special risks for humans based on tissue cross-reactivity testing, safety pharmacology, repeated dose and reproductive toxicity studies performed with secukinumab or a murine anti-murine IL-17A antibody.
Since secukinumab binds to cynomolgus monkey and human IL-17A, its safety was studied in the cynomolgus monkey. No undesirable effects of secukinumab were seen following subcutaneous administration to cynomolgus monkeys for up to 13 weeks and intravenous administration up to 26 weeks (including pharmacokinetic, pharmacodynamic, immunogenicity and immunotoxicity (e.g. T-cell dependent antibody response and NK cell activity) evaluations). The average serum concentrations observed in monkeys after 13 weekly subcutaneous doses of 150 mg/kg were considerably higher than the predicted average serum concentration expected in psoriatic patients at the highest clinical dose. Antibodies to secukinumab were detected in only one of the exposed animals. No non-specific tissue cross-reactivity was observed when secukinumab was applied to normal human tissue.
Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab.
In an embryofoetal development study in cynomolgus monkeys, secukinumab showed no maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and late gestation.
No undesirable effects of a murine anti-murine IL-17A antibody were seen in fertility and early embryonic development and pre-and postnatal development studies in mice. The high dose used in these studies was in excess of the maximum effective dose in terms of IL-17A suppression and activity.
Plaque psoriasis
Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.
Psoriatic arthritis
Cosentyx, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate.
Ankylosing spondylitis
Cosentyx is indicated for the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy.
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 ankylosing spondylitis 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.
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
Plaque psoriasis
The safety and efficacy of Cosentyx 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 Cosentyx 150 mg and 300 mg were evaluated versus either placebo or etanercept. In addition, one study assessed a chronic treatment regimen versus a “retreatment as needed†regimen [SCULPTURE].
Of the 2,403 patients who were included in the placebo-controlled studies, 79% were biologic-naive, 45% were non-biologic failures and 8% were biologic failures (6% were anti-TNF failures, and 2% were anti-p40 failures). Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline.
Psoriasis Study 1 (ERASURE) evaluated 738 patients. Patients randomised to Cosentyx received 150 mg or 300 mg doses at Weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis Study 2 (FIXTURE) evaluated 1,306 patients. Patients randomised to Cosentyx received 150 mg or 300 mg doses at Weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. In both Study 1 and Study 2, patients randomised to receive placebo who were non-responders at Week 12 then crossed over to receive Cosentyx (either 150 mg or 300 mg) at Weeks 12, 13, 14, and 15, followed by the same dose every month starting at Week 16. All patients were followed for up to 52 weeks following first administration of study treatment.
Psoriasis Study 3 (FEATURE) evaluated 177 patients using a pre-filled syringe compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of Cosentyx self-administration via the pre-filled syringe. Psoriasis Study 4 (JUNCTURE) evaluated 182 patients using a pre-filled pen compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of Cosentyx self-administration via the pre-filled pen. In both Study 3 and Study 4, patients randomised to Cosentyx received 150 mg or 300 mg doses at Weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients were also randomised to receive placebo at Weeks 0, 1, 2, 3 and 4, followed by the same dose every month.
Psoriasis Study 5 (SCULPTURE) evaluated 966 patients. All patients received Cosentyx 150 mg or 300 mg doses at Weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomised to receive either a maintenance regimen of the same dose every month starting at Week 12 or a “retreatment as needed†regimen of the same dose. Patients randomised to “retreatment as needed†did not achieve adequate maintenance of response and therefore a fixed monthly maintenance regimen is recommended.
The co-primary endpoints in the placebo and active-controlled studies were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 “clear†or “almost clear†response versus placebo at Week 12 (see Tables 2 and 3). The 300 mg dose provided improved skin clearance particularly for “clear†or “almost clear†skin across the efficacy endpoints of PASI 90, PASI 100, and IGA mod 2011 0 or 1 response across all studies with peak effects seen at Week 16, therefore this dose is recommended.
