Ixekizumab

1 INDICATIONS AND USAGE TALTZ ® is a humanized interleukin-17A antagonist indicated for the treatment of: patients aged 6 years or older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. ( 1.1 ) adults with active psoriatic arthritis. ( 1.2 ) adults with active ankylosing spondylitis. ( 1.3 ) adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation. ( 1.4 ) 1.1 Plaque Psoriasis TALTZ ® is indicated for the treatment of patients 6 years of age and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. 1.2 Psoriatic Arthritis TALTZ is indicated for the treatment of adult patients with active psoriatic arthritis. 1.3 Ankylosing Spondylitis TALTZ is indicated for the treatment of adult patients with active ankylosing spondylitis. 1.4 Non-radiographic Axial Spondyloarthritis TALTZ is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation.

2 DOSAGE AND ADMINISTRATION Administer by subcutaneous injection. Adult Plaque Psoriasis ( 2.2 ) Recommended dosage is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. Pediatric Plaque Psoriasis ( 2.3 ) For patients weighing greater than 50 kg, recommended dosage is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks. For patients weighing 25-50 kg, recommended dosage is 80 mg at Week 0, followed by 40 mg every 4 weeks. For patients weighing less than 25 kg, recommended dosage is 40 mg at Week 0, followed by 20 mg every 4 weeks. Psoriatic Arthritis ( 2.4 ) Recommended dosage is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks. For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis. ( 2.2 ) TALTZ may be administered alone or in combination with a conventional DMARD (e.g., methotrexate). Ankylosing Spondylitis ( 2.5 ) Recommended dosage is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks. Non-radiographic Axial Spondyloarthritis ( 2.6 ) Recommended dosage is 80 mg by subcutaneous injection every 4 weeks. 2.1 Testing and Procedures Prior to Treatment Initiation Perform the following evaluations prior to TALTZ initiation: Evaluate patients for tuberculosis (TB) infection. TALTZ initiation is not recommended in patients with active TB infection. Initiate treatment of latent TB prior to initiation of TALTZ [see Warnings and Precautions ( 5.2 )] . Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with TALTZ [see Warnings and Precautions ( 5.6 )] . 2.2 Recommended Dosage in Adult Plaque Psoriasis TALTZ is administered by subcutaneous injection. The recommended dosage in adults with moderate-to-severe plaque psoriasis is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. 2.3 Recommended Dosage in Pediatric Plaque Psoriasis TALTZ is administered by subcutaneous injection every 4 weeks (Q4W). The recommended dosage in pediatric patients from 6 to less than 18 years of age with moderate-to-severe plaque psoriasis is based on the following weight categories. Table 1: Recommended Dosage for Pediatric Patients 6 Years of Age and Older with Plaque Psoriasis Pediatric Patient's Weight Starting Dose (Week 0) Dose every 4 weeks (Q4W) Thereafter Greater than 50 kg 160 mg (two 80 mg injections) 80 mg 25 to 50 kg 80 mg 40 mg Less than 25 kg 40 mg 20 mg 2.4 Recommended Dosage in Psoriatic Arthritis The recommended dosage is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks. For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis [see Dosage and Administration ( 2.2 )] . TALTZ may be administered alone or in combination with a conventional disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate). 2.5 Recommended Dosage in Ankylosing Spondylitis The recommended dosage is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks. 2.6 Recommended Dosage in Non-radiographic Axial Spondyloarthritis The recommended dosage is 80 mg by subcutaneous injection every 4 weeks. 2.7 Preparation and Administration Instructions TALTZ is intended for use under the guidance and supervision of a healthcare provider. Adult patients may self-inject or caregivers may give injections of TALTZ after training in subcutaneous injection technique using the autoinjector or prefilled syringe. Safety and effectiveness of pediatric self-administration has not been established. Therefore, TALTZ should be administered to pediatric patients by a healthcare provider or by a caregiver who has received training and demonstrated proper subcutaneous injection technique. TALTZ 20 mg and 40 mg doses prepared from the TALTZ 80 mg/mL prefilled syringe should only be administered by a qualified healthcare professional [see Dosage and Administration ( 2.8 )] . The TALTZ “Instructions for Use” contains more detailed instructions on the preparation and administration of TALTZ [see Instructions for Use] . Before injection, remove TALTZ autoinjector or TALTZ prefilled syringe from the refrigerator and allow TALTZ to reach room temperature (30 minutes) without removing the needle cap. Inspect TALTZ visually for particulate matter and discoloration prior to administration. TALTZ is a clear and colorless to slightly yellow solution. Do not use if the liquid contains visible particles, is discolored or cloudy (other than clear and colorless to slightly yellow). 