cts treated with placebo [see adverse reactions (6.1) ] . in patients with a chronic infection or a history of recurrent infection, consider the potential risks and expected clinical benefits of treatment prior to prescribing spevigo. treatment with spevigo is not recommended for use in patients with any clinically important active infection until the infection resolves or is adequately treated. instruct patients to seek medical advice if signs or symptoms of clinically important infection occur after treatment with spevigo. 5.2 risk of tuberculosis evaluate patients for tuberculosis (tb) infection prior to initiating treatment with spevigo. do not administer spevigo to patients with active tb infection. consider initiating anti-tb therapy prior to initiating spevigo in patients with latent tb or a history of tb in whom an adequate course of treatment cannot be confirmed. monitor patients for signs and symptoms of active tb during and after spevigo treatment. 5.3 hypersensitivity and infusion-related reactions spevigo-associated hypersensitivity reactions may include immediate reactions such as anaphylaxis and delayed reactions such as drug reaction with eosinophilia and systemic symptoms (dress). drug reaction with eosinophilia and systemic symptoms (dress) has been reported in clinical trials with spesolimab-sbzo in subjects with gpp [see adverse reactions (6.1) ] . if a patient develops signs of anaphylaxis or other serious hypersensitivity, discontinue spevigo immediately and initiate appropriate treatment [see contraindications (4) ] . if a patient develops mild or moderate infusion-related reactions, stop spevigo infusion and consider appropriate medical therapy (e.g., systemic antihistamines and/or corticosteroids). upon resolution of the reaction, the infusion may be restarted at a slower infusion rate with gradual increase to complete the infusion. 5.4 vaccinations avoid use of live vaccines in patients treated with spevigo. no specific studies have been conducted in spevigo-treated patients who have recently received live viral or live bacterial vaccines.

dy, discolored, or contains large or colored particulates. preparation use aseptic technique to prepare the solution for infusion. draw and discard 15 ml from a 100 ml container of sterile 0.9% sodium chloride injection. slowly replace with 15 ml of spevigo (complete content from two vials of 450 mg/7.5 ml). mix gently before use. use the diluted spevigo solution immediately. administration do not mix spevigo with other medicinal products. administer spevigo as a continuous intravenous infusion through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron) over 90 minutes. if the infusion is slowed or temporarily stopped, the total infusion time (including stop time) should not exceed 180 minutes [see warnings and precautions (5.3) ] . a pre-existing intravenous line may be used for administration of spevigo. the line must be flushed with sterile 0.9% sodium chloride injection prior to and at the end of infusion. no other infusion should be administered in parallel via the same intravenous access. no incompatibilities have been observed between spevigo and infusion sets composed of polyvinylchloride (pvc), polyethylene (pe), polypropylene (pp), polybutadiene and polyurethane (pur), and in-line filter membranes composed of polyethersulfone (pes, neutral and positively charged) and positively charged polyamide (pa). storage of diluted solution if not administered immediately, refrigerate the diluted solution at 2°c to 8°c (36°f to 46°f) for no more than 4 hours. protect from light. 2.3 testing and procedures prior to treatment initiation evaluate patients for tuberculosis (tb) infection. spevigo initiation is not recommended in patients with active tb infection. consider initiating treatment of latent tb prior to initiation of spevigo [see warnings and precautions (5.2) ] .

