STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. TALTZ is sterile and preservative-free. Discard any unused portion.TALTZ must be protected from light until use.Store refrigerated at 2C to 8C (36F to 46F).If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. Do not freeze. Do not use TALTZ if it has been frozen.Do not shake.Discard the TALTZ single-dose autoinjector or syringe after use in puncture-resistant container.Not made with natural rubber latex.. TALTZ must be protected from light until use.. Store refrigerated at 2C to 8C (36F to 46F).If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.. Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.. For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light.. Do not freeze. Do not use TALTZ if it has been frozen.. Do not shake.. Discard the TALTZ single-dose autoinjector or syringe after use in puncture-resistant container.. Not made with natural rubber latex.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TALTZ during pregnancy. Pregnant women should be encouraged to enroll themselves in the registry by calling 1-800-284-1695.Risk SummaryThere are no available data on TALTZ use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, TALTZ may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataAn embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.In pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on mg/kg basis of mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through months of age.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TALTZ and any potential adverse effects on the breastfed infant from TALTZ or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of TALTZ have been established in pediatric subjects aged years to less than 18 years with moderate-to-severe plaque psoriasis. The safety and effectiveness of TALTZ in other pediatric indications and for pediatric subjects less than years of age have not been established.. 8.5 Geriatric Use. Of the 4204 adult psoriasis subjects exposed to TALTZ, total of 301 were 65 years or older, and 36 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 and over is not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

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)] Inflammatory Bowel Disease [see Warnings and Precautions (5.4)] Infections [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.3)] Inflammatory Bowel Disease [see Warnings and Precautions (5.4)] 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 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 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. 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 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 summarizes the adverse reactions that occurred at rate of at least 1% and at 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 12a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.b U.S. approved etanercept.Adverse ReactionsTALTZ 80 mg Q2W(N=1167) (%)Etanerceptb(N=287) (%)Placebo(N=791) (%)Injection site reactions196 (17)32 (11)26 (3)Upper respiratory tract infectionsa163 (14)23 (8)101 (13)Nausea23 (2)1 (<1)5 (1)Tinea infections17 (2)01 (<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 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 to 60:Over the entire treatment period (Weeks 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 ReactionsThe 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.. InfectionsIn 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 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 DiseaseIn adult subjects with plaque psoriasis, Crohns disease and ulcerative colitis, including exacerbations, occurred at greater frequency in the TALTZ 80 mg Q2W group (Crohns 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 (5.4)].. Laboratory Assessment of Cytopenia. NeutropeniaOver the entire treatment period (Weeks 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 to 12.In the 12-week, placebo-controlled period, neutropenia >= Grade (<1,000 cells/mm3) 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% for TALTZ 80 mg Q2W versus 0.3% for placebo; >=1,000 to <1,500 cells/mm3) or Grade (7% for TALTZ 80 mg Q2W versus 3% for placebo; >=1,500 cells/mm3 to 2,000 cells/mm3). Neutropenia in the TALTZ group was not associated with an increased rate of infection compared to the placebo group.. ThrombocytopeniaNinety eight percent of cases of thrombocytopenia were Grade (3% for TALTZ 80 mg Q2W versus 1% for placebo; >=75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with TALTZ was not associated with an increased rate of bleeding compared to subjects treated with placebo.. Active Comparator TrialsIn 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 PsoriasisTALTZ was evaluated in placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis to less than 18 years of age. 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 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, Crohns disease occurred at greater frequency in the TALTZ group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohns disease occurred in total of TALTZ treated subjects (2.0%) in the clinical trial [see Warnings and Precautions (5.4)].. Psoriatic ArthritisTALTZ was studied in two placebo-controlled trials in patients with psoriatic arthritis. total of 678 patients were studied (454 patients on TALTZ and 224 on placebo). total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 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 SpondylitisTALTZ was studied in two placebo-controlled trials in patients with ankylosing spondylitis. total of 566 patients were studied (376 patients on TALTZ and 190 on placebo). total of 195 patients in these trials received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 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, Crohns disease and ulcerative colitis, including exacerbations, occurred in patients (1.0%) and patient (0.5%), respectively, in the TALTZ 80 mg Q4W group and 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 patient in the TALTZ 80 mg Q4W group and patient in the placebo group [see Warnings and Precautions (5.4)].. Non-radiographic Axial SpondyloarthritisTALTZ was studied in placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. total of 303 patients were studied (198 patients on TALTZ and 105 on placebo). total of 96 patients in this trial received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 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 PopulationBy Week 12, approximately 9% of adult subjects treated with TALTZ every 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, 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 PopulationFor subjects treated with TALTZ 80 mg every weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies.. Ankylosing Spondylitis PopulationFor patients treated with TALTZ 80 mg every weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies.. Non-radiographic Axial Spondyloarthritis PopulationOf patients treated with TALTZ 80 mg every 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to TALTZ exposure.Immune system disorders: anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of TALTZ. Moreover published literature is mixed on potential effects on malignancy risk due to the inhibition of IL-17A activity, the pharmacological action of TALTZ. Some published literature suggests that IL-17A directly promotes cancer cell invasion, suggesting potential beneficial effect by TALTZ, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection, suggesting potential adverse effect by TALTZ. However, neutralization of IL-17A with TALTZ has not been studied in these models. Depletion of IL-17A with neutralizing antibody inhibited tumor development in mice, suggesting potential beneficial effect by TALTZ. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown.No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were administered ixekizumab for 13 weeks at subcutaneous dose of 50 mg/kg/week (19 times the MRHD on mg/kg basis). The monkeys were not mated to evaluate fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ixekizumab is humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.. 12.2 Pharmacodynamics. No formal pharmacodynamic studies have been conducted with TALTZ.. 