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 TALTZ in the upper, outer arm may be performed by a caregiver or healthcare provider [see Instructions for Use] . TALTZ does not contain preservatives, therefore discard any unused product. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. 2.8 Alternative Preparation Instructions of TALTZ Doses for Pediatric Patients with Plaque Psoriasis Weighing 50 kg or Less If the 20 mg/0.25 mL or 40 mg/0.5 mL prefilled syringe is unavailable, TALTZ doses of 20 mg or 40 mg for pediatric patients with plaque psoriasis [see Dosage and Administration ( 2.3 )] must be manually prepared according to the steps below using only the TALTZ 80 mg/mL prefilled syringe. The preparation and administration of the 20 mg and 40 mg doses should only be performed by a qualified healthcare professional. For additional preparation and administration instructions, [see Dosage and Administration ( 2.7 )] . Gather the following necessary supplies for preparation: 0.5 mL or 1 mL disposable syringe Sterile needle for withdrawal 27-gauge sterile needle for administration Sterile, clear glass vial. Expel the entire contents of the prefilled syringe into the sterile vial. DO NOT shake or swirl the vial. Do not add other medications to solutions containing TALTZ. Using the 0.5 mL or 1 mL disposable syringe and sterile needle, withdraw the prescribed dose from the vial (0.25 mL for 20 mg; 0.5 mL for 40 mg). Remove the needle from the syringe and replace it with a 27-gauge needle prior to administering TALTZ. Storage of Prepared TALTZ If necessary, TALTZ 20 mg or 40 mg doses prepared from an 80 mg/mL prefilled syringe may be stored at room temperature for up to 4 hours from first puncturing the sterile vial.

6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: Infections [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] Eczematous Eruptions [see Warnings and Precautions ( 5.4 )] Inflammatory Bowel Disease [see Warnings and Precautions ( 5.5 )] Most common (≥1%) adverse reactions associated with TALTZ treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 (1-800-LillyRx) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying and controlled 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. Adult Plaque Psoriasis Weeks 0 to 12 : Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of TALTZ compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received TALTZ (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of TALTZ (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept [see Clinical Studies ( 14 )] . In the 12-week, placebo-controlled period, adverse events occurred in 58% of the TALTZ Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the TALTZ group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up). Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the TALTZ group than in the placebo group during the 12-week placebo-controlled period of the pooled clinical trials. Table 2: Adverse Reactions Occurring in ≥1% of the TALTZ Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection. b U.S. approved etanercept. Adverse Reactions TALTZ 80 mg Q2W (N=1167) n (%) Etanercept b (N=287) n (%) Placebo (N=791) n (%) Injection site reactions 196 (17) 32 (11) 26 (3) Upper respiratory tract infections a 163 (14) 23 (8) 101 (13) Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) Adverse reactions that occurred at rates less than 1% in the TALTZ group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema. Weeks 13 to 60 : A total of 332 subjects received the recommended maintenance regimen of TALTZ 80 mg dosed every 4 weeks. During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with TALTZ (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with TALTZ (0.05 per subject-year of follow-up) and none in the subjects treated with placebo. Weeks 0 to 60 : Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with TALTZ (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with TALTZ (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up). Specific Adverse Drug Reactions Injection Site Reactions The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of TALTZ. Infections In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with TALTZ (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with TALTZ (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) [see Warnings and Precautions ( 5.1 )] . During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with TALTZ (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with TALTZ (0.01 per subject-year of follow-up) and none in the subjects treated with placebo. Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with TALTZ (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with TALTZ (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up). Inflammatory Bowel Disease In adult subjects with plaque psoriasis, Crohn's disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ 80 mg Q2W group (Crohn's disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials [see Warnings and Precautions ( 5.5 )] . Laboratory Assessment of Cytopenia Neutropenia Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with TALTZ (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with TALTZ, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12. In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm 3 ) occurred in 0.2% of the TALTZ group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for TALTZ 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm 3 ) or Grade 1 (7% for TALTZ 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm 3 to ˂2,000 cells/mm 3 ). Neutropenia in the TALTZ group was not associated with an increased rate of infection compared to the placebo group. Thrombocytopenia Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for TALTZ 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm 3 to <150,000 cells/mm 3 ). Thrombocytopenia in subjects treated with TALTZ was not associated with an increased rate of bleeding compared to subjects treated with placebo. Active Comparator Trials In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for TALTZ 80 mg Q2W. The rate of serious infections was 0.3% for both TALTZ 80 mg Q2W and U.S. approved etanercept. Pediatric Plaque Psoriasis TALTZ was evaluated in a placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis 6 to less than 18 years of age. A total of 171 subjects were studied (115 subjects on TALTZ and 56 subjects on placebo). Overall, the safety profile observed in pediatric subjects with plaque psoriasis treated with TALTZ every 4 weeks is consistent with the safety profile in adult subjects with plaque psoriasis with the exception of the frequencies of conjunctivitis (2.6%), influenza (1.7%), and urticaria (1.7%). In this clinical trial, Crohn's disease occurred at a greater frequency in the TALTZ group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohn's disease occurred in a total of 4 TALTZ treated subjects (2.0%) in the clinical trial [see Warnings and Precautions ( 5.5 )] . Psoriatic Arthritis TALTZ was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on TALTZ and 224 on placebo). A total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with psoriatic arthritis treated with TALTZ Q4W is consistent with the safety profile in adult patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%). Ankylosing Spondylitis TALTZ was studied in two placebo-controlled trials in patients with ankylosing spondylitis. A total of 566 patients were studied (376 patients on TALTZ and 190 on placebo). A total of 195 patients in these trials received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with ankylosing spondylitis treated with TALTZ Q4W is consistent with the safety profile in adult patients with plaque psoriasis. In adult patients with ankylosing spondylitis, Crohn's disease and ulcerative colitis, including exacerbations, occurred in 2 patients (1.0%) and 1 patient (0.5%), respectively, in the TALTZ 80 mg Q4W group and 1 patient (0.5%) and 0%, respectively, in the placebo group during the 16-week, placebo-controlled period in clinical trials. Of these patients, serious events occurred in 1 patient in the TALTZ 80 mg Q4W group and 1 patient in the placebo group [see Warnings and Precautions ( 5.5 )] . Non-radiographic Axial Spondyloarthritis TALTZ was studied in a placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. A total of 303 patients were studied (198 patients on TALTZ and 105 on placebo). A total of 96 patients in this trial received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with non-radiographic axial spondyloarthritis treated with TALTZ 80 mg Q4W up to Week 16 is consistent with the previous experience of TALTZ in other indications. 6.2 Immunogenicity As with all therapeutic proteins there is the potential for immunogenicity with TALTZ. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated. Plaque Psoriasis Population By Week 12, approximately 9% of adult subjects treated with TALTZ every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with TALTZ at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response. Of the adult subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with TALTZ at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy. In pediatric psoriasis subjects treated with ixekizumab at the recommended dosing regimen up to 12 weeks, 21 subjects (18%) developed anti-drug antibodies, 5 subjects (4%) had confirmed neutralizing antibodies associated with low drug concentrations. No conclusive evidence could be obtained on the potential association of neutralizing antibodies and clinical response and/or adverse events due to small number of pediatric subjects in the study. Psoriatic Arthritis Population For subjects treated with TALTZ 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies. Ankylosing Spondylitis Population For patients treated with TALTZ 80 mg every 4 weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies. Non-radiographic Axial Spondyloarthritis Population Of patients treated with TALTZ 80 mg every 4 weeks for up to 52 weeks (nr-axSpA1), 8.9% developed anti-drug antibodies, all of which were low titer. No patient had neutralizing antibodies. 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 TALTZ across indications or with the incidences of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TALTZ. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to TALTZ exposure. Immune system disorders: anaphylaxis [see Contraindications ( 4 )] . Infections: bacterial, viral, and fungal opportunistic infections, including cryptococcal meningoencephalitis, esophageal and disseminated mucocutaneous candidiasis, pulmonary tuberculosis, toxoplasmosis, varicella zoster virus reactivation, cytomegalovirus colitis, pulmonary aspergillosis. Skin and subcutaneous tissue disorders: Eczematous eruptions (erythroderma, atopic dermatitis-like eruptions, and dyshidrotic eczema).

12.3 Pharmacokinetics The pharmacokinetic (PK) properties of ixekizumab were similar across the adult plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis indications. Absorption Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (C max ) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose. Steady-state concentrations were achieved by Week 8 following the 160 mg starting dose and 80 mg every 2 weeks dosing regimen; the mean ±SD steady-state trough concentration was 9.3 ±5.3 mcg/mL. Steady-state concentrations were achieved approximately 10 weeks after switching from the 80 mg every 2 weeks dosing regimen to the 80 mg every 4 weeks dosing regimen at Week 12. The mean ±SD steady-state trough concentration was 3.5 ±2.5 mcg/mL. In studies of subjects with plaque psoriasis, ixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen. Distribution The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis. Elimination The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab 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 was 0.39 L/day (37%) and the mean (geometric CV%) half-life was 13 days (40%) in subjects with plaque psoriasis. Weight Ixekizumab clearance and volume of distribution increase as body weight increases. Dose Linearity Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg (not the recommended dose) to 160 mg following subcutaneous administration. Specific Populations Age: Geriatric Population Population pharmacokinetic analysis indicated that age did not significantly influence the clearance of ixekizumab in adult subjects with plaque psoriasis. Subjects who are 65 years or older had a similar ixekizumab clearance as compared to subjects less than 65 years old. Pediatric Population Pediatric psoriasis subjects (6 to less than 18 years of age) were administered ixekizumab at the recommended pediatric dosing regimen for 12 weeks. Subjects weighing >50 kg and 25 to 50 kg had a mean ±SD steady-state trough concentration of 3.8 ±2.2 mcg/mL and 3.9 ±2.4 mcg/mL at Week 12, respectively. There were limited PK data (n=2) in subjects weighing <25 kg at Week 12. Drug Interaction Studies Population PK data analyses indicated that the clearance of ixekizumab was not impacted by concomitant administration of methotrexate, or by prior exposure to methotrexate or adalimumab in patients with psoriatic arthritis. Population PK data analyses indicated that the clearance of ixekizumab was not impacted by concomitant administration of oral corticosteroids, NSAIDs, or cDMARDs (sulfasalazine and methotrexate) in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Cytochrome P450 Substrates No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate) or midazolam (CYP3A substrate) were observed in subjects with plaque psoriasis when used concomitantly with a single 160 mg dose of ixekizumab, or multiple doses of 80 mg every 2 weeks. The potential effect of ixekizumab on the CYP2D6 activity cannot be ruled out due to high variability in exposure (approximately ±2-fold) of dextromethorphan and its CYP2D6 metabolite dextrorphan in psoriasis subjects.