in subjects with generalized pustular psoriasis flare. subjects in either treatment group who continued to experience flare symptoms at week 1 were eligible to receive a single open-label intravenous dose of 900 mg of spevigo (second dose and first dose for subjects in the spevigo and placebo groups, respectively). at week 1, 12 (34%) subjects and 15 subjects (83%) in the spevigo and placebo groups, respectively, received open-label spevigo. after week 1 to week 12, subjects in either treatment group whose gpp flare reoccurred after achieving a clinical response were eligible to receive a single open-label rescue intravenous dose of 900 mg of spevigo, with a maximum of 3 total doses of spevigo throughout the study. six subjects received a single open-label rescue dose of spevigo. thirty-six subjects received 1 dose of spevigo, 13 subjects received 2 doses of spevigo, and 2 subjects received 3 doses of spevigo throughout the study [see clinical studies (14) ] . subjects ranged in age from 21 to 69 years (mean age of 43 years); 45% were white and 55% were asian; and 68% were female. table 1 summarizes selected adverse reactions that occurred at a rate of at least 1% and at a higher rate in the spevigo group than in the placebo group through week 1. table 1 selected adverse reactions occurring in ≥1% of the spevigo group and more frequently than in the placebo group through week 1 (study effisayil-1) adverse reaction spevigo n = 35 n (%) placebo n = 18 n (%) asthenia and fatigue 3 (9) 0 nausea and vomiting 3 (9) 1 (6) headache 3 (9) 1 (6) pruritus and prurigo 2 (6) 0 infusion site hematoma and bruising 2 (6) 0 urinary tract infection 2 (6) 0 bacteremia 1 (3) 0 bacteriuria 1 (3) 0 cellulitis 1 (3) 0 herpes dermatitis and oral herpes 1 (3) 0 upper respiratory tract infection 1 (3) 0 dyspnea 1 (3) 0 eye edema 1 (3) 0 urticaria 1 (3) 0 specific adverse reactions infections the most frequent adverse reactions that occurred in subjects treated with spevigo were infections. during the 1-week placebo-controlled period in study effisayil-1, infections were reported in 14% of subjects treated with spevigo compared with 6% of subjects treated with placebo. serious infection (urinary tract infection) was reported in 1 subject (3%) treated with spevigo and no subjects treated with placebo. infections observed through week 1 in study effisayil-1 in subjects treated with spevigo were mild (29%) to moderate (71%). drug reaction with eosinophilia and systemic symptoms (dress) two cases of dress were reported in study effisayil-1 in subjects with gpp who were treated with spesolimab-sbzo. regiscar dress validation scoring (with the following categories: "no", "possible", "probable", or "definite" dress) was applied to the reported cases. reported cases were assessed as "no dress" and "possible dress". safety through week 12 and 17 in study effisayil-1, additional adverse reactions that occurred through week 12 in subjects treated with 1 single dose of randomized spevigo were mild to moderate infections: device-related infection (3%), subcutaneous abscess (3%), furuncle (3%), and influenza (3%). additional adverse reactions that occurred through week 17 in subjects treated with a single dose of open-label spevigo at week 1 (second dose and first dose for subjects in the spevigo and placebo groups, respectively) were mild to moderate infections: otitis externa (7%), vulvovaginal candidiasis (4%), vulvovaginal mycotic infection (4%), and latent tuberculosis (4%), diarrhea (11%), and gastritis (4%). no new adverse reactions were identified for up to 16 weeks in subjects treated with a single dose of open-label rescue spevigo from week 1 to week 12 (range 1-3 total doses). clinical development guillain-barre syndrome among approximately 750 subjects exposed to spesolimab-sbzo during clinical development, guillain-barre syndrome (gbs) was reported in 3 subjects who received various doses of spesolimab-sbzo via various methods of administration in clinical trials for unapproved indications. injection site reactions during clinical development, injection site reactions (including injection site erythema, injection site swelling, injection site pain, injection site induration, and injection site warmth) occurred with spesolimab-sbzo.

s were performed in mice using a surrogate mouse specific il36r antagonist monoclonal antibody. in the embryo-fetal development study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly during the period of organogenesis. the surrogate was not associated with embryo-fetal lethality or fetal malformations. in the pre- and postnatal development toxicity study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly from gestation day 6 through lactation day 18. there were no maternal effects observed. there were no treatment-related effects observed on postnatal developmental, neurobehavioral, or reproductive performance of offspring. 8.2 lactation risk summary there are no data on the presence of spesolimab-sbzo in human milk, the effects on the breastfed infant, or the effects on milk production. spesolimab-sbzo is a monoclonal antibody and is expected to be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for spevigo and any potential adverse effects on the breastfed infant from spevigo or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of spevigo in pediatric patients have not been established. 8.5 geriatric use in study effisayil-1, 2 (6%) of spevigo-treated subjects were 65 to 74 years of age and no subjects were 75 years of age or older. clinical studies of spevigo did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects.

a surrogate mouse specific il36r antagonist monoclonal antibody. in the embryo-fetal development study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly during the period of organogenesis. the surrogate was not associated with embryo-fetal lethality or fetal malformations. in the pre- and postnatal development toxicity study, the surrogate was administered intravenously at doses up to 50 mg/kg to pregnant female mice twice weekly from gestation day 6 through lactation day 18. there were no maternal effects observed. there were no treatment-related effects observed on postnatal developmental, neurobehavioral, or reproductive performance of offspring.