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.. AbsorptionFollowing single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (+-SD) serum concentrations (Cmax) of 16.2 +-6.6 mcg/mL by approximately days post dose.Steady-state concentrations were achieved by Week following the 160 mg starting dose and 80 mg every 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 weeks dosing regimen to the 80 mg every 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 higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.. DistributionThe mean (geometric CV%) volume of distribution at steady-state was 7.11 (29%) in subjects with plaque psoriasis.. EliminationThe metabolic pathway of ixekizumab has not been characterized. As 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.. WeightIxekizumab clearance and volume of distribution increase as body weight increases.. Dose LinearityIxekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over dose range from mg (not the recommended dose) to 160 mg following subcutaneous administration.. Specific Populations. Age: Geriatric PopulationPopulation 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 similar ixekizumab clearance as compared to subjects less than 65 years old.. Pediatric PopulationPediatric 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 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 StudiesPopulation 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 SubstratesNo 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 single 160 mg dose of ixekizumab, or multiple doses of 80 mg every 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Plaque Psoriasis. Three multicenter, randomized, double-blind, placebo-controlled trials, Trials 1, 2, and (NCT 01474512, NCT 01597245, NCT 01646177), enrolled total of 3866 subjects 18 years of age and older with plaque psoriasis who had minimum body surface area involvement of 10%, static Physician Global Assessment (sPGA) score of >=3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on severity scale of to 5, Psoriasis Area and Severity Index (PASI) score >=12, and who were candidates for phototherapy or systemic therapy.In all three trials, subjects were randomized to either placebo or TALTZ (80 mg every weeks [Q2W]) for 12 weeks, following 160 mg starting dose. In the two active comparator trials (Trials and 3), subjects were also randomized to receive U.S. approved etanercept 50 mg twice weekly for 12 weeks.All three trials assessed the changes from baseline to Week 12 in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema and scaling) within the affected regions, and 2) sPGA of 0 (clear) or 1 (minimal), the proportion of subjects with an sPGA or and at least 2-point improvement.Other evaluated outcomes included the proportion of subjects with an sPGA score of (clear), reduction of at least 90% in PASI (PASI 90), reduction of 100% in PASI (PASI 100), and an improvement of itch severity as measured by reduction of at least points on an 11-point itch Numeric Rating Scale.Subjects in all treatment groups had median baseline PASI score ranging from approximately 17 to 18. Baseline sPGA score was severe or very severe in 51% of subjects in Trial 1, 50% in Trial 2, and 48% in Trial 3.Of all subjects, 44% had received prior phototherapy, 49% had received prior conventional systemic therapy, and 26% had received prior biologic therapy for the treatment of psoriasis. Of the subjects who had received prior biologic therapy, 15% had received at least one anti-TNF alpha agent, and 9% had received an anti-IL 12/IL23. total of 23% of study subjects had history of psoriatic arthritis.. Clinical Response at Week 12The results of Trials 1, 2, and are presented in Table 3.Table 3: Efficacy Results at Week 12 in Adults with Plaque Psoriasis in Trials 1, 2, and 3; NRIa Abbreviations: = number of patients in the intent-to-treat population; NRI Non-Responder Imputation.b At Week 0, subjects received 160 mg of TALTZ.c Co-primary endpoints.d Itch NRS (>=4 improvement) in subjects with baseline Itch NRS >=4. The number of ITT subjects with baseline Itch NRS Score >=4 are as follows: Trial 1, TALTZ n=391, PBO n=374; Trial 2, TALTZ n=303, PBO n=135; Trial 3, TALTZ n=320, PBO n=158.Trial 1Trial 2Trial 3TALTZ 80 mgbQ2W (N=433)n (%)Placebo(N=431)n (%)TALTZ 80 mgbQ2W (N=351)n (%)Placebo(N=168)n (%)TALTZ 80 mgbQ2W (N=385)n (%)Placebo(N=193)n (%)sPGA of 0 (clear) or 1 (minimal)c354 (82)14 (3)292 (83)4 (2)310 (81)13 (7)sPGA of 0 (clear)160 (37)0147 (42)1 (1)155 (40)0PASI 75c386 (89)17 (4)315 (90)4 (2)336 (87)14 (7)PASI 90307 (71)2 (1)248 (71)1 (1)262 (68)6 (3)PASI 100153 (35)0142 (40)1 (1)145 (38)0Itch NRS (>=4 point improvement)d336 (86)58 (16)258 (85)19 (14)264 (83)33 (21)Examination of age, gender, race, body weight, and previous treatment with biologic did not identify differences in response to TALTZ among these subgroups at Week 12.An integrated analysis of the U.S. sites in the two active comparator studies using U.S. approved etanercept, TALTZ demonstrated superiority to U.S. approved etanercept (50 mg twice weekly) on sPGA and PASI scores during the 12 week treatment period. The respective response rates for TALTZ 80 mg Q2W and U.S. approved etanercept 50 mg twice weekly were: sPGA of or (73% and 27%); PASI 75 (87% and 41%); sPGA of (34% and 5%); PASI 90 (64% and 18%), and PASI 100 (34% and 4%).. Maintenance and Durability of ResponseTo evaluate the maintenance and durability of response, subjects originally randomized to TALTZ and who were responders at Week 12 (i.e., sPGA of or 1) in Trial and Trial were re-randomized to an additional 48 weeks of either maintenance dose of TALTZ 80 mg Q4W (every weeks) or placebo. Non-responders (sPGA >1) at Week 12 and subjects who relapsed (sPGA >=3) during the maintenance period were placed on TALTZ 80 mg Q4W.For responders at Week 12, the percentage of subjects who maintained this response (sPGA or 1) at Week 60 (48 weeks following re-randomization) in the integrated trials (Trial and Trial 2) was higher for subjects treated with TALTZ 80 mg Q4W (75%) compared to those treated with placebo (7%).For responders at Week 12 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA >=3) was 164 days in the integrated trials. Among these subjects, 66% regained response of at least or on the sPGA within 12 weeks of restarting treatment with TALTZ 80 mg Q4W.. Psoriasis Involving the Genital AreaA randomized, double-blind, placebo-controlled trial (Trial 4) was conducted in 149 adult subjects with plaque psoriasis who had minimum body surface area (BSA) involvement of 1%, sPGA score of >=3 (moderate psoriasis), sPGA of Genitalia score of >=3 (moderate psoriasis involving the genital area), who failed to respond to or were intolerant of at least one topical therapy used for treatment of psoriasis affecting the genital area, and who were candidates for phototherapy and/or systemic therapy.Subjects had median baseline PASI score of approximately 12. Baseline BSA involvement was at least 10% for approximately 60% of the enrolled subjects. Baseline sPGA of Genitalia score was severe or very severe in approximately 42% of the subjects; baseline sPGA score was severe or very severe in approximately 47% of the subjects.Subjects randomized to TALTZ received an initial dose of 160 mg followed by 80 mg every weeks for 12 weeks. The trial evaluated the primary endpoint of the proportion of subjects who achieved 0 (clear) or 1 (minimal) response at Week 12 on sPGA of Genitalia. Other evaluated outcomes at Week 12 included the proportion of subjects who achieved sPGA score of 0 (clear) or 1 (minimal), improvement of genital itch severity as measured by reduction of at least points in the 11-point Genital Psoriasis Symptoms Scale (GPSS) score Itch numeric rating scale (NRS), and the patient-perceived impact of psoriasis affecting the genital area on limiting frequency of sexual activity (intercourse or other activities) as measured by the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item (In the past week how often did your genital psoriasis limit the frequency of your sexual activity). SFQ Item score ranges from to (0=never, 1=rarely, 2=sometimes, 3=often, 4=always); where higher scores indicate greater limitations on the frequency of sexual activity in the past week.The results of Trial are presented in Table 4.Table 4: Efficacy Results at Week 12 in Adults with Genital Psoriasis in Trial 4; NRIa Abbreviations: NRI Non-Responder Imputation; GPSS Genital Psoriasis Symptoms Scale; GenPs-SFQ Genital Psoriasis Sexual Frequency Questionnaire.b At Week 0, subjects received 160 mg of TALTZ, followed by 80 mg every weeks for 12 weeks.EndpointsTALTZ 80 mg Q2Wbn (%)Placebon (%)Number of subjects randomizedN=75N=74 sPGA of Genitalia 0 (clear) or 1 (minimal)55 (73%)6 (8%) sPGA 0 (clear) or 1 (minimal)55 (73%)2 (3%)Number of subjects with baseline GPSSaItch NRS Score >=4N=56N=51 GPSS Genital Itch (>=4 point improvement)31 (55%)3 (6%)Number of subjects with baseline GenPs-SFQaItem Score >=2N=37N=42 GenPs-SFQ Item score 0 (never) or 1 (rarely)29 (78%)9 (21%). 14.2 Pediatric Plaque Psoriasis. randomized, double-blind, multicenter, placebo-controlled trial (IXORA-Peds, NCT03073200) enrolled 171 pediatric subjects to less than 18 years of age, with moderate-to-severe plaque psoriasis (as defined by sPGA score >=3, involving >=10% of the body surface area, and PASI score >=12) who were candidates for phototherapy or systemic therapy or were inadequately controlled on topical therapy.Subjects were randomized to placebo or TALTZ with dosing stratified by weight.