Ixekizumab

TALTZ ® is a humanized interleukin-17A antagonist indicated for the treatment of: patients aged 6 years or older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. ( 1.1 ) adults with active psoriatic arthritis. ( 1.2 ) adults with active ankylosing spondylitis. ( 1.3 ) adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation. ( 1.4 )

1.1 Plaque Psoriasis TALTZ ® is indicated for the treatment of patients 6 years of age and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

1.2 Psoriatic Arthritis TALTZ is indicated for the treatment of adult patients with active psoriatic arthritis.

1.3 Ankylosing Spondylitis TALTZ is indicated for the treatment of adult patients with active ankylosing spondylitis.

1.4 Non-radiographic Axial Spondyloarthritis TALTZ is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation.

TALTZ is a clear and colorless to slightly yellow solution available as: Injection: 80 mg/mL solution of TALTZ in a single-dose prefilled autoinjector Injection: 80 mg/mL solution of TALTZ in a single-dose prefilled syringe Injection: 40 mg/0.5 mL solution of TALTZ in a single-dose prefilled syringe Injection: 20 mg/0.25 mL solution of TALTZ in a single-dose prefilled syringe Injection: ( 3 ) 80 mg/mL solution in a single-dose prefilled autoinjector 80 mg/mL solution in a single-dose prefilled syringe 40 mg/0.5 mL solution in a single-dose prefilled syringe 20 mg/0.25 mL solution in a single-dose prefilled syringe

TALTZ is contraindicated in patients with a 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 )

Infections : Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue TALTZ until the infection resolves. ( 5.1 ) Tuberculosis (TB) : Evaluate for TB prior to initiating treatment. ( 5.2 ) Hypersensitivity : If a serious allergic reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy. ( 5.3 ) Eczematous Eruptions: In the postmarketing setting, cases of severe eczematous eruptions were reported in patients receiving TALTZ. Treatment may need to be discontinued to resolve the eczematous eruption. ( 5.4 ) Inflammatory Bowel Disease : Crohn's 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. ( 5.5 ) Immunizations : Avoid use of live vaccines. ( 5.6 )

5.1 Infections TALTZ may increase the risk of infection. In clinical trials in adult patients with plaque psoriasis, the TALTZ group had a 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. A 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 )] . In the postmarketing setting, serious bacterial, viral, and fungal opportunistic infections have been reported in patients receiving IL-17 inhibitors including TALTZ. Instruct patients treated with TALTZ to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a 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 a 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 a serious hypersensitivity reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy.

5.4 Eczematous Eruptions In the postmarketing setting, cases of severe eczematous eruptions, including atopic dermatitis-like eruptions, dyshidrotic eczema, and erythroderma were reported in patients receiving TALTZ; some cases resulted in hospitalization. The onset of eczematous eruptions was variable, ranging from days to months after the first dose of TALTZ. Treatment may need to be discontinued to resolve the eczematous eruption. Some patients with limited psoriasis treatment options were successfully treated for eczema while continuing TALTZ.

5.5 Inflammatory Bowel Disease Patients treated with TALTZ may be at increased risk of inflammatory bowel disease. In clinical trials, Crohn's disease and ulcerative colitis, including exacerbations, occurred at a 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.

5.6 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.

The following adverse drug reactions are discussed in greater detail in other sections of the label: Infections [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] Eczematous Eruptions [see Warnings and Precautions ( 5.4 )] Inflammatory Bowel Disease [see Warnings and Precautions ( 5.5 )] Most common (≥1%) adverse reactions associated with TALTZ treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 (1-800-LillyRx) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Plaque Psoriasis Weeks 0 to 12 : Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of TALTZ compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received TALTZ (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of TALTZ (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept [see Clinical Studies ( 14 )] . In the 12-week, placebo-controlled period, adverse events occurred in 58% of the TALTZ Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the TALTZ group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up). Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the TALTZ group than in the placebo group during the 12-week placebo-controlled period of the pooled clinical trials. Table 2: Adverse Reactions Occurring in ≥1% of the TALTZ Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection. b U.S. approved etanercept. Adverse Reactions TALTZ 80 mg Q2W (N=1167) n (%) Etanercept b (N=287) n (%) Placebo (N=791) n (%) Injection site reactions 196 (17) 32 (11) 26 (3) Upper respiratory tract infections a 163 (14) 23 (8) 101 (13) Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) Adverse reactions that occurred at rates less than 1% in the TALTZ group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema. Weeks 13 to 60 : A total of 332 subjects received the recommended maintenance regimen of TALTZ 80 mg dosed every 4 weeks. During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with TALTZ (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with TALTZ (0.05 per subject-year of follow-up) and none in the subjects treated with placebo. Weeks 0 to 60 : Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with TALTZ (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with TALTZ (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up). Specific Adverse Drug Reactions Injection Site Reactions The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of TALTZ. Infections In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with TALTZ (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with TALTZ (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) [see Warnings and Precautions ( 5.1 )] . During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with TALTZ (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with TALTZ (0.01 per subject-year of follow-up) and none in the subjects treated with placebo. Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with TALTZ (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with TALTZ (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up). Inflammatory Bowel Disease In adult subjects with plaque psoriasis, Crohn's disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ 80 mg Q2W group (Crohn's disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials [see Warnings and Precautions ( 5.5 )] . Laboratory Assessment of Cytopenia Neutropenia Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with TALTZ (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with TALTZ, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12. In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm 3 ) occurred in 0.2% of the TALTZ group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for TALTZ 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm 3 ) or Grade 1 (7% for TALTZ 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm 3 to ˂2,000 cells/mm 3 ). Neutropenia in the TALTZ group was not associated with an increased rate of infection compared to the placebo group. Thrombocytopenia Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for TALTZ 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm 3 to <150,000 cells/mm 3 ). Thrombocytopenia in subjects treated with TALTZ was not associated with an increased rate of bleeding compared to subjects treated with placebo. Active Comparator Trials In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for TALTZ 80 mg Q2W. The rate of serious infections was 0.3% for both TALTZ 80 mg Q2W and U.S. approved etanercept. Pediatric Plaque Psoriasis TALTZ was evaluated in a placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis 6 to less than 18 years of age. A total of 171 subjects were studied (115 subjects on TALTZ and 56 subjects on placebo). […]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TALTZ during pregnancy. Pregnant women exposed to TALTZ are encouraged to enroll in the TALTZ Pregnancy Registry by calling 1-800-284-1695. Contact information for the registry is also available on http://www.pregnancyregistry.lilly.com. Risk Summary Available data from the published literature and the pharmacovigilance database with TALTZ use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. 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 during organogenesis 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data An 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 a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys. In a 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 a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a 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 surviving infants from birth through 6 months of age.

8.2 Lactation Risk Summary There are no available 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. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's 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 6 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 6 years of age have not been established.

8.5 Geriatric Use Of the 4204 adult psoriasis subjects exposed to TALTZ, a 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 )] .

Ixekizumab is a 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 a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.