4750 (4510, 4970) mcg ∙ day/ml and 238 (218, 256) mcg/ml, respectively. spesolimab-sbzo auc increased dose-proportionally from 0.3 to 20 mg/kg, and cl and terminal half-life were independent of dose. distribution based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 l. elimination metabolism the metabolic pathway of spesolimab-sbzo has not been characterized. as a humanized igg1 monoclonal antibody, spesolimab-sbzo is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous igg. excretion in the linear dose range (0.3 to 20 mg/kg), based on the population pk model, spesolimab-sbzo clearance (95% ci) in a typical gpp patient without ada, weighing 70 kg was 0.184 (0.175, 0.194) l/day. the terminal half-life was 25.5 (24.4, 26.3) days. specific populations age, gender, and race based on population pharmacokinetic analyses, age, gender, and race did not have an effect on the pharmacokinetics of spesolimab-sbzo. hepatic and renal impairment as a monoclonal antibody, spesolimab-sbzo is not expected to undergo hepatic or renal elimination. no formal study of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab-sbzo was conducted. body weight spesolimab-sbzo concentrations were lower in subjects with higher body weight. the clinical impact of body weight on spesolimab-sbzo plasma concentrations is unknown. drug interaction studies no formal drug interactions studies have been conducted with spesolimab-sbzo. 12.6 immunogenicity the observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of spesolimab-sbzo or of other spesolimab products. in subjects with gpp treated with spevigo in effisayil-1, adas formed with a median onset of 2.3 weeks. following administration of 900 mg intravenous spevigo, (12/50) 24% of subjects had a maximum ada titer greater than 4000 and were neutralizing antibody-positive by the end of the trial (weeks 12 to 17). females appeared to have higher immunogenicity response; the percentage of subjects with ada titer greater than 4000 was 30% in females, and 12% in males, respectively. anti-drug antibody effects on pharmacokinetics in subjects with ada titers below 4000, there was no apparent impact on spesolimab-sbzo pharmacokinetics. in most subjects with ada titer values greater than 4000, plasma spesolimab-sbzo concentrations were significantly reduced after reaching this ada titer. there are limited data on the impact of adas on safety and efficacy upon retreatment as the majority of subjects did not experience a subsequent, new flare in an open-label extension trial.

ar dose range (0.3 to 20 mg/kg), based on the population pk model, spesolimab-sbzo clearance (95% ci) in a typical gpp patient without ada, weighing 70 kg was 0.184 (0.175, 0.194) l/day. the terminal half-life was 25.5 (24.4, 26.3) days. specific populations age, gender, and race based on population pharmacokinetic analyses, age, gender, and race did not have an effect on the pharmacokinetics of spesolimab-sbzo. hepatic and renal impairment as a monoclonal antibody, spesolimab-sbzo is not expected to undergo hepatic or renal elimination. no formal study of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab-sbzo was conducted. body weight spesolimab-sbzo concentrations were lower in subjects with higher body weight. the clinical impact of body weight on spesolimab-sbzo plasma concentrations is unknown. drug interaction studies no formal drug interactions studies have been conducted with spesolimab-sbzo.

the double-blind portion of the study. the study population consisted of 32% men and 68% women. the mean age was 43 years (range: 21 to 69 years); 55% of subjects were asian and 45% were white. most subjects included in the study had a gpppga pustulation sub score of 3 (43%) or 4 (36%), and subjects had a gpppga total score of 3 (81%) or 4 (19%). in this study, 25% of subjects had been previously treated with biologic therapy for gpp. at baseline acute flare, of the subjects with white blood cell count (wbc) assessments, 45% and 31% of subjects in the spevigo and placebo groups, respectively, had (wbc) >12 × 10 9 /l. seventeen percent and 11% of subjects in the spevigo and placebo groups, respectively, had temperature >38° celsius. of the subjects with wbc assessments, 12% and 6% of subjects in the spevigo and placebo groups, respectively, had both wbc >12 × 10 9 /l and temperature >38° celsius [see adverse reactions (6.1) ]. the primary endpoint of the study was the proportion of subjects with a gpppga pustulation sub score of 0 (indicating no visible pustules) at week 1 after treatment. the results of the primary endpoint are presented in table 2. table 2 gpppga pustulation sub score at week 1 in study effisayil-1 spevigo (n=35) placebo (n=18) gpppga = generalized pustular psoriasis physician global assessment subjects achieving a gpppga pustulation sub score of 0, n (%) 19 (54) 1 (6) risk difference versus placebo, % (95% ci) 49 (21, 67) in study effisayil-1, subjects in either treatment group who continued to experience flare symptoms at week 1 were eligible to receive a single open-label intravenous dose of 900 mg of spevigo (second dose and first dose for subjects in the spevigo and placebo groups, respectively). at week 1, 12 (34%) subjects and 15 subjects (83%) in the spevigo and placebo groups, respectively, received open-label spevigo. in subjects who were randomized to spevigo and received an open-label dose of spevigo at week 1, 5 (42%) subjects had a gpppga pustulation sub score of 0 at week 2 (one week after their second dose of spevigo). this study did not include sufficient numbers of subjects to determine if there are differences in response according to biological sex, age, race, baseline gpppga pustulation sub score, and baseline gpppga total score.