<25 kg: 40 mg at Week followed by 20 mg Q4W25 kg to 50 kg: 80 mg at Week followed by 40 mg Q4W>50 kg: 160 mg at Week followed by 80 mg Q4WResponse to treatment was assessed at 12 weeks of therapy and was defined by the proportion of subjects who achieved an sPGA score of 0 (clear) or 1 (almost clear) with at least 2 point improvement from baseline and the proportion of subjects that achieved reduction in PASI score of at least 75% (PASI 75) from baseline.Other evaluated outcomes included the proportion of subjects who achieved PASI 90, PASI 100, sPGA of 0 and an improvement of itch severity as measured by reduction of at least points on an 11-point itch Numeric Rating Scale.Subjects had median baseline PASI score of 17 (range 12-49). Baseline sPGA score was severe or very severe in 49%. Of all subjects, 22% had received prior phototherapy and 32% had received prior conventional systemic therapy for the treatment of psoriasis.. <25 kg: 40 mg at Week followed by 20 mg Q4W. 25 kg to 50 kg: 80 mg at Week followed by 40 mg Q4W. >50 kg: 160 mg at Week followed by 80 mg Q4W. Clinical ResponseThe efficacy results of IXORA-Peds are presented in Table 5.Table 5: Efficacy Results in Pediatric Subjects with Plaque Psoriasis in IXORA-Peds, NRIa Abbreviations: = Number of subjects in the intent-to-treat population; NRI Non-Responder Imputation.b At Week 0, subjects received 160 mg, 80 mg, or 40 mg of TALTZ, followed by 80 mg, 40 mg, or 20 mg every weeks, depending on weight category, for 12 weeks.c Co-primary endpoints.d Itch NRS (>=4 improvement) in subjects with baseline Itch NRS >=4. The number of ITT subjects with baseline Itch NRS Score >=4 are as follows: TALTZ, = 83; PBO, = 40.TALTZb(N=115)n (%)Placebo(N=56)n (%)Week 12 sPGA 0 (clear) or 1 (minimal)c93 (81%)6 (11%) sPGA 0 (clear)60 (52%)1 (2%) PASI 75 102 (89%)14 (25%) PASI 90 90 (78%)3 (5%) PASI 100 57 (50%)1 (2%) Itch NRS (>=4 point improvement)d59 (71%)8 (20%)Week sPGA 0 (clear) or 1 (minimal)55 (48%)4 (7%) PASI 75 62 (54%)5 (9%). 14.3 Psoriatic Arthritis. The safety and efficacy of TALTZ were assessed in 679 patients, in randomized, double-blind, placebo-controlled studies (PsA1 and PsA2) in adult patients, age 18 years and older with active psoriatic arthritis (at least swollen and at least tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy. Patients in these studies had diagnosis of PsA for at least months across both studies. At baseline, 60% and 23% of the patients had enthesitis and dactylitis, respectively. In PsA2, all patients discontinued previous treatment with anti-TNF agents due to either inadequate response or intolerance. In addition, approximately 47% of patients from both studies had concomitant methotrexate (MTX) use.PsA1 Study (NCT 01695239) evaluated 417 biologic-naive patients, who were treated with either TALTZ 160 mg at Week followed by 80 mg every weeks (Q2W) or weeks (Q4W), adalimumab 40 mg every weeks, or placebo. PsA2 Study (NCT 02349295) evaluated 363 anti-TNF experienced patients, who were treated with TALTZ 160 mg at Week followed by 80 mg every or weeks, or placebo. Patients receiving placebo were re-randomized to receive TALTZ (80 mg every or weeks) at Week 16 or Week 24 based on responder status. The primary endpoint was the percentage of patients achieving an ACR20 response at Week 24.. Clinical ResponseIn both studies, patients treated with TALTZ 80 mg Q4W demonstrated greater clinical response including ACR20, ACR50, and ACR70 compared to placebo at Week 24 (Table 6). In PsA2, responses were seen regardless of prior anti-TNF exposure.Table 6: Responsesa at Week 12 and 24; NRIb Patients who met escape criteria (less than 20% improvement in tender and swollen joint counts) at Week 16 or had missing data at Week 24 were considered non-responders at Week 24.b Abbreviations: = number of patients in the intent-to-treat population; NRI Non-Responder Imputation.c At Week 0, patients received 160 mg of TALTZ.PsA1 anti-TNF naivePsA2 anti-TNF experiencedTALTZ80 mgcQ4W(N=107)Placebo (N=106)Difference from placebo (95% CI)TALTZ80 mgcQ4W(N=122)Placebo (N=118)Difference from placebo (95% CI)ACR20 responseWeek 12 (%)573126 (13, 39)502228 (16, 40)Week 24 (%)583028 (15, 41)532034 (22, 45)ACR50 responseWeek 12 (%)34529 (19, 39)31328 (19, 37)Week 24 (%)401525 (14, 37)35530 (21, 40)ACR70 responseWeek 12 (%)15015 (8, 22)15213 (6, 20)Week 24 (%)23618 (9, 27)22022 (15, 30)The percentage of patients achieving ACR20 response by visit is shown in Figure 1.Figure 1: Percent of Patients Achieving ACR20 Responseain PsA1 Through Week 24a Patients who met escape criteria (less than 20% improvement in tender and swollen joint counts) at Week 16 or had missing data at Week 24 were considered non-responders at Week 24.The improvements in the components of the ACR response criteria are shown in Table 7.Table 7: Efficacy results in ACR Components at Week 12 and 16a At Week 0, subjects received 160 mg of TALTZ.b Disability Index of the Health Assessment Questionnaire; = best, = worst, measures the patients ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.PsA1PsA2TALTZ 80 mgaQ4W (N=107)Placebo(N=106)TALTZ 80 mgaQ4W (N=122)Placebo(N=118)No. of Swollen Joints Baseline11.410.613.110.3 Mean Change at Week 12-6.2-3.2-5.8-2.6 Mean Change at Week 16-6.2-3.0-7.4-2.6No. of Tender Joints Baseline20.519.222.023.0 Mean Change at Week 12-10.3-3.5-9.4-5.4 Mean Change at Week 16-9.7-4.0-10.1-3.0Patients Assessment of Pain Baseline60.158.563.963.9 Mean Change at Week 12-26.6-9.1-29.8-11.9 Mean Change at Week 16-26.1-10.6-30.1-12.3Patient Global Assessment Baseline62.761.166.464.1 Mean Change at Week 12-29.7-11.1-34.5-10.7 Mean Change at Week 16-30.4-13.2-35.3-15.7Physician Global Assessment Baseline57.655.960.358.9 Mean Change at Week 12-34.0-16.6-34.4-15.9 Mean Change at Week 16-35.5-16.5-32.9-9.7Disability Index (HAQ-DI)b Baseline1.21.21.21.2 Mean Change at Week 12-0.4-0.1-0.4-0.1 Mean Change at Week 16-0.4-0.1-0.5-0.1CRP (mg/L) Baseline12.815.117.012.1 Mean Change at Week 12-8.8-3.2-11.4-4.3 Mean Change at Week 16-9.3-3.2-11.2-5.9Treatment with TALTZ resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.Treatment with TALTZ 80 mg Q4W resulted in an improvement in psoriatic skin lesions in patients with PsA.. Figure 1. Radiographic ResponseRadiographic changes were assessed in PsA1. Inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) at Week 16, compared to baseline. The total Sharp score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints.TALTZ 80 mg Q4W inhibited the progression of structural joint damage (mTSS) compared to placebo at Week 16. The adjusted mean change from baseline in the mTSS was 0.13 for TALTZ 80 mg Q4W and 0.36 for placebo (difference in means TALTZ minus placebo: -0.23, 95% CI: (-0.42, -0.04)).. Physical FunctionTALTZ treated patients showed improvement in physical function compared to patients treated with placebo as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 and 24. In both studies, the proportion of HAQ-DI responders (>=0.35 improvement in HAQ-DI score) was greater in the TALTZ 80 mg Q4W groups compared to placebo at week 12 and 24.. Other Health-Related OutcomesGeneral health status was assessed by the Short Form health survey (SF-36). At Week 12 in PsA1 and PsA2, patients treated with TALTZ showed greater improvement from baseline in the SF-36 physical component summary (PCS) score compared to patients treated with placebo but this improvement was not consistent in both studies for the SF-36 mental component summary (MCS) score. At Week 12, there was consistent evidence of effect in the physical-functioning, role-physical, bodily-pain, and general health domains but not in the social-functioning, role-emotional, vitality, and mental health domains.. 14.4 Ankylosing Spondylitis. The safety and efficacy of TALTZ were assessed in 567 patients, in randomized, double-blind, placebo-controlled studies (AS1 and AS2) in adult patients, age 18 years and older with active ankylosing spondylitis. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >=4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid, or disease modifying anti-rheumatic drug (DMARD) therapy. At baseline, patients had symptoms of AS for an average of 17 years across both studies. At baseline, approximately 32% of the patients were on concomitant cDMARD. In AS2, all patients discontinued previous treatment with or TNF inhibitors due to either inadequate response or intolerance.AS1 Study (NCT 02696785) evaluated 341 biologic-naive patients, who were treated with either TALTZ 80 mg or 160 mg at Week followed by 80 mg every weeks (Q2W) or weeks (Q4W), adalimumab 40 mg every weeks, or with placebo. Patients receiving placebo were re-randomized at Week 16 to receive TALTZ (160 mg starting dose, followed by 80 mg Q2W or Q4W). Patients receiving adalimumab were re-randomized at Week 16 to receive TALTZ (80 mg Q2W or Q4W). AS2 Study (NCT 02696798) evaluated 316 TNF-inhibitor experienced patients (90% were inadequate responders and 10% were intolerant to TNF inhibitors). All patients were treated with TALTZ 80 or 160 mg at Week followed by 80 mg Q2W or Q4W, or with placebo. Patients receiving placebo were re-randomized at Week 16 to receive TALTZ (160 mg initial dose, followed by 80 mg Q2W or Q4W). The primary endpoint in both studies was the percentage of patients achieving an Assessment of Spondyloarthritis International Society 40 (ASAS40) response at Week 16.. Clinical ResponseIn both studies, patients treated with TALTZ 80 mg Q4W demonstrated greater improvements in ASAS40 and ASAS20 responses compared to placebo at Week 16 (Table 8). Responses were seen regardless of concomitant therapies. In AS2, responses were seen regardless of prior TNF-inhibitor exposure.Table 8: ASAS20 and ASAS40 Responses at Week 16, NRIa,b Abbreviations: = number of patients in the intent-to-treat population; NRI Non-responder Imputation.b Patients with missing data were counted as non-responders.c At Week 0, patients received 80 mg or 160 mg of TALTZ.d An ASAS20 response is defined as >=20% improvement and an absolute improvement from baseline of >=1 units (range to 10) in >=3 of domains (Patient Global, Spinal Pain, Function, and Inflammation), and no worsening of >=20% and >=1 unit (range to 10) in the remaining domain. An ASAS40 response is defined as >=40% improvement and an absolute improvement from baseline of >=2 units in >=3 of domains without any worsening in the remaining domain.e Primary endpoint.AS1 biologic-naiveAS2 TNF-inhibitor experiencedTALTZ80 mgQ4Wc(N=81)Placebo (N=87)Difference from placebo (95% CI)TALTZ80 mgQ4Wc(N=114)Placebo (N=104)Difference from placebo (95% CI)ASAS20 responsed, %644024 (9, 39)483018 (6, 31)ASAS40 responsed,e, %481830 (16, 43)251313 (3, 23)The percent of patients achieving ASAS40 response by visit in AS1 is shown in Figure 2.Figure 2: ASAS40 Response through Week 16, NRIaa Patients with missing data were counted as non-responders.The improvement in the main components of the ASAS40 response criteria and other measures of disease activity are shown in Table 9.Table 9: ASAS Components and Other Measures of Disease Activity at Week 16a,b Abbreviations: ASDAS Ankylosing Spondylitis Disease Activity Score; BASDAI Bath Ankylosing Spondylitis Disease Activity Index; BASFI Bath Ankylosing Spondylitis Functional Index; BASMI Bath Ankylosing Spondylitis Metrology Index; hsCRP High sensitivity C-reactive protein.b Mean changes are least-squares mean changes from baseline at Week 16.c At Week 0, patients received 80 or 160 mg of TALTZ.d Inflammation is the mean of patient-reported stiffness self-assessments (questions and 6) in BASDAI.AS1 biologic-naiveAS2 TNF-inhibitor experiencedTALTZ 80 mgQ4Wc(N=81)Placebo(N=87)TALTZ 80 mgQ4Wc(N=114)Placebo(N=104)ASAS Components Patient Global Assessment (0-10) Baseline6.97.18.07.8 Mean Change from Baseline-2.5-1.4-2.4-0.7 Total Spinal Pain (0-10) Baseline7.27.47.97.8 Mean Change from Baseline-3.2-1.7-2.4-1.0 BASFI (0-10) Baseline6.16.47.47.0 Mean Change from Baseline-2.4-1.2-1.7-0.6 Inflammation (0-10)d Baseline6.56.87.27.2 Mean Change from Baseline-3.2-1.3-2.4-0.7Other Measures of Disease Activity BASDAI Score Baseline6.86.87.57.3 Mean Change from Baseline-2.9-1.4-2.2-0.9 BASMI Baseline3.94.54.74.9 Mean Change from Baseline-0.5-0.1-0.3-0.0 hsCRP (mg/L) Baseline12.216.020.216.0 Mean Change from Baseline-5.21.4-11.19.7. Figure 2. Health-Related OutcomesGeneral health status and quality of life was assessed by the Short Form health survey (SF-36). At Week 16, in AS1 and AS2, compared to placebo, patients treated with TALTZ showed greater improvement from baseline in the SF-36 physical component summary (PCS) score and the physical functioning, role physical, bodily pain, vitality, and general health domains, with no consistent improvements in the mental component summary (MCS), social functioning, role emotional, and mental health domains.. 14.5 Non-radiographic Axial Spondyloarthritis. The efficacy and safety of TALTZ were assessed in randomized, double-blind, 52-week placebo-controlled study (nr-axSpA1) (NCT 02757352) in patients >=18 years of age with active axial spondyloarthritis for at least months. Patients must have had objective signs of inflammation indicated by elevated C-reactive protein (CRP) (defined as greater than mg/L), and/or sacroilitis on magnetic resonance imaging (MRI), and no definitive radiographic evidence of structural damage on sacroiliac joints. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >=4, and spinal pain >=4 on 0 to 10 Numerical Rating Scale (NRS). Patients must have been intolerant to or had an inadequate response to at least two NSAIDs. Patients were treated with either placebo or TALTZ 80 mg or 160 mg at Week 0, followed by either 80 mg every weeks (Q2W) or 80 mg every weeks (Q4W). Initiation and/or dose adjustment of concomitant medications (NSAIDs, cDMARDs, corticosteroids, analgesics) were permitted starting at Week 16. Patients were allowed to transition to use of open-label TALTZ 80 mg Q2W starting at Week 16 up to Week 44 at the discretion of the investigator.At baseline, patients had symptoms of nr-axSpA for an average of 11 years. Approximately 39% of the patients were on concomitant cDMARD.The primary endpoint was the percentage of patients achieving an Assessment of Spondyloarthritis International Society 40 (ASAS40) response at Week 52. The ASAS40 response was also evaluated at Week 16 as major secondary endpoint.. Clinical ResponseAt both Weeks 16 and 52, greater proportion of patients treated with TALTZ 80 mg Q4W had ASAS40 response compared to patients treated with placebo (Table 10). The components of ASAS response criteria and CRP are shown in Table 11.Table 10: ASAS40 Responses at Week 16 and Week 52, NRIa,b Abbreviations: = number of patients in the intent-to-treat population; NRI Non-responder Imputation.b Patients who initiated open-label TALTZ 80 mg Q2W, or discontinued initially randomized treatment and remained in the study, or were missing Week 16 or Week 52 data were counted as non-responders.c Starting at Week 16 and up to Week 44, patients who were determined as inadequate responders by investigators were given the option to make changes in their background therapy and/or transition to open label TALTZ 80 mg Q2W.d At Week 0, patients received 80 mg or 160 mg of TALTZ.e An ASAS40 response is defined as >=40% improvement and an absolute improvement from baseline of >=2 units in >=3 of domains without any worsening in the remaining domain.Week 16Week 52TALTZ80 mgQ4Wc,d(N=96)Placebo (N=105)Difference from placebo (95% CI)TALTZ80 mgQ4Wc,d(N=96)Placebo (N=105)Difference from placebo (95% CI)ASAS40 responsee, %35.419.016.4 (4.2, 28.5)30.213.316.9 (5.6, 28.1)The improvement in the main components of the ASAS40 response criteria and other measures of disease activity at Week 16 are shown in Table 11.Table 11: ASAS Components and Other Measures of Disease Activity at Week 16a Abbreviations: BASDAI Bath Ankylosing Spondylitis Disease Activity Index; BASFI Bath Ankylosing Spondylitis Functional Index; BASMI Bath Ankylosing Spondylitis Metrology Index; hsCRP High sensitivity C-reactive protein; NRI Non-responder Imputation.b At Week 0, patients received 80 or 160 mg of TALTZ.c Mean changes are least-squares mean changes from baseline at Week 16 using mixed model for repeated measures adjusting for treatment group, screening MRI/CRP classification, visit, continuous baseline, interaction of visit with treatment, interaction of continuous baseline with visit.d Inflammation is the mean of patient-reported stiffness self-assessments (questions and 6) in BASDAI questionnaire.TALTZ 80 mgQ4Wb(N=96)Placebo(N=105)ASAS Components Patient Global Assessment (0-10) Baseline7.17.4 Mean Change from Baselinec -2.3-1.3 Total Spinal Pain (0-10) Baseline7.37.4 Mean Change from Baselinec -2.4-1.5 BASFI (0-10) Baseline6.46.7 Mean Change from Baselinec -2.0-1.3 Inflammation (0-10)d Baseline6.87.0 Mean Change from Baselinec -2.5-1.5Other Measures of Disease Activity BASDAI Score (0-10) Baseline7.07.2 Mean Change from Baselinec -2.2-1.5 BASMI (0-10) Baseline3.23.2 Mean Change from Baselinec -0.4-0.2 hsCRP (mg/L) Baseline12.414.3 Mean Change from Baselinec -8.0-3.0The percent of patients achieving ASAS40 responses by visit is shown in Figure 3. Figure 3: ASAS40 Responses through Week 16, NRIaa Patients with missing data were counted as non-responders.. Figure 3. Health-Related OutcomesGeneral health status and quality of life was assessed by the Short Form health survey (SF-36). At Week 16, compared to placebo, nr-axSpA patients treated with TALTZ 80 mg Q4W showed greater improvement from baseline in the SF-36 physical component summary (PCS) score and physical functioning, bodily pain, vitality, and social functioning domains, with no consistent improvements in the mental component summary (MCS), role physical, general health, role emotional, and mental health domains.

CLINICAL TRIALS EXPERIENCE SECTION.

