Spevigo Drug Information

is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. SPEVIGO is an interleukin-36 receptor antagonist indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg.

Testing and Procedures

Prior to Treatment Initiation Evaluate patients for active or latent 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 . Complete all age-appropriate vaccinations according to current immunization guidelines prior to initiating SPEVIGO for treatment of GPP .

Important

Administration Information Subcutaneous Use for Treatment of GPP When Not Experiencing a Flare SPEVIGO prefilled syringes are for subcutaneous use for treatment of GPP when not experiencing a flare. When using SPEVIGO 300 mg/2 mL prefilled syringe: If the healthcare professional determines that it is appropriate, a patient 12 years of age or older may self-inject or the caregiver may administer the loading dose and the subsequent doses of SPEVIGO after proper training in subcutaneous injection technique. In pediatric patients 12 years of age and older, administer SPEVIGO under the supervision of an adult.

When using SPEVIGO 150 mg/mL prefilled syringe: If required, the 600 mg subcutaneous loading dose of SPEVIGO is to be administered by a healthcare professional . For subsequent 300 mg doses, if the healthcare professional determines that it is appropriate, a patient 12 years of age or older may self-inject or the caregiver may administer SPEVIGO after proper training in subcutaneous injection technique. In pediatric patients 12 years of age and older, administer SPEVIGO under the supervision of an adult. If a patient experiences a GPP flare while receiving subcutaneous SPEVIGO, the GPP flare may be treated with intravenous SPEVIGO . Intravenous Use for Treatment of GPP Flare SPEVIGO vials are for intravenous use for treatment of GPP flare.

Intravenous infusion of SPEVIGO is only to be administered by a healthcare professional in a healthcare setting. Prepare SPEVIGO intravenous infusion by diluting SPEVIGO single-dose vials . Do not mix SPEVIGO with other medicinal products.

Recommended Subcutaneous Dosage for Treatment of

GPP When Not Experiencing a Flare The recommended dosage of SPEVIGO for treatment of GPP when not experiencing a flare in adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a loading dose of 600 mg followed by 300 mg administered subcutaneously 4 weeks later and every 4 weeks thereafter. Initiating or Reinitiating Subcutaneous SPEVIGO After Treatment of a GPP Flare with Intravenous SPEVIGO Four weeks after treatment of a GPP flare with intravenous SPEVIGO , initiate or reinitiate subcutaneous SPEVIGO for treatment of GPP at a dose of 300 mg administered every 4 weeks. A subcutaneous loading dose is not required following treatment of a GPP flare with intravenous SPEVIGO.

Recommended Intravenous Dosage for Treatment of

GPP Flare The recommended dosage of SPEVIGO for treatment of GPP flare in adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a single 900 mg dose administered by intravenous infusion over 90 minutes. If GPP flare symptoms persist, an additional intravenous 900 mg dose (over 90 minutes) may be administered one week after the initial dose.

Preparation and

Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permits. SPEVIGO is a colorless to slightly brownish-yellow, clear to slightly opalescent solution. Do not use if the solution is cloudy, discolored, or contains large or colored particulates.

Prefilled Syringe (Subcutaneous Use for Treatment of GPP When Not Experiencing a Flare) Before subcutaneous injection, remove SPEVIGO prefilled syringes from the refrigerator and allow SPEVIGO to reach room temperature (15 to 30 minutes) without removing the needle cap. Administer SPEVIGO subcutaneously in the upper thighs or abdomen. Do not inject into areas where the skin is tender, bruised, erythematous, indurated, or scarred.

If more than one injection is needed to achieve the recommended dose, administer each injection one right after the other. Choose a different injection site for each injection, at least 1 inch away from the other injection sites. Alternate between the upper thigh and abdomen injection sites for each complete dose.

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. The SPEVIGO "Instructions for Use" contains more detailed instructions on the preparation and administration of SPEVIGO . Vial (Intravenous Use for Treatment of GPP Flare) Preparation SPEVIGO solution for intravenous infusion must be diluted before use.

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 (two vials of 450 mg/7.5 mL). Mix gently before use.

Use the diluted SPEVIGO solution immediately. 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.

Administration 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. 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.

If the infusion is slowed or temporarily stopped, the total infusion time (including stop time) should not exceed 180 minutes . 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).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions with Intravenous SPEVIGO for Treatment of GPP Flare (Study Effisayil-1) SPEVIGO was studied in Study Effisayil-1, a randomized, double-blind, placebo-controlled study comparing a single intravenous 900 mg dose of SPEVIGO (n=35) with placebo (n=18) in subjects with generalized pustular psoriasis (GPP) 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 . 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 intravenous SPEVIGO group than in the placebo group through Week 1. Table 1 Selected Adverse Reactions Occurring in ≥1% of the Intravenous SPEVIGO Group and More Frequently than in the Placebo Group through Week 1 in Subjects with GPP Flare (Study Effisayil-1) Adverse Reaction Intravenous SPEVIGO N = 35 n (%) Placebo N = 18 n (%) Asthenia and Fatigue 3 1 Headache 3 1 Nausea 2 0 Pruritus and prurigo 2 0 Infusion site hematoma and bruising 2 0 Urinary tract infection 2 0 Bacteremia 1 0 Bacteriuria 1 0 Cellulitis 1 0 Herpes dermatitis and oral herpes 1 0 Upper respiratory tract infection 1 0 Dyspnea 1 0 Eye edema 1 0 Urticaria 1 0 Specific Adverse Reactions Infections The most frequent adverse reactions that occurred in subjects treated with intravenous 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 intravenous SPEVIGO. 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 intravenous 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 intravenous 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%), 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 intravenous dose of open-label rescue SPEVIGO from Week 1 to Week 12 (range 1-3 total doses). Adverse Reactions with Subcutaneous SPEVIGO for Treatment of GPP When Not Experiencing a Flare (