to accentuate Cosentyx Generic Name: secukinumab Dosage Form: injection Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings User Reviews Support Group Q & A Pricing & Coupons INDICATIONS AND USAGE Plaque Psoriasis Cosentyx is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. Psoriatic Arthritis Cosentyx is indicated for the treatment of adult patients with active psoriatic arthritis. Ankylosing Spondylitis Cosentyx is indicated for the treatment of adult patients with active ankylosing spondylitis. Slideshow 21 Arthritis Facts: It's A Game Changer DOSAGE AND ADMINISTRATION Plaque Psoriasis The recommended dosage is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks. Each 300 mg dosage is given as 2 subcutaneous injections of 150 mg. For some patients, a dosage of 150 mg may be acceptable. Psoriatic Arthritis For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, use the dosing and administration recommendations for plaque psoriasis [see Dosage and Administration (2.1)] . For other psoriatic arthritis patients, administer Cosentyx with or without a loading dosage by subcutaneous injection. The recommended dosage: With a loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter Without a loading dosage is 150 mg every 4 weeks If a patient continues to have active psoriatic arthritis, consider a dosage of 300 mg. Cosentyx may be administered with or without methotrexate. 2.3 Ankylosing Spondylitis Administer Cosentyx with or without a loading dosage by subcutaneous injection. The recommended dosage: With a loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter Without a loading dosage is 150 mg every 4 weeks Assessment Prior to Initiation of Cosentyx Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Cosentyx [see Warnings and Precautions (5.2)] . Important Administration Instructions There are three presentations for Cosentyx (i.e., Sensoready pen, prefilled syringe, and lyophilized powder in vial for reconstitution). The Cosentyx Instructions for Use for each presentation contains more detailed instructions on the preparation and administration of Cosentyx [see Instructions for Use] . Cosentyx is intended for use under the guidance and supervision of a physician. Patients may self-inject after proper training in subcutaneous injection technique using the Sensoready pen or prefilled syringe and when deemed appropriate. The lyophilized powder for reconstitution is for healthcare provider use only. Administer each injection at a different anatomic location (such as upper arms, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis. Administration of Cosentyx in the upper, outer arm may be performed by a caregiver or healthcare provider. Preparation for Use of Cosentyx Sensoready Pen and Prefilled Syringe Before injection, remove Cosentyx Sensoready pen or Cosentyx prefilled syringe from the refrigerator and allow Cosentyx to reach room temperature (15 to 30 minutes) without removing the needle cap. The removable cap of the Cosentyx Sensoready pen and the Cosentyx prefilled syringe contains natural rubber latex and should not be handled by latex-sensitive individuals [see Warnings and Precautions (5.5)] . Inspect Cosentyx visually for particulate matter and discoloration prior to administration. Cosentyx injection is a clear to slightly opalescent, colorless to slightly yellow solution. Do not use if the liquid contains visible particles, is discolored or cloudy. Cosentyx does not contain preservatives; therefore, administer the Sensoready pen or prefilled syringe within 1 hour after removal from the refrigerator. Discard any unused product remaining in the Sensoready pen or prefilled syringe. Reconstitution and Preparation of Cosentyx Lyophilized Powder Cosentyx lyophilized powder should be prepared and reconstituted with Sterile Water for Injection by a trained healthcare provider using aseptic technique and without interruption. The preparation time from piercing the stopper until end of reconstitution on average takes 20 minutes and should not exceed 90 minutes. a) Remove the vial of Cosentyx lyophilized powder from the refrigerator and allow to stand for 15 to 30 minutes to reach room temperature. Ensure the Sterile Water for Injection is at room temperature. b) Slowly inject 1 mL of Sterile Water for Injection into the vial containing Cosentyx lyophilized powder and direct the stream of Sterile Water for Injection onto the lyophilized powder. c) Tilt the vial at an angle of approximately 45 degrees and gently rotate between the fingertips for approximately 1 minute. Do not shake or invert the vial. d) Allow the vial to stand for about 10 minutes at room temperature to allow for dissolution. Note that