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 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 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. 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 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 summarizes the adverse reactions that occurred at rate of at least 1% and at 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 12a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.b U.S. approved etanercept.Adverse ReactionsTALTZ 80 mg Q2W(N=1167) (%)Etanerceptb(N=287) (%)Placebo(N=791) (%)Injection site reactions196 (17)32 (11)26 (3)Upper respiratory tract infectionsa163 (14)23 (8)101 (13)Nausea23 (2)1 (<1)5 (1)Tinea infections17 (2)01 (<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 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 to 60:Over the entire treatment period (Weeks 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 ReactionsThe 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.. InfectionsIn 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 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 DiseaseIn adult subjects with plaque psoriasis, Crohns disease and ulcerative colitis, including exacerbations, occurred at greater frequency in the TALTZ 80 mg Q2W group (Crohns 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 (5.4)].. Laboratory Assessment of Cytopenia. NeutropeniaOver the entire treatment period (Weeks 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 to 12.In the 12-week, placebo-controlled period, neutropenia >= Grade (<1,000 cells/mm3) 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% for TALTZ 80 mg Q2W versus 0.3% for placebo; >=1,000 to <1,500 cells/mm3) or Grade (7% for TALTZ 80 mg Q2W versus 3% for placebo; >=1,500 cells/mm3 to 2,000 cells/mm3). Neutropenia in the TALTZ group was not associated with an increased rate of infection compared to the placebo group.. ThrombocytopeniaNinety eight percent of cases of thrombocytopenia were Grade (3% for TALTZ 80 mg Q2W versus 1% for placebo; >=75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with TALTZ was not associated with an increased rate of bleeding compared to subjects treated with placebo.. Active Comparator TrialsIn 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 PsoriasisTALTZ was evaluated in placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis to less than 18 years of age. 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 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, Crohns disease occurred at greater frequency in the TALTZ group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohns disease occurred in total of TALTZ treated subjects (2.0%) in the clinical trial [see Warnings and Precautions (5.4)].. Psoriatic ArthritisTALTZ was studied in two placebo-controlled trials in patients with psoriatic arthritis. total of 678 patients were studied (454 patients on TALTZ and 224 on placebo). total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 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 SpondylitisTALTZ was studied in two placebo-controlled trials in patients with ankylosing spondylitis. total of 566 patients were studied (376 patients on TALTZ and 190 on placebo). total of 195 patients in these trials received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 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, Crohns disease and ulcerative colitis, including exacerbations, occurred in patients (1.0%) and patient (0.5%), respectively, in the TALTZ 80 mg Q4W group and 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 patient in the TALTZ 80 mg Q4W group and patient in the placebo group [see Warnings and Precautions (5.4)].. Non-radiographic Axial SpondyloarthritisTALTZ was studied in placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. total of 303 patients were studied (198 patients on TALTZ and 105 on placebo). total of 96 patients in this trial received TALTZ 80 or 160 mg at Week 0, followed by 80 mg every 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TALTZ is contraindicated in patients with previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients [see Warnings and Precautions (5.3)].. Serious hypersensitivity reaction to ixekizumab or to any of the excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ixekizumab is humanized immunoglobulin subclass (IgG4) monoclonal antibody (mAb) with neutralizing activity against IL-17A. Ixekizumab is produced by recombinant DNA technology in recombinant mammalian cell line and purified using standard technology for bioprocessing. Ixekizumab is comprised of two identical light chain polypeptides of 219 amino acids each and two identical heavy chain polypeptides of 445 amino acids each, and has molecular weight of 146,158 Daltons for the protein backbone of the molecule.TALTZ injection is sterile, preservative free, clear and colorless to slightly yellow solution, for subcutaneous use available as 80 mg of ixekizumab in 1 mL single-dose prefilled autoinjector or single-dose prefilled syringe. The prefilled autoinjector and prefilled syringe each contain 1 mL glass syringe with fixed 27 gauge 1/2 inch needle. The TALTZ 80 mg prefilled autoinjector and prefilled syringe are manufactured to deliver 80 mg of ixekizumab.Each mL is composed of ixekizumab (80 mg); Citric Acid Anhydrous, USP (0.51 mg); Polysorbate 80, USP (0.3 mg); Sodium Chloride, USP (11.69 mg); Sodium Citrate Dihydrate, USP (5.11 mg); and Water for Injection, USP. The TALTZ solution has pH of 5.3 6.1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer by subcutaneous injection.Adult Plaque Psoriasis (2.1)Recommended dose 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 weeks.Pediatric Plaque Psoriasis (2.2)For patients weighing greater than 50 kg, recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg every weeks.For patients weighing 25-50 kg, recommended dose is 80 mg at Week 0, followed by 40 mg every weeks.For patients weighing less than 25 kg, recommended dose is 40 mg at Week 0, followed by 20 mg every weeks.Psoriatic Arthritis (2.3)Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis. (2.1)TALTZ may be administered alone or in combination with conventional DMARD (e.g., methotrexate).Ankylosing Spondylitis (2.4)Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.Non-radiographic Axial Spondyloarthritis (2.5)Recommended dose is 80 mg by subcutaneous injection every weeks.. Recommended dose 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 weeks.. For patients weighing greater than 50 kg, recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg every weeks.. For patients weighing 25-50 kg, recommended dose is 80 mg at Week 0, followed by 40 mg every weeks.. For patients weighing less than 25 kg, recommended dose is 40 mg at Week 0, followed by 20 mg every weeks.. Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.. For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis. (2.1). TALTZ may be administered alone or in combination with conventional DMARD (e.g., methotrexate).. Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.. Recommended dose is 80 mg by subcutaneous injection every weeks.. 2.1 Adult Plaque Psoriasis. TALTZ is administered by subcutaneous injection. The recommended dose 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 weeks.. 2.2 Pediatric Plaque Psoriasis. TALTZ is administered by subcutaneous injection every weeks (Q4W). The recommended dose in pediatric patients from to less than 18 years of age with moderate-to-severe plaque psoriasis is based on the following weight categories.Table 1: Recommended Dosing and Administration for Pediatric PatientsPediatric Patients WeightStarting Dose (Week 0)Dose every weeks (Q4W) ThereafterGreater than 50 kg160 mg (two 80 mg injections)80 mg25 to 50 kg80 mg40 mgLess than 25 kg40 mg20 mg. 2.3 Psoriatic Arthritis. The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis [see Dosage and Administration (2.1)].TALTZ may be administered alone or in combination with conventional disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate).. 2.4 Ankylosing Spondylitis. The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every weeks.. 2.5 Non-radiographic Axial Spondyloarthritis. The recommended dose is 80 mg by subcutaneous injection every weeks.. 2.6 Tuberculosis Assessment Prior to Initiation of TALTZ. Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TALTZ [see Warnings and Precautions (5.2)].. 2.7 Important Administration Instructions. TALTZ is intended for use under the guidance and supervision of physician. Adult patients may self-inject or caregivers may give injections of TALTZ 80 mg after training in subcutaneous injection technique using the autoinjector or prefilled syringe. Caregivers may give injections of TALTZ 80 mg to pediatric patients weighing more than 50 kg using the autoinjector or prefilled syringe after training and demonstration of proper subcutaneous injection technique.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 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 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 caregiver or healthcare provider [see Instructions for Use].TALTZ does not contain preservatives, therefore discard any unused product.If dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.. Pediatric Patients Weighing 50 kg or LessTALTZ doses of 20 mg or 40 mg [see Dosage and Administration (2.2)] must be prepared and administered by qualified healthcare professional. Use only the commercial TALTZ 80 mg/1 mL prefilled syringe when preparing the prescribed 20 mg and 40 mg pediatric dose.Gather the following necessary supplies for preparation:0.5 mL or mL disposable syringeSterile needle for withdrawal27-gauge sterile needle for administrationSterile, clear glass vial. Expel the entire contents of the prefilled syringe into the sterile vial. DO NOT shake or swirl the vial. No other medications should be added to solutions containing TALTZ.Using the 0.5 mL or 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 27-gauge needle prior to administering TALTZ to the patient.StorageIf necessary, the prepared TALTZ may be stored at room temperature for up to hours from first puncturing the sterile vial.. Gather the following necessary supplies for preparation:0.5 mL or mL disposable syringeSterile needle for withdrawal27-gauge sterile needle for administrationSterile, clear glass vial. 0.5 mL or 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. No other medications should be added to solutions containing TALTZ.. Using the 0.5 mL or 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 27-gauge needle prior to administering TALTZ to the patient.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TALTZ is clear and colorless to slightly yellow solution available as:AutoinjectorInjection: 80 mg/mL solution of TALTZ in single-dose prefilled autoinjectorPrefilled SyringeInjection: 80 mg/mL solution of TALTZ in single-dose prefilled syringe. Injection: 80 mg/mL solution of TALTZ in single-dose prefilled autoinjector. Injection: 80 mg/mL solution of TALTZ in single-dose prefilled syringe. AutoinjectorInjection: 80 mg/mL solution in single-dose prefilled autoinjector. (3)Prefilled SyringeInjection: 80 mg/mL solution in single-dose prefilled syringe. (3). Injection: 80 mg/mL solution in single-dose prefilled autoinjector. (3). Injection: 80 mg/mL solution in single-dose prefilled syringe. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 4204 adult psoriasis subjects exposed to TALTZ, total of 301 were 65 years or older, and 36 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 and over is not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. TALTZ injection is sterile, preservative free, clear and colorless to slightly yellow solution available in single-dose prefilled autoinjector or single-dose prefilled syringe to deliver 80 mg ixekizumab.TALTZ is supplied as:Pack SizeNDC CodeAutoinjector 80 mg single-doseCarton of 10002-1445-11 80 mg single-doseCarton of 20002-1445-27 80 mg single-doseCarton of 30002-1445-09Prefilled syringe 80 mg single-doseCarton of 10002-7724-11. 16.2 Storage and Handling. TALTZ is sterile and preservative-free. Discard any unused portion.TALTZ must be protected from light until use.Store refrigerated at 2C to 8C (36F to 46F).If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. Do not freeze. Do not use TALTZ if it has been frozen.Do not shake.Discard the TALTZ single-dose autoinjector or syringe after use in puncture-resistant container.Not made with natural rubber latex.. TALTZ must be protected from light until use.. Store refrigerated at 2C to 8C (36F to 46F).If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. If needed, patients/caregivers may store TALTZ at room temperature up to 30C (86F) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator and discard, if unused, within days.. Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.. For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light.. Do not freeze. Do not use TALTZ if it has been frozen.. Do not shake.. Discard the TALTZ single-dose autoinjector or syringe after use in puncture-resistant container.. Not made with natural rubber latex.