Table 2 Summary of PASI 50/75/90/100 & IGA* mod 2011 “clear†or “almost clear†clinical response in Psoriasis Studies 1, 3 and 4 (ERASURE, FEATURE and JUNCTURE)
|
Week 12 |
Week 16 |
Week 52 | |||||
|
Placebo |
150 mg |
300 mg |
150 mg |
300 mg |
150 mg |
300 mg | |
|
Study 1 | |||||||
|
Number of patients |
246 |
244 |
245 |
244 |
245 |
244 |
245 |
|
PASI 50 response n (%) |
22 (8.9%) |
203 (83.5%) |
222 (90.6%) |
212 (87.2%) |
224 (91.4%) |
187 (77%) |
207 (84.5%) |
|
PASI 75 response n (%) |
11 (4.5%) |
174 (71.6%)** |
200 (81.6%)** |
188 (77.4%) |
211 (86.1%) |
146 (60.1%) |
182 (74.3%) |
|
PASI 90 response n (%) |
3 (1.2%) |
95 (39.1%)** |
145 (59.2%)** |
130 (53.5%) |
171 (69.8%) |
88 (36.2%) |
147 (60.0%) |
|
PASI 100 response n (%) |
2 (0.8%) |
31 (12.8%) |
70 (28.6%) |
51 (21.0%) |
102 (41.6%) |
49 (20.2%) |
96 (39.2%) |
|
IGA mod 2011 “clear†or “almost clear†response n (%) |
6 (2.40%) |
125 (51.2%)** |
160 (65.3%)** |
142 (58.2%) |
180 (73.5%) |
101 (41.4%) |
148 (60.4%) |
|
Study 3 | |||||||
|
Number of patients |
59 |
59 |
58 |
- |
- |
- |
- |
|
PASI 50 response n (%) |
3 (5.1%) |
51 (86.4%) |
51 (87.9%) |
- |
- |
- |
- |
|
PASI 75 response n (%) |
0 (0.0%) |
41 (69.5%)** |
44 (75.9%)** |
- |
- |
- |
- |
|
PASI 90 response n (%) |
0 (0.0%) |
27 (45.8%) |
35 (60.3%) |
- |
- |
- |
- |
|
PASI 100 response n (%) |
0 (0.0%) |
5 (8.5%) |
25 (43.1%) |
- |
- |
- |
- |
|
IGA mod 2011 “clear†or “almost clear†response n (%) |
0 (0.0%) |
31 (52.5%)** |
40 (69.0%)** |
- |
- |
- |
- |
|
Study 4 | |||||||
|
Number of patients |
61 |
60 |
60 |
- |
- |
- |
- |
|
PASI 50 response n (%) |
5 (8.2%) |
48 (80.0%) |
58 (96.7%) |
- |
- |
- |
- |
|
PASI 75 response n (%) |
2 (3.3%) |
43 (71.7%)** |
52 (86.7%)** |
- |
- |
- |
- |
|
PASI 90 response n (%) |
0 (0.0%) |
24 (40.0%) |
33 (55.0%) |
- |
- |
- |
- |
|
PASI 100 response n(%) |
0 (0.0%) |
10 (16.7%) |
16 (26.7%) |
- |
- |
- |
- |
|
IGA mod 2011 “clear†or “almost clear†response n (%) |
0 (0.0%) |
32 (53.3%)** |
44 (73.3%)** |
- |
- |
- |
- |
|
* The IGA mod 2011 is a 5-category scale including “0 = clearâ€, “1 = almost clearâ€, “2 = mildâ€, “3 = moderate†or “4 = severeâ€, indicating the physician's overall assessment of the psoriasis severity focusing on induration, erythema and scaling. Treatment success of “clear†or “almost clear†consisted of no signs of psoriasis or normal to pink colouration of lesions, no thickening of the plaque and none to minimal focal scaling. ** p values versus placebo and adjusted for multiplicity: p<0.0001. | |||||||
Table 3 Summary of clinical response on Psoriasis Study 2 (FIXTURE)
|
Week 12 |
Week 16 |
Week 52 | ||||||||
|
Placebo |
150 mg |
300 mg |
Etanercept |
150 mg |
300 mg |
Etanercept |
150 mg |
300 mg |
Etanercept | |
|
Number of patients |
324 |
327 |
323 |
323 |
327 |
323 |
323 |
327 |
323 |
323 |
|
PASI 50 response n (%) |
49 (15.1%) |
266 (81.3%) |
296 (91.6%) |
226 (70.0%) |
290 (88.7%) |
302 (93.5%) |
257 (79.6%) |
249 (76.1%) |
274 (84.8%) |
234 (72.4%) |
|
PASI 75 response n (%) |
16 (4.9%) |
219 (67.0%)** |
249 (77.1%)** |
142 (44.0%) |
247 (75.5%) |
280 (86.7%) |
189 (58.5%) |
215 (65.7%) |
254 (78.6%) |
179 (55.4%) |
|
PASI 90 response n (%) |
5 (1.5%) |
137 (41.9%) |
175 (54.2%) |
67 (20.7%) |
176 (53.8%) |
234 (72.4%) |
101 (31.3%) |
147 (45.0%) |
210 (65.0%) |
108 (33.4%) |
|
PASI 100 response n (%) |
0 (0%) |
47 (14.4%) |
78 (24.1%) |
14 (4.3%) |
84 (25.7%) |
119 (36.8%) |
24 (7.4%) |
65 (19.9%) |
117 (36.2%) |
32 (9.9%) |
|
IGA mod 2011 “clear†or “almost clear†response n (%) |
9 (2.8%) |
167 (51.1%)** |
202 (62.5%)** |
88 (27.2%) |
200 (61.2%) |
244 (75.5%) |
127 (39.3%) |
168 (51.4%) |
219 (67.8%) |
120 (37.2%) |
** p values versus etanercept: p=0.0250
In an additional psoriasis study (CLEAR) 676 patients were evaluated. Secukinumab 300 mg met the primary and secondary endpoints by showing superiority to ustekinumab based on PASI 90 response at Week 16 (primary endpoint), speed of onset of PASI 75 response at Week 4, and long-term PASI 90 response at Week 52. Greater efficacy of secukinumab compared to ustekinumab for the endpoints PASI 75/90/100 and IGA mod 2011 0 or 1 response (“clear†or “almost clearâ€) was observed early and continued through to Week 52.
Table 4 Summary of clinical response on CLEAR Study
|
Week 4 |
Week 16 |
Week 52 | ||||
|
Secukinumab 300 mg |
Ustekinumab* |
Secukinumab 300 mg |
Ustekinumab* |
Secukinumab 300 mg |
Ustekinumab* | |
|
Number of patients |
334 |
335 |
334 |
335 |
334 |
335 |
|
PASI 75 response n (%) |
166 (49.7%)** |
69 (20.6%) |
311 (93.1%) |
276 (82.4%) |
306 (91.6%) |
262 (78.2%) |
|
PASI 90 response n (%) |
70 (21.0%) |
18 (5.4%) |
264 (79.0%)** |
192 (57.3%) |
250 (74.9%)*** |
203 (60.6%) |
|
PASI 100 response n (%) |
14 (4.2%) |
3 (0.9%) |
148 (44.3%) |
95 (28.4%) |
150 (44.9%) |
123 (36.7%) |
|
IGA mod 2011 “clear†or “almost clear†response n (%) |
128 (38.3%) |
41 (12.2%) |
278 (83.2%) |
226 (67.5%) |
261 (78.1%) |
213 (63.6%) |
* Patients treated with secukinumab received 300 mg doses at Weeks 0, 1, 2, 3 and 4, followed by the same dose every 4 weeks until Week 52. Patients treated with ustekinumab received 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks until Week 52 (dosed by weight as per approved posology)
** p values versus ustekinumab: p<0.0001 for primary endpoint of PASI 90 at Week 16 and secondary endpoint of PASI 75 at Week 4
*** p values versus ustekinumab: p=0.0001 for secondary endpoint of PASI 90 at Week 52
Cosentyx was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients. Improvements in PASI 75 in patients with concurrent psoriatic arthritis at baseline were similar to those in the overall plaque psoriasis population.
Cosentyx was associated with a fast onset of efficacy with a 50% reduction in mean PASI by Week 3 for the 300 mg dose.
Figure 1 Time course of percentage change from baseline of mean PASI score in Study 1 (ERASURE)
Specific locations/forms of plaque psoriasis
In two additional placebo-controlled studies, improvement was seen in both nail psoriasis (TRANSFIGURE, 198 patients) and palmoplantar plaque psoriasis (GESTURE, 205 patients). In the TRANSFIGURE Study, secukinumab was superior to placebo at Week 16 (46.1% for 300 mg, 38.4% for 150 mg and 11.7% for placebo) as assessed by significant improvement from baseline in the Nail Psoriasis Severity Index (NAPSI %) for patients with moderate to severe plaque psoriasis with nail involvement. In the GESTURE Study, secukinumab was superior to placebo at Week 16 (33.3% for 300 mg, 22.1% for 150 mg, and 1.5% for placebo) as assessed by significant improvement of ppIGA 0 or 1 response (“clear†or “almost clearâ€) for patients with moderate to severe palmoplantar plaque psoriasis.
A placebo-controlled study evaluated 102 patients with moderate to severe scalp psoriasis, defined as having a Psoriasis Scalp Severity Index (PSSI) score of >12, an IGA mod 2011 scalp only score of 3 or greater and at least 30% of the scalp surface area affected. Secukinumab 300 mg was superior to placebo at Week 12 as assessed by significant improvement from baseline in both the PSSI 90 response (52.9% versus 2.0%) and IGA mod 2011 0 or 1 scalp only response (56.9% versus 5.9%). Improvement in both endpoints was sustained for secukinumab patients who continued treatment through to Week 24.
Quality of life/patient-reported outcomes
Statistically significant improvements at Week 12 (Studies 1-4) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Mean decreases (improvements) in DLQI from baseline ranged from -10.4 to -11.6 with secukinumab 300 mg, from -7.7 to -10.1 with secukinumab 150 mg, versus -1.1 to -1.9 for placebo at Week 12. These improvements were maintained for 52 weeks (Studies 1 and 2).
Forty percent of the participants in Studies 1 and 2 completed the Psoriasis Symptom Diary©. For the participants completing the diary in each of these studies, statistically significant improvements at Week 12 from baseline compared to placebo in patient-reported signs and symptoms of itching, pain and scaling were demonstrated.
Statistically significant improvements at Week 4 from baseline in patients treated with secukinumab compared to patients treated with ustekinumab (CLEAR) were demonstrated in the DLQI and these improvements were maintained for up to 52 weeks.
Statistically significant improvements in patient-reported signs and symptoms of itching, pain and scaling at Week 16 and Week 52 (CLEAR) were demonstrated in the Psoriasis Symptom Diary© in patients treated with secukinumab compared to patients treated with ustekinumab.
Statistically significant improvements (decreases) at Week 12 from baseline in the scalp psoriasis study were demonstrated in patient reported signs and symptoms of scalp itching, pain and scaling compared to placebo.
Psoriatic arthritis
The safety and efficacy of Cosentyx were assessed in 1,003 patients in two randomised, double-blind, placebo-controlled phase III studies in patients with active psoriatic arthritis (>3 swollen and >3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients with each subtype of PsA were enrolled in these studies, including polyarticular arthritis with no evidence of rheumatoid nodules, spondylitis with peripheral arthritis, asymmetric peripheral arthritis, distal interphalangeal involvement and arthritis mutilans. Patients in these studies had a diagnosis of PsA for a median of 3.9 to 5.3 years. The majority of patients also had active psoriasis skin lesions or a documented history of psoriasis. Over 62% and 47% of the PsA patients had enthesitis and dactylitis at baseline, respectively. For both studies, the primary endpoint was American College of Rheumatology (ACR) 20 response at Week 24.
In Psoriatic Arthritis Study 1 (PsA Study 1) and Psoriatic Arthritis Study 2 (PsA Study 2) 29% and 35% of patients, respectively, 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).
PsA Study 1 (FUTURE 1) evaluated 606 patients, of whom 60.7% had concomitant MTX. Patients randomised to Cosentyx received 10 mg/kg intravenously at Weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at Week 8. Patients randomised to placebo who were non-responders at Week 16 (early rescue) and other placebo patients at Week 24 were crossed over to receive Cosentyx (either 75 mg or 150 mg subcutaneously) followed by the same dose every month.
PsA Study 2 (FUTURE 2) evaluated 397 patients, of whom 46.6% had concomitant MTX. Patients randomised to Cosentyx received 75 mg, 150 mg or 300 mg subcutaneously at Weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to receive placebo who were non-responders at Week 16 (early rescue) were crossed over to receive Cosentyx (either 150 mg or 300 mg subcutaneously) at Week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at Week 16 were crossed over to receive Cosentyx (either 150 mg or 300 mg subcutaneously) at Week 24 followed by the same dose every month.
Signs and symptoms
Treatment with Cosentyx resulted in significant improvement in measures of disease activity compared to placebo at Week 24 (see Table 5).
Table 5 Clinical response in PsA Study 2 at Week 24
|
Week 24 | ||||
|
Placebo |
75 mg |
150 mg |
300 mg | |
|
Number of patients randomised |
98 |
99 |
100 |
100 |
|
ACR20 response n (%) |
15 (15.3%) |
29 (29.3%*) |
51 (51.0%***) |
54 (54.0%***) |
|
ACR50 response n (%) |
7 (7.1%) |
18 (18.2%) |
35 (35.0%) |
35 (35.0%**) |
|
ACR70 response n (%) |
1 (1.0%) |
6 (6.1%) |
21 (21.0%**) |
20 (20.0%**) |
|
DAS28-CRP |
-0.96 |
-1.12 |
-1.58** |
-1.61** |
|
Number of patients with >3% BSA psoriasis skin involvement at baseline |
43 (43.9%) |
50 (50.5%) |
58 (58.0%) |
41 (41.0%) |
|
PASI 75 response n (%) |
7 (16.3%) |
14 (28.0%) |
28 (48.3%**) |
26 (63.4%***) |
|
Pharmacokinetic properties
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Plaque psoriasis 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. Distribution The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments. Biotransformation The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis. Elimination Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent. The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration. Linearity/non-linearity The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens. Psoriatic arthritis The pharmacokinetic properties of secukinumab observed in psoriatic arthritis patients were similar to those displayed in plaque psoriasis patients. The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model. Ankylosing spondylitis The pharmacokinetic properties of secukinumab observed in ankylosing spondylitis patients were similar to those displayed in plaque psoriasis patients. Special populations Elderly patients Of the 3,430 plaque psoriasis patients exposed to Cosentyx in clinical studies, a total of 230 patients were 65 years of age or older and 32 patients were 75 years of age or older. Of the 974 psoriatic arthritis patients exposed to Cosentyx in clinical studies, a total of 85 patients were 65 years of age or older and 4 patients were 75 years of age or older. Of the 571 ankylosing spondylitis patients exposed to Cosentyx in clinical studies, a total of 24 patients were 65 years of age or older and 3 patients were 75 years of age or older. Based on population pharmacokinetic analysis with a limited number of elderly patients (n=71 for age >65 years and n=7 for age >75 years), clearance in elderly patients and patients less than 65 years of age was similar. Patients with renal or hepatic impairment No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact Cosentyx, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of Cosentyx. Effect of weight on pharmacokinetics Secukinumab clearance and volume of distribution increase as body weight increases. | ||||
26.04.2018
Cosentyx® 150 mg solution for injection in pre-filled syringe
Cosentyx® 150 mg solution for injection in pre-filled pen
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland
Store in a refrigerator (2°C - 8°C). Do not freeze. If necessary, Cosentyx may be stored unrefrigerated for a single period of up to 4 days at room temperature, not above 30°C.
Store the syringes in the original package in order to protect from light.
Store the pens in the original package in order to protect from light.
Cosentyx 150 mg solution for injection in pre-filled syringe
Cosentyx is supplied in a pre-filled 1 ml glass syringe with a FluroTec-coated plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber assembled in a passive safety device of polycarbonate.
Cosentyx is available in unit packs containing 1 or 2 pre-filled syringes and in multipacks containing 6 (3 packs of 2) pre-filled syringes.
Cosentyx 150 mg solution for injection in pre-filled pen
Cosentyx is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen with transparent window and label (SensoReady pen). The pre-filled syringe inside the pen is a 1 ml glass syringe with a FluroTec-coated plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber.
Cosentyx is available in unit packs containing 1 or 2 pre-filled pens and in multipacks containing 6 (3 packs of 2) pre-filled pens.
Not all pack sizes may be marketed.
Cosentyx 150 mg solution for injection in pre-filled syringe
EU/1/14/980/002
EU/1/14/980/003
EU/1/14/980/006
Cosentyx 150 mg solution for injection in pre-filled pen
EU/1/14/980/004
EU/1/14/980/005
EU/1/14/980/007
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 pregnancy, embryonic/foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of Cosentyx in 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 Cosentyx 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.
Each pre-filled syringe contains 150 mg secukinumab* in 1 ml.
Each pre-filled pen contains 150 mg secukinumab* in 1 ml.
*Secukinumab is a recombinant fully human monoclonal antibody selective for interleukin-17A. Secukinumab is of the IgG1/κ-class produced in Chinese Hamster Ovary (CHO) cells.
Infections
Cosentyx has the potential to increase the risk of infections. In clinical studies, infections have been observed in patients receiving Cosentyx. 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 Cosentyx, 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).
Caution should be exercised when considering the use of Cosentyx 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 Cosentyx should not be administered until the infection resolves.
No increased susceptibility to tuberculosis was reported from clinical studies. However, Cosentyx should not be given to patients with active tuberculosis. Anti-tuberculosis therapy should be considered prior to initiation of Cosentyx in patients with latent tuberculosis.
Crohn's disease
Caution should be exercised when prescribing Cosentyx to patients with Crohn's disease as exacerbations of Crohn's disease, in some cases serious, were observed in clinical studies in both Cosentyx and placebo groups. Patients who are treated with Cosentyx and have Crohn's disease should be followed closely.
Hypersensitivity reactions
In clinical studies, rare cases of anaphylactic reactions have been observed in patients receiving Cosentyx. If an anaphylactic or other serious allergic reactions occur, administration of Cosentyx should be discontinued immediately and appropriate therapy initiated.
Latex-sensitive individuals
Cosentyx 150 mg solution for injection in pre-filled syringe
The removable needle cap of the Cosentyx 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 pre-filled syringes in latex-sensitive individuals has not been studied and there is therefore a potential risk of hypersensitivity reactions which cannot be completely ruled out.
Cosentyx 150 mg solution for injection in pre-filled pen
The removable cap of the Cosentyx pre-filled pen contains a derivative of natural rubber latex. No natural rubber latex has to date been detected in the removable cap. Nevertheless, the use of Cosentyx pre-filled pens in latex-sensitive individuals has not been studied and there is therefore a potential risk for hypersensitivity reactions which cannot be completely ruled out.
Vaccinations
Live vaccines should not be given concurrently with Cosentyx.
Patients receiving Cosentyx 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 Cosentyx does not suppress the humoral immune response to the meningococcal or influenza vaccines.
Concomitant immunosuppressive therapy
Cosentyx has no or negligible influence on the ability to drive and use machines.
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
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. Each 300 mg dose is given as two subcutaneous injections of 150 mg.
Psoriatic arthritis
For patients with concomitant moderate to severe plaque psoriasis or 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.
Ankylosing spondylitis
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.
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.
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 below the age of 18 years 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.
After proper training in subcutaneous injection technique, patients may self-inject Cosentyx if a physician determines that this is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients 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 150 mg solution for injection is supplied in a single-use pre-filled syringe or pen for individual use. Do not shake or freeze the syringe or pen. The syringe or pen should be taken out of the refrigerator 20 minutes before injecting to allow it to reach room temperature.
Prior to use, a visual inspection of the pre-filled syringe or pen is recommended. The liquid should be clear. Its colour may vary from colourless to slightly yellow. You may see a small air bubble, which is normal. Do not use if the liquid contains easily visible particles, is cloudy or is distinctly brown. Detailed instructions for use are provided in the package leaflet.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
15.01.2015
In a study in subjects with plaque psoriasis, no interaction was observed between secukinumab and midazolam (CYP3A4 substrate).
No interaction was seen when Cosentyx was administered concomitantly with methotrexate (MTX) and/or corticosteroids in arthritis studies (including in patients with psoriatic arthritis and ankylosing spondylitis).