foaming may occur. e) Tilt the vial at an angle of approximately 45 degrees and gently rotate between the fingertips for approximately 1 minute. Do not shake or invert the vial. f) Allow the vial to stand undisturbed at room temperature for approximately 5 minutes. The reconstituted Cosentyx solution should be essentially free of visible particles, clear to opalescent, and colorless to slightly yellow. Do not use if the lyophilized powder has not fully dissolved or if the liquid contains visible particles, is cloudy or discolored. g) Prepare the required number of vials (1 vial for the 150 mg dose or 2 vials for the 300 mg dose). h) The Cosentyx reconstituted solution contains 150 mg of secukinumab in 1 mL of solution. After reconstitution, use the solution immediately or store in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours. Do not freeze. i) If stored at 2ºC to 8ºC (36ºF to 46ºF), allow the reconstituted Cosentyx solution to reach room temperature (15 to 30 minutes) before administration. Cosentyx does not contain preservatives; therefore, administer within 1 hour after removal from 2ºC to 8ºC (36ºF to 46ºF) storage. DOSAGE FORMS AND STRENGTHS Injection: 150 mg/mL solution in a single-use Sensoready pen Injection: 150 mg/mL solution in a single-use prefilled syringe For Injection: 150 mg, lyophilized powder in a single-use vial for reconstitution (for healthcare professional use only) CONTRAINDICATIONS Cosentyx is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients [see Warnings and Precautions (5.4)] . WARNINGS AND PRECAUTIONS Infections Cosentyx may increase the risk of infections. In clinical trials, a higher rate of infections was observed in Cosentyx treated subjects compared to placebo-treated subjects. In placebo-controlled clinical trials in patients with moderate to severe plaque psoriasis, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with Cosentyx compared with placebo. A similar increase in risk of infection was seen in placebo-controlled trials in patients with psoriatic arthritis and ankylosing spondylitis [see Adverse Reactions (6.1)] . The incidence of some types of infections appeared to be dose-dependent in clinical studies [see Adverse Reactions (6.1)] . Exercise caution when considering the use of Cosentyx in patients with a chronic infection or a history of recurrent infection. Instruct patients 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 be discontinued until the infection resolves. Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Cosentyx. Do not administer Cosentyx to patients with active TB infection. Initiate treatment of latent TB prior to administering Cosentyx. Consider anti-TB therapy prior to initiation of Cosentyx in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Cosentyx should be monitored closely for signs and symptoms of active TB during and after treatment. Inflammatory Bowel Disease Caution should be used when prescribing Cosentyx to patients with inflammatory bowel disease. Exacerbations, in some cases serious, occurred in Cosentyx treated patients during clinical trials in plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. In addition, new onset inflammatory bowel disease cases occurred in clinical trials with Cosentyx. In an exploratory study in 59 patients with active Crohn s disease, there were trends toward greater disease activity and increased adverse events in the secukinumab group as compared to the placebo group. Patients who are treated with Cosentyx should be monitored for signs and symptoms of inflammatory bowel disease [see Adverse Reactions (6.1)] . Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in Cosentyx treated patients in clinical trials. If an anaphylactic or other serious allergic reaction occurs, administration of Cosentyx should be discontinued immediately and appropriate therapy initiated [see Adverse Reactions (6.1)] . Risk of Hypersensitivity in Latex-sensitive Individuals The removable cap of the Cosentyx Sensoready pen and the Cosentyx prefilled syringe contains natural rubber latex which may cause an allergic reaction in latex-sensitive individuals. The safe use of Cosentyx Sensoready pen or prefilled syringe in latex-sensitive individuals has not been studied. Vaccinations Prior to initiating therapy with Cosentyx, consider completion of all age appropriate immunizations according to current immunization guidelines. Patients treated with Cosentyx should not receive live vaccines. Non-live vaccinations received during a course of Cosentyx may not elicit an immune response sufficient to prevent disease. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the labeling: Infections [see Warnings and Precautions (5.1)] Inflammatory Bowel Disease [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis A total of 3430 plaque psoriasis subjects were treated with Cosentyx in controlled and uncontrolled clinical trials. Of these, 1641 subjects were exposed for at least 1 year. Four placebo-controlled phase 3 trials in plaque psoriasis subjects were pooled to evaluate the safety of Cosentyx in comparison to placebo up to 12 weeks after treatment initiation, in Trials 1, 2, 3, and 4. In total, 2077 subjects were evaluated (691 to Cosentyx 300 mg group, 692 to Cosentyx 150 mg group, and 694 to placebo group) [see Clinical Studies (14)] . Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Cosentyx groups than the placebo group during the 12-week placebo-controlled period of the placebo-controlled trials. Table 1: Adverse Reactions Reported by Greater Than 1% of Subjects with Plaque Psoriasis Through Week 12 in Trials 1, 2, 3, and 4 Cosentyx Adverse Reactions 300 mg (N=691) n (%) 150 mg (N=692) n (%) Placebo (N=694) n (%) Nasopharyngitis 79 (11.4) 85 (12.3) 60 (8.6) Diarrhea 28 (4.1) 18 (2.6) 10 (1.4) Upper respiratory tract infection 17 (2.5) 22 (3.2) 5 (0.7) Rhinitis 10 (1.4) 10 (1.4) 5 (0.7) Oral herpes 9 (1.3) 1 (0.1) 2 (0.3) Pharyngitis 8 (1.2) 7 (1.0) 0 (0) Urticaria 4 (0.6) 8 (1.2) 1 (0.1) Rhinorrhea 8 (1.2) 2 (0.3) 1 (0.1) Adverse reactions that occurred at rates less than 1% in the placebo-controlled period of Trials 1, 2, 3, and 4 through Week 12 included: sinusitis, tinea pedis, conjunctivitis, tonsillitis, oral candidiasis, impetigo, otitis media, otitis externa, inflammatory bowel disease, increased liver transaminases, and neutropenia. Infections In the placebo-controlled period of the clinical trials in plaque psoriasis (a total of 1382 subjects treated with Cosentyx and 694 subjects treated with placebo up to 12 weeks), infections were reported in 28.7% of subjects treated with Cosentyx compared with 18.9% of subjects treated with placebo. Serious infections occurred in 0.14% of patients treated with Cosentyx and in 0.3% of patients treated with placebo [see Warnings and Precautions (5.1)] . Over the entire treatment period (a total of 3430 plaque psoriasis subjects treated with Cosentyx for up to 52 weeks for the majority of subjects), infections were reported in 47.5% of subjects treated with Cosentyx (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of subjects treated with Cosentyx (0.015 per patient-year of follow-up). Phase 3 data showed an increasing trend for some types of infection with increasing serum concentration of secukinumab. Candida infections, herpes viral infections, staphylococcal skin infections, and infections requiring treatment increased as serum concentration of secukinumab increased. Neutropenia was observed in clinical trials. Most cases of secukinumab-associated neutropenia were transient and reversible. No serious infections were associated with cases of neutropenia. Inflammatory Bowel Disease Cases of inflammatory bowel disease, in some cases serious, were observed in clinical trials with Cosentyx. In the plaque psoriasis program, with 3430 patients exposed to Cosentyx over the entire treatment period for up to 52 weeks (2,725 patient-years), there were 3 cases (0.11 per 100 patient-years) of exacerbation of Crohn s disease, 2 cases (0.08 per 100 patient-years) of exacerbation of ulcerative colitis, and 2 cases (0.08 per 100 patient-years) of new onset ulcerative colitis. There were no cases in placebo patients (N=793; 176 patient-years) during the 12 week placebo-controlled period. One case of exacerbation of Crohn s disease was reported from long-term non-controlled portions of ongoing clinical trials in plaque psoriasis [see Warnings and Precautions (5.3)] . Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in Cosentyx treated patients in clinical trials [see Warnings and Precautions (5.4)] . Psoriatic Arthritis Cosentyx was studied in two placebo controlled psoriatic arthritis trials with 1003 patients (703 patients on Cosentyx and 300 patients on placebo). Of the 703 patients who received Cosentyx, 299 patients received a subcutaneous loading dose of Cosentyx (PsA1) and 404 patients received an intravenous loading dose of secukinumab (PsA2) followed by Cosentyx administered by subcutaneous injection every four weeks. During the 16-week placebo-controlled period of the trials in patients with psoriatic arthritis, the overall proportion of patients with adverse events was similar in the secukinumab and placebo-treatment groups (59% and 58%, respectively). The adverse events that occurred at a proportion of at least 2% and at a higher proportion in the Cosentyx groups than the placebo groups during the 16-week placebo-controlled period were nasopharyngitis, upper respiratory tract infection, headache, nausea, and hypercholesterolemia. The safety profile observed in patients with psoriatic arthritis treated with Cosentyx is consistent with the safety profile in psoriasis. Similar to the clinical trials in patients with psoriasis, there was an increased proportion of patients with infections in the Cosentyx groups (29%) compared to placebo group (26%) [see Warnings and Precautions (5.1)] . There were cases of Crohn s disease and ulcerative colitis that include patients who experienced either exacerbations or the development of new disease. There were three cases of inflammatory bowel disease, of which two patients received secukinumab and one received placebo [see Warnings and Precautions (5.3)] . Ankylosing Spondylitis Cosentyx was studied in two placebo controlled ankylosing spondylitis trials with 590 patients (394 patients on Cosentyx and 196 patients on placebo). Of the 394 patients who received Cosentyx, 145 patients received a subcutaneous load of Cosentyx (study AS1) and 249 received an intravenous loading dose of secukinumab (study AS2) followed by Cosentyx administered by subcutaneous injection every four weeks. During the 16-week placebo-controlled period of the trials in patients with ankylosing spondylitis, the overall proportion of patients with adverse events was higher in the secukinumab groups than the placebo-treatment groups (66% and 59%, respectively). The adverse events that occurred at a proportion of at least 2% and at a higher proportion in the Cosentyx groups than the placebo groups during the 16-week placebo-controlled period were nasopharyngitis, nausea, and upper respiratory tract infection. The safety profile observed in patients with ankylosing spondylitis treated with Cosentyx is consistent with the safety profile in psoriasis. Similar to clinical trials in patients with psoriasis, there was an increased proportion of patients with infections in the Cosentyx groups (31%) compared to the placebo group (18%) [see Warnings and Precautions (5.1)] . In the ankylosing spondylitis program, with 571 patients exposed to Cosentyx there were 8 cases of inflammatory bowel disease during the entire treatment period (5 Crohn s (0.7 per 100 patient-years) and 3 ulcerative colitis (0.4 per 100 patient-years). During the placebo-controlled 16-week period, there were 2 Crohn s disease exacerbations and 1 new onset ulcerative colitis case that was a serious adverse event in patients treated with Cosentyx compared to none of the patients treated with placebo. During the remainder of the study when all patients received Cosentyx, 1 patient developed Crohn s disease, 2 patients had Crohn s exacerbations, 1 patient developed ulcerative colitis, and 1 patient had an ulcerative colitis exacerbation [see Warnings and Precautions (5.3)] . Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The immunogenicity of Cosentyx was evaluated using an electrochemiluminescence-based bridging immunoassay. Less than 1% of subjects treated with Cosentyx developed antibodies to secukinumab in up to 52 weeks of treatment. However, this assay has limitations in detecting anti-secukinumab antibodies in the presence of secukinumab; therefore the incidence of antibody development might not have been reliably determined. Of the subjects who developed antidrug antibodies, approximately one-half had antibodies that were classified as neutralizing. Neutralizing antibodies were not associated with loss of efficacy. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Cosentyx with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS Live Vaccines Patients treated with Cosentyx may not receive live vaccinations [see Warnings and Precautions (5.6)] . Non-Live Vaccines Patients treated with Cosentyx may receive non-live vaccinations. Healthy individuals who received a single 150 mg dose of Cosentyx 2 weeks prior to vaccination with a non-U.S. approved group C meningococcal polysaccharide conjugate vaccine and a non-U.S. approved inactivated seasonal influenza vaccine had similar antibody responses compared to individuals who did not receive Cosentyx prior to vaccination. The clinical effectiveness of meningococcal and influenza vaccines has not been assessed in patients undergoing treatment with Cosentyx [see Warnings and Precautions (5.6)] . CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4. Upon initiation or discontinuation of Cosentyx in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed [see Clinical Pharmacology (12.3)] . USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B There are no adequate and well controlled trials of Cosentyx in pregnant women. Developmental toxicity studies conducted with monkeys found no evidence of harm to the fetus due to secukinumab. Cosentyx should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. An embryofetal development study was performed in cynomolgus monkeys with secukinumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys that were administered secukinumab weekly by the subcutaneous route during the period of organogenesis at doses up to 30 times the maximum recommended human dose (MRHD; on a mg/kg basis at a maternal dose of 150 mg/kg). A pre- and post-natal development toxicity study was performed in mice with a murine analog of secukinumab. No treatment related effects on functional, morphological or immunological development were observed in fetuses from pregnant mice that were administered the murine analog of secukinumab on gestation days 6, 11, and 17 and on postpartum days 4, 10, and 16 at doses up to 150 mg/kg/dose. Nursing Mothers It is not known whether secukinumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Cosentyx is administered to a nursing woman. Pediatric Use Safety and effectiveness of Cosentyx in pediatric patients have not been evaluated. Geriatric Use Of the 3430 plaque psoriasis subjects exposed to Cosentyx in clinical trials, a total of 230 were 65 years or older, and 32 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects. OVERDOSAGE Doses up to 30 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. DESCRIPTION Secukinumab is a recombinant human monoclonal IgG1/κ antibody that binds specifically to IL-17A. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. Secukinumab has a molecular mass of approximately 151 kDa; both heavy chains of secukinumab contain oligosaccharide chains. Cosentyx Injection Cosentyx injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution. Cosentyx is supplied in a single-use Sensoready pen with a 27-gauge fixed -inch needle, or a single-use prefilled syringe with a 27-gauge fixed -inch needle. The removable cap of the Cosentyx Sensoready pen or prefilled syringe contains natural rubber latex. Each Cosentyx Sensoready pen or prefilled syringe contains 150 mg of secukinumab formulated in: L-histidine/histidine hydrochloride monohydrate (3.103 mg), L-methionine (0.746 mg), polysorbate 80 (0.2 mg), trehalose dihydrate (75.67 mg), and Sterile Water for Injection, USP, at pH of 5.8. Cosentyx for Injection Cosentyx for injection is supplied as a sterile, preservative free, white to slightly yellow, lyophilized powder in single-use vials. Each Cosentyx vial contains 150 mg of secukinumab formulated in L-histidine/histidine hydrochloride monohydrate (4.656 mg), polysorbate 80 (0.6 mg), and sucrose (92.43 mg). Following reconstitution with 1 mL Sterile Water for Injection, USP, the resulting pH is approximately 5.8. CLINICAL PHARMACOLOGY Mechanism of Action Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab inhibits the release of proinflammatory cytokines and chemokines. Pharmacodynamics Elevated levels of IL-17A are found in psoriatic plaques. Treatment with Cosentyx may reduce epidermal neutrophils and IL-17A levels in psoriatic plaques. Serum levels of total IL-17A (free and secukinumab-bound IL-17A) measured at Week 4 and Week 12 were increased following secukinumab treatment. These pharmacodynamic activities are based on small exploratory studies. The relationship between these pharmacodynamic activities and the mechanism(s) by which secukinumab exerts its clinical effects is unknown. Increased numbers of IL-17A producing lymphocytes and innate immune cells and increased levels of IL-17A have been found in the blood of patients with psoriatic arthritis and ankylosing spondylitis. Pharmacokinetics The PK properties of secukinumab observed in psoriatic arthritis and ankylosing spondylitis patients were similar to the PK properties displayed in plaque psoriasis patients. Absorption Following a single subcutaneous dose of either 150 mg (one-half the recommended dose) or 300 mg in plaque psoriasis patients, secukinumab reached peak mean ( SD) serum concentrations (C max ) of 13.7 4.8 mcg/mL and 27.3 9.5 mcg/mL, respectively, by approximately 6 days post dose. Following multiple subcutaneous doses of secukinumab, the mean ( SD) serum trough concentrations of secukinumab ranged from 22.8 10.2 mcg/mL (150 mg) to 45.4 21.2 mcg/mL (300 mg) at Week 12. At the 300 mg dose at Week 4 and Week 12, the mean trough concentrations resulted from the Sensoready pen were 23% to 30% higher than those from the lyophilized powder and 23% to 26% higher than those from the prefilled syringe based on cross-study comparisons. Steady-state concentrations of secukinumab were achieved by Week 24 following the every 4 week dosing regimens. The mean ( SD) steady-state trough concentrations ranged from 16.7 8.2 mcg/mL (150 mg) to 34.4 16.6 mcg/mL (300 mg). In healthy subjects and subjects with plaque psoriasis, secukinumab bioavailability ranged from 55% to 77% following subcutaneous dose of 150 mg (one-half the recommended dose) or 300 mg. Distribution The mean volume of distribution during the terminal phase (Vz) following a single intravenous administration ranged from 7.10 to 8.60 L in plaque psoriasis patients. Intravenous use is not recommended [see Dosage and Administration (2)] . Secukinumab concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis patients ranged from 27% to 40% of those in serum at 1 and 2 weeks after a single subcutaneous dose of secukinumab 300 mg. Elimination The metabolic pathway of secukinumab has not been characterized. As a human IgG1κ monoclonal antibody secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. The mean systemic clearance (CL) ranged from 0.14 L/day to 0.22 L/day and the mean half-life ranged from 22 to 31 days in plaque psoriasis subjects following intravenous and subcutaneous administration across all psoriasis trials. Intravenous use is not recommended [see Dosage and Administration (2)] . Dose Linearity Secukinumab exhibited dose-proportional pharmacokinetics in subjects with psoriasis over a dose range from 25 mg (approximately 0.083 times the recommended dose) to 300 mg following subcutaneous administrations. Weight Secukinumab clearance and volume of distribution increase as body weight increases. Specific Populations Hepatic or Renal Impairment: No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of secukinumab was conducted. Age: Geriatric Population: Population pharmacokinetic analysis indicated that the clearance of secukinumab was not significantly influenced by age in adult subjects with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. Subjects who are 65 years or older had apparent clearance of secukinumab similar to subjects less than 65 years old. Drug Interactions Cytochrome P450 Substrates In subjects with plaque psoriasis, midazolam (CYP3A4 substrate) pharmacokinetics was similar when administered alone, or when administered following either a single or five weekly subcutaneous administrations of 300 mg secukinumab [see Drug interactions (7.3)] . NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of Cosentyx. Some published literature suggests that IL-17A directly promotes cancer cell invasion in vitro, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male and female mice that were administered a murine analog of secukinumab at subcutaneous doses up to 150 mg/kg once weekly prior to and during the mating period. CLINICAL STUDIES Plaque Psoriasis Four multicenter, randomized, double-blind, placebo-controlled trials (Trials 1, 2, 3, and 4) enrolled 2403 subjects (691 randomized to Cosentyx 300 mg, 692 to Cosentyx 150 mg, 694 to placebo, and 323 to a biologic active control) 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score greater than or equal to 12, and who were candidates for phototherapy or systemic therapy. Trial 1 enrolled 738 subjects (245 randomized to Cosentyx 300 mg, 245 to Cosentyx 150 mg, and 248 to placebo). Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to Cosentyx received 300 mg or 150 mg doses at Weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 were then crossed over to receive Cosentyx (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of study treatment. Trial 2 enrolled 1306 subjects (327 randomized to Cosentyx 300 mg, 327 to Cosentyx 150 mg, 326 to placebo, and 323 to a biologic active control). Cosentyx and placebo data are described. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to Cosentyx received 300 mg or 150 mg doses at Weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 then crossed over to receive Cosentyx (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of study treatment. Trial 3 enrolled 177 subjects (59 randomized to Cosentyx 300 mg, 59 to Cosentyx 150 mg, and 59 to placebo) and assessed safety, tolerability, and usability of Cosentyx self-administration via prefilled syringe for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total. Trial 4 enrolled 182 subjects (60 randomized to Cosentyx 300 mg, 61 to Cosentyx 150 mg, and 61 to placebo) and assessed safety, tolerability, and usability of Cosentyx self-administration via Sensoready pen for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total. Endpoints In all trials, the endpoin prior to
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