IMMUNOGENICITY.

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 PopulationBy Week 12, approximately 9% of adult subjects treated with TALTZ every 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, 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 PopulationFor subjects treated with TALTZ 80 mg every weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies.. Ankylosing Spondylitis PopulationFor patients treated with TALTZ 80 mg every weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies.. Non-radiographic Axial Spondyloarthritis PopulationOf patients treated with TALTZ 80 mg every 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TALTZ(R) is humanized interleukin-17A antagonist indicated for the treatment of:patients aged 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). patients aged 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(R) is indicated for the treatment of patients 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using TALTZ, and each time the prescription is renewed, as there may be new information they need to know.Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly [see Instructions for Use].Infection: Inform patients that TALTZ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.1)].Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.3)].Pregnancy: Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TALTZ during pregnancy. Advise patients to contact the registry at 1-800-284-1695 to enroll [see Use in Specific Populations (8.1)].Eli Lilly and Company, Indianapolis, IN 46285, USAUS License Number 1891Product of IrelandCopyright (C) 2016, 2021, Eli Lilly and Company. All rights reserved.TAL-0011-USPI-20211118.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USETALTZ(R) (tol(t)s)(ixekizumab)injection, for subcutaneous useAutoinjectorBefore you use the TALTZ autoinjector, read and carefully follow all the step-by-step instructions.Important information:Your healthcare provider or nurse should show you how to prepare and inject TALTZ using the autoinjector. Do not inject yourself or someone else until you have been shown how to inject TALTZ.You and your caregiver should read this Instructions for Use before you start using TALTZ and each time you get refill. Keep the Instructions for Use and refer to them as needed.Each TALTZ autoinjector contains dose of TALTZ. The autoinjector is for one-time use only. The autoinjector contains glass parts. Handle autoinjector carefully. If you drop it on hard surface, do not use it. Use new TALTZ autoinjector for your injection.Your healthcare provider may help you decide where on your body to inject your dose. Do not give an injection in an area of the skin that is tender, bruised, red or hard, or in an area of skin that is affected by psoriasis. Read the Choose your injection site section of these instructions to help you choose which area can work best for you.If you have vision or hearing problems, do not use TALTZ autoinjector without help from caregiver.INSTRUCTIONS FOR USEBefore you use the TALTZ autoinjector, read and carefully follow all the step-by-step instructions.Parts of the TALTZ autoinjector1Get Ready1aTake the TALTZ autoinjector from the refrigerator.Remove the autoinjector from the package. Put the original package with any unused autoinjectors back in the refrigerator. Leave the base cap on until you are ready to inject.Wait 30 minutes to let the autoinjector warm to room temperature before you use it.Do not microwave the autoinjector, run hot water over it, or leave it in direct sunlight.Do not shake the autoinjector.1bGather the supplies needed for your injection:1 alcohol wipe1 cotton ball or piece of gauze1 sharps disposal container. See Dispose of the used autoinjector. 1cInspect the autoinjector.Make sure the name TALTZ appears on the label.The medicine inside should be clear. Its color may be colorless to slightly yellow.Do not use the autoinjector, and dispose of as directed by your healthcare provider or pharmacist if: the expiration date printed on the label has passed.it looks damaged.the medicine is frozen.the medicine is cloudy, discolored, or has small particles. The medicine should look clear and colorless to slightly yellow. 1dWash your hands with soap and water before you inject TALTZ.1eChoose your injection site.You may inject in your stomach area (abdomen) or in your thigh, or in the back of your arm. To inject in your arm, you will need someone to help you.Do not give an injection into areas where the skin is tender, bruised, red or hard, or in an area of skin that is affected by psoriasis. Do not inject within inch of the navel (belly button). Alternate your injection sites. Do not inject in the exact same spot every time. For example, if your last injection was in your left thigh, your next injection should be in your right thigh, your abdomen, or the back of either arm.Talk with your healthcare provider about where on your body to best inject TALTZ. 1fPrepare your skin. Clean your injection site with an alcohol wipe. Let the injection site dry before you inject TALTZ.2Inject TALTZ2aMake sure the lock ring is in the lock position.Leave the base cap on until you are ready to inject.Do not touch the needle.Twist off the base cap in the direction of the arrows.Throw the base cap in the trash. You will not need to put the base cap back on. If you do, you could damage the needle or stick yourself by accident.2bPlace the clear base flat and firmly against your skin at the injection site.2cWhile holding the clear base against your skin, turn the lock ring to the unlock position. You are now ready to inject.2dPress the green injection button. There will be loud click. Keep holding the clear base firmly against your skin.You will hear second click in about 10 seconds after the first one. The second click tells you that your injection is complete. You will see the gray plunger at the top of the clear base. Remove the autoinjector from your skin. Press cotton ball or gauze over the injection site. Do not rub the injection site, as this may cause bruising. You may have slight bleeding. This is normal. Do not put the base cap back on the autoinjector.3Dispose of (throw away) the used autoinjector.3aPut the used TALTZ autoinjector in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the TALTZ autoinjector in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposalDo not recycle your used sharps disposal container.Commonly asked questions and answers. Q.What if see bubbles in the TALTZ autoinjectorA.It is normal to have air bubbles in the autoinjector. Q.What if there is drop of liquid on the tip of the needle when remove the base capA.It is okay to see drop of liquid on the tip of the needle. Q.What if unlocked the autoinjector and pressed the green injection button before twisted off the base capA.Do not remove the base cap. Dispose of the autoinjector and get new one. Q.Do need to hold the injection button down until the injection is completeA.You do not need to hold the injection button down, but it may help you keep the autoinjector steady and firm against your skin. Q.What if the needle did not retract after my injection or am not sure that the autoinjector worked in the right wayA.Do not touch the needle or replace the base cap. Store the autoinjector in safe place (e.g., household container as described in Dispose of the used autoinjector.) to avoid an accidental needlestick and contact Lilly (1-800-545-5979) for instructions on how to return the autoinjector. Q.What if hear more than clicks during my injection Did get my complete doseA.You may hear soft click right before the second loud click. This is the normal operation of the autoinjector. Do not remove the autoinjector from your skin until you hear the second loud click. Q.How can tell if my injection is completeA.After you press the green injection button, you will hear loud clicks. The second click tells you that your injection is complete. You will also see the gray plunger at the top of the clear base. Q.What if the autoinjector is left at room temperature for longer than 30 minutesA.If needed, the autoinjector may be left out of the refrigerator at room temperature up to 86F (30C) for up to days if protected from light. Throw away TALTZ if not used within the 5-day period at room temperature. See How should store TALTZ autoinjector for more detail. If you have more questions about how to use the TALTZ autoinjector:Call your healthcare providerCall Lilly at 1-800-545-5979 (1-800-Lilly-Rx)Visit www.taltz.com How should store TALTZ autoinjectorProtect TALTZ from light.Store TALTZ in the refrigerator between 36F to 46F (2C to 8C).If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. Do not freeze TALTZ. Do not use if TALTZ has been frozen.Do not shake TALTZ.Keep TALTZ and all medicines out of the reach of children. Read the full Prescribing Information and Medication Guide for TALTZ inside this box to learn more about your medicine. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 TALTZ is trademark of Eli Lilly and Company. Copyright (C) 2016, 2021, Eli Lilly and Company. All rights reserved. The TALTZ autoinjector meets the current dose accuracy and functional requirements of ISO 11608-1 and 11608-5. TALAI-0007-IFU-20210622 Revised: June 2021. Your healthcare provider or nurse should show you how to prepare and inject TALTZ using the autoinjector. Do not inject yourself or someone else until you have been shown how to inject TALTZ.. You and your caregiver should read this Instructions for Use before you start using TALTZ and each time you get refill. Keep the Instructions for Use and refer to them as needed.. Each TALTZ autoinjector contains dose of TALTZ. The autoinjector is for one-time use only. The autoinjector contains glass parts. Handle autoinjector carefully. If you drop it on hard surface, do not use it. Use new TALTZ autoinjector for your injection.. Your healthcare provider may help you decide where on your body to inject your dose. Do not give an injection in an area of the skin that is tender, bruised, red or hard, or in an area of skin that is affected by psoriasis. Read the Choose your injection site section of these instructions to help you choose which area can work best for you.. If you have vision or hearing problems, do not use TALTZ autoinjector without help from caregiver.. Take the TALTZ autoinjector from the refrigerator.. Remove the autoinjector from the package. Put the original package with any unused autoinjectors back in the refrigerator. Leave the base cap on until you are ready to inject.. Wait 30 minutes to let the autoinjector warm to room temperature before you use it.. Do not microwave the autoinjector, run hot water over it, or leave it in direct sunlight.. Do not shake the autoinjector.. alcohol wipe. cotton ball or piece of gauze. sharps disposal container. See Dispose of the used autoinjector. Make sure the name TALTZ appears on the label.. The medicine inside should be clear. Its color may be colorless to slightly yellow.. the expiration date printed on the label has passed.. it looks damaged.. the medicine is frozen.. the medicine is cloudy, discolored, or has small particles. The medicine should look clear and colorless to slightly yellow.. Do not inject in the exact same spot every time. For example, if your last injection was in your left thigh, your next injection should be in your right thigh, your abdomen, or the back of either arm.. Talk with your healthcare provider about where on your body to best inject TALTZ.. Leave the base cap on until you are ready to inject.. Do not touch the needle.. Throw the base cap in the trash. You will not need to put the base cap back on. If you do, you could damage the needle or stick yourself by accident.. Keep holding the clear base firmly against your skin.. You will hear second click in about 10 seconds after the first one. The second click tells you that your injection is complete. You will see the gray plunger at the top of the clear base.. Press cotton ball or gauze over the injection site. Do not rub the injection site, as this may cause bruising. You may have slight bleeding. This is normal. Put the used TALTZ autoinjector in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the TALTZ autoinjector in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not recycle your used sharps disposal container.. Call your healthcare provider. Call Lilly at 1-800-545-5979 (1-800-Lilly-Rx). Visit www.taltz.com Protect TALTZ from light.. Store TALTZ in the refrigerator between 36F to 46F (2C to 8C).If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light. If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.. Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.. For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Ensure the unrefrigerated TALTZ is protected from light.. Do not freeze TALTZ. Do not use if TALTZ has been frozen.. Do not shake TALTZ.. Figure. Logo. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TALTZ and any potential adverse effects on the breastfed infant from TALTZ or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ixekizumab is humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of TALTZ. Moreover published literature is mixed on potential effects on malignancy risk due to the inhibition of IL-17A activity, the pharmacological action of TALTZ. Some published literature suggests that IL-17A directly promotes cancer cell invasion, suggesting potential beneficial effect by TALTZ, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection, suggesting potential adverse effect by TALTZ. However, neutralization of IL-17A with TALTZ has not been studied in these models. Depletion of IL-17A with neutralizing antibody inhibited tumor development in mice, suggesting potential beneficial effect by TALTZ. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown.No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were administered ixekizumab for 13 weeks at subcutaneous dose of 50 mg/kg/week (19 times the MRHD on mg/kg basis). The monkeys were not mated to evaluate fertility.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON Taltz Autoinjector 80 mg. Single-Dose prefilled autoinjectortaltz(R) (ixekizumab) injection80 mg/mLFor Subcutaneous Use OnlySingle-Dose OnlyNDC 0002-1445-11Each prefilled autoinjector contains 80 mg of TALTZ.Rx OnlyDispense enclosed Medication Guide to each patient.Lilly. PACKAGE CARTON Taltz Autoinjector 80 mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of TALTZ have been established in pediatric subjects aged years to less than 18 years with moderate-to-severe plaque psoriasis. The safety and effectiveness of TALTZ in other pediatric indications and for pediatric subjects less than years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. No formal pharmacodynamic studies have been conducted with TALTZ.

PHARMACOKINETICS SECTION.

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.. AbsorptionFollowing single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (+-SD) serum concentrations (Cmax) of 16.2 +-6.6 mcg/mL by approximately days post dose.Steady-state concentrations were achieved by Week following the 160 mg starting dose and 80 mg every 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 weeks dosing regimen to the 80 mg every 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 higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.. DistributionThe mean (geometric CV%) volume of distribution at steady-state was 7.11 (29%) in subjects with plaque psoriasis.. EliminationThe metabolic pathway of ixekizumab has not been characterized. As 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.. WeightIxekizumab clearance and volume of distribution increase as body weight increases.. Dose LinearityIxekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over dose range from mg (not the recommended dose) to 160 mg following subcutaneous administration.. Specific Populations. Age: Geriatric PopulationPopulation 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 similar ixekizumab clearance as compared to subjects less than 65 years old.. Pediatric PopulationPediatric 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 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 StudiesPopulation 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 SubstratesNo 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 single 160 mg dose of ixekizumab, or multiple doses of 80 mg every 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.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of TALTZ. Because the reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to TALTZ exposure.Immune system disorders: anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.3)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TALTZ during pregnancy. Pregnant women should be encouraged to enroll themselves in the registry by calling 1-800-284-1695.Risk SummaryThere are no available data on TALTZ use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, TALTZ may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataAn embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.In pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on mg/kg basis of mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through months of age.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: November 2021Medication GuideTALTZ(R)(tolts)(ixekizumab)injection, for subcutaneous useWhat is the most important information should know about TALTZTALTZ is medicine that affects your immune system. TALTZ may lower the ability of your immune system to fight infections and may increase your risk of infections, which can sometimes become serious.Your healthcare provider should check you for tuberculosis (TB) before you start treatment with TALTZ.Your healthcare provider may treat you with medicine for TB before you begin treatment with TALTZ if you have past history of TB or have TB.Your healthcare provider should watch you closely for signs and symptoms of TB during and after treatment with TALTZ.Before starting TALTZ, tell your healthcare provider if you:are being treated for an infectionhave an infection that does not go away or that keeps coming backhave TB or have been in close contact with someone with TBthink you have an infection or have symptoms of an infection such as: fever, sweats, or chillsmuscle achescoughshortness of breathblood in your phlegm (mucus)weight losswarm, red, or painful skin or sores on your bodydiarrhea or stomach painburning when you urinate or urinate more often than normalAfter starting TALTZ, call your healthcare provider right away if you have any of the symptoms of infection listed above.Do not use TALTZ if you have any symptoms of infection unless you are instructed to by your healthcare provider.See What are the possible side effects of TALTZ for more information about side effects.What is TALTZTALTZ is prescription medicine used to treat:people years of age and older with moderate-to-severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet or UV light).adults with active psoriatic arthritis. TALTZ can be used alone or with the medicine methotrexate.adults with active ankylosing spondylitis.adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation.It is not known if TALTZ is safe and effective in children for conditions other than plaque psoriasis or in children under years of age.Do not use TALTZ if you have had severe allergic reaction to ixekizumab or any of the other ingredients in TALTZ.See the end of this Medication Guide for complete list of ingredients in TALTZ.Before using TALTZ, tell your healthcare provider about all of your medical conditions, including if you:have any of the conditions or symptoms listed in the section What is the most important information should know about TALTZ have Crohns disease or ulcerative colitishave recently received or are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with TALTZ.are pregnant or plan to become pregnant. It is not known if TALTZ can harm your unborn baby. Pregnancy Registry: If you become pregnant while taking TALTZ, you are encouraged to enroll in the pregnancy registry. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider or call 1-800-284-1695 to enroll in the registry.are breastfeeding or plan to breastfeed. It is not known if TALTZ passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use TALTZSee the detailed Instructions for Use that comes with your TALTZ for information on how to prepare and inject dose of TALTZ, and how to properly throw away (dispose of) used TALTZ autoinjectors and prefilled syringes.Use TALTZ exactly as prescribed by your healthcare provider.For children weighing 110 pounds (50 kg) or less, TALTZ must be given by healthcare provider. TALTZ will be given every weeks.For children weighing more than 110 pounds (50 kg), if your healthcare provider decides that your caregiver may give your injections of TALTZ at home, your caregiver should ask and receive training from the healthcare provider on the right way to prepare and inject TALTZ. TALTZ will be given every weeks.For adults, if your healthcare provider decides that you or caregiver may give your injections of TALTZ at home, you should receive training on the right way to prepare and inject TALTZ. Do not try to inject TALTZ yourself, until you or your caregiver have been shown how to inject TALTZ.TALTZ comes in an autoinjector and prefilled syringe that you or your caregiver may use at home to give injections. Your healthcare provider will decide which type of TALTZ is best for you to use at home.TALTZ is given as an injection under your skin (subcutaneous injection), in your thighs or stomach area (abdomen) by you or caregiver. caregiver may also give you an injection of TALTZ in the back of your arm.Do not give an injection in an area of the skin that is tender, bruised, red or hard, or in an area of skin that is affected by psoriasis.Each TALTZ injection should be given at different site. Do not use the inch area around your navel (belly button).If you forget to take your dose:Do not miss any doses of TALTZ unless your healthcare provider says it is okay. If you forget to take your TALTZ dose, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time.If you inject more TALTZ than prescribed, call your healthcare provider or go to the nearest emergency room right away.What are the possible side effects of TALTZTALTZ may cause serious side effects, including:See What is the most important information should know about TALTZSerious allergic reactions. If you have severe allergic reaction, do not give another injection of TALTZ. Get emergency medical help right away if you get any of the following symptoms of serious allergic reaction: feel faintswelling of your face, eyelids, lips, mouth, tongue, or throattrouble breathing or throat tightnesschest tightnessskin rashCrohns disease or ulcerative colitis (inflammatory bowel disease) can happen during treatment with TALTZ, including worsening symptoms. Tell your healthcare provider if you have new or worsening symptoms of inflammatory bowel disease during treatment with TALTZ, including:stomach (abdomen) paindiarrhea with or without bloodweight lossThe most common side effects of TALTZ in adults and children include:injection site reactionsupper respiratory infectionsnauseafungal infectionsThese are not all of the possible side effects of TALTZ. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TALTZProtect TALTZ from light.Store TALTZ in the refrigerator between 36F to 46F (2C to 8C).If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Make sure the unrefrigerated TALTZ is protected from light. Do not freeze TALTZ. Do not use if TALTZ has been frozen.Do not shake TALTZ.Keep TALTZ and all medicines out of the reach of children.General information about the safe and effective use of TALTZ.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TALTZ for condition for which it was not prescribed. Do not give TALTZ to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TALTZ that is written for health professionals.What are the ingredients in TALTZActive ingredient: ixekizumab Inactive ingredients: Citric Acid Anhydrous, Polysorbate 80, Sodium Chloride, Sodium Citrate Dihydrate, and Water for InjectionNot made with natural rubber latex. For more information about TALTZ, call 1-800-545-5979 (1-800-LillyRx) or go to the following website: www.taltz.com. TALTZ(R) (ixekizumab) injection is registered trademark of Eli Lilly and Company.Eli Lilly and Company Indianapolis, IN 46285, USA, US License Number 1891, Product of IrelandCopyright (C) 2016, 2021, Eli Lilly and Company. All rights reserved.TAL-0007-MG-20211118. Your healthcare provider should check you for tuberculosis (TB) before you start treatment with TALTZ.. Your healthcare provider may treat you with medicine for TB before you begin treatment with TALTZ if you have past history of TB or have TB.. Your healthcare provider should watch you closely for signs and symptoms of TB during and after treatment with TALTZ.. are being treated for an infection. have an infection that does not go away or that keeps coming back. have TB or have been in close contact with someone with TB. think you have an infection or have symptoms of an infection such as: fever, sweats, or chills. muscle aches. cough. shortness of breath. blood in your phlegm (mucus). weight loss. warm, red, or painful skin or sores on your body. diarrhea or stomach pain. burning when you urinate or urinate more often than normal. people years of age and older with moderate-to-severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet or UV light).. adults with active psoriatic arthritis. TALTZ can be used alone or with the medicine methotrexate.. adults with active ankylosing spondylitis.. adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation.. have any of the conditions or symptoms listed in the section What is the most important information should know about TALTZ have Crohns disease or ulcerative colitis. have recently received or are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with TALTZ.. are pregnant or plan to become pregnant. It is not known if TALTZ can harm your unborn baby. Pregnancy Registry: If you become pregnant while taking TALTZ, you are encouraged to enroll in the pregnancy registry. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider or call 1-800-284-1695 to enroll in the registry.. are breastfeeding or plan to breastfeed. It is not known if TALTZ passes into your breast milk.. Use TALTZ exactly as prescribed by your healthcare provider.. For children weighing 110 pounds (50 kg) or less, TALTZ must be given by healthcare provider. TALTZ will be given every weeks.. For children weighing more than 110 pounds (50 kg), if your healthcare provider decides that your caregiver may give your injections of TALTZ at home, your caregiver should ask and receive training from the healthcare provider on the right way to prepare and inject TALTZ. TALTZ will be given every weeks.. For adults, if your healthcare provider decides that you or caregiver may give your injections of TALTZ at home, you should receive training on the right way to prepare and inject TALTZ. Do not try to inject TALTZ yourself, until you or your caregiver have been shown how to inject TALTZ.. TALTZ comes in an autoinjector and prefilled syringe that you or your caregiver may use at home to give injections. Your healthcare provider will decide which type of TALTZ is best for you to use at home.. TALTZ is given as an injection under your skin (subcutaneous injection), in your thighs or stomach area (abdomen) by you or caregiver. caregiver may also give you an injection of TALTZ in the back of your arm.. Do not give an injection in an area of the skin that is tender, bruised, red or hard, or in an area of skin that is affected by psoriasis.. Each TALTZ injection should be given at different site. Do not use the inch area around your navel (belly button).. Do not miss any doses of TALTZ unless your healthcare provider says it is okay. If you forget to take your TALTZ dose, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time.. If you inject more TALTZ than prescribed, call your healthcare provider or go to the nearest emergency room right away.. See What is the most important information should know about TALTZ. Serious allergic reactions. If you have severe allergic reaction, do not give another injection of TALTZ. Get emergency medical help right away if you get any of the following symptoms of serious allergic reaction: feel faint. swelling of your face, eyelids, lips, mouth, tongue, or throat. trouble breathing or throat tightness. chest tightness. skin rash. Crohns disease or ulcerative colitis (inflammatory bowel disease) can happen during treatment with TALTZ, including worsening symptoms. Tell your healthcare provider if you have new or worsening symptoms of inflammatory bowel disease during treatment with TALTZ, including:stomach (abdomen) paindiarrhea with or without bloodweight loss. stomach (abdomen) pain. diarrhea with or without blood. weight loss. injection site reactions. upper respiratory infections. nausea. fungal infections. Protect TALTZ from light.. Store TALTZ in the refrigerator between 36F to 46F (2C to 8C).If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Make sure the unrefrigerated TALTZ is protected from light. If needed, you or caregiver may store TALTZ at room temperature up to 86F (30C) for up to days in the original carton to protect from light. Once TALTZ has been stored at room temperature, do not return to the refrigerator. Throw away TALTZ if it is not used within days at room temperature.. Record the date when TALTZ is first removed from the refrigerator in the spaces provided on the carton.. For the or autoinjector pack, remove single autoinjector at time leaving the remaining autoinjector(s) in the original carton in the refrigerator. Make sure the unrefrigerated TALTZ is protected from light.. Do not freeze TALTZ. Do not use if TALTZ has been frozen.. Do not shake TALTZ.

SPL UNCLASSIFIED SECTION.

1.1 Plaque Psoriasis. TALTZ(R) is indicated for the treatment of patients years of age and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infections: Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If serious infection develops, discontinue TALTZ until the infection resolves. (5.1)Tuberculosis (TB): Evaluate for TB prior to initiating treatment. (5.2)Hypersensitivity: If serious allergic reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy. (5.3)Inflammatory Bowel Disease: Crohns disease and ulcerative colitis, including exacerbations, occurred during clinical trials. Monitor closely when prescribing TALTZ to patients with inflammatory bowel disease (IBD). Discontinue TALTZ and initiate appropriate medical management if IBD develops. (5.4). Infections: Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If serious infection develops, discontinue TALTZ until the infection resolves. (5.1). Tuberculosis (TB): Evaluate for TB prior to initiating treatment. (5.2). Hypersensitivity: If serious allergic reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy. (5.3). Inflammatory Bowel Disease: Crohns disease and ulcerative colitis, including exacerbations, occurred during clinical trials. Monitor closely when prescribing TALTZ to patients with inflammatory bowel disease (IBD). Discontinue TALTZ and initiate appropriate medical management if IBD develops. (5.4). 5.1 Infections. TALTZ may increase the risk of infection. In clinical trials in adult patients with plaque psoriasis, the TALTZ group had higher rate of infections than the placebo group (27% vs. 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the TALTZ group than in the placebo group. similar increase in risk of infection was seen in placebo-controlled trials in patients with pediatric psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis [see Adverse Reactions (6.1)].Instruct patients treated with TALTZ to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If patient develops serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TALTZ until the infection resolves.. 5.2 Pre-treatment Evaluation for Tuberculosis. Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TALTZ. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering TALTZ. Consider anti-TB therapy prior to initiating TALTZ in patients with past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving TALTZ should be monitored closely for signs and symptoms of active TB during and after treatment.. 5.3 Hypersensitivity. Serious hypersensitivity reactions, including angioedema and urticaria (each <=0.1%), occurred in the TALTZ group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post marketing use with TALTZ [see Adverse Reactions (6.1, 6.3)]. If serious hypersensitivity reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy.. 5.4 Inflammatory Bowel Disease. Patients treated with TALTZ may be at increased risk of inflammatory bowel disease. In clinical trials, Crohns disease and ulcerative colitis, including exacerbations, occurred at greater frequency in the TALTZ group than the placebo control group [see Adverse Reactions (6.1)]. During TALTZ treatment, monitor for onset or exacerbation of inflammatory bowel disease and if IBD occurs, discontinue TALTZ and initiate appropriate medical management.. 5.5 Immunizations. Prior to initiating therapy with TALTZ, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TALTZ. No data are available on the response to live vaccines.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration: Testing and Procedures Prior to Treatment Initiation (2.1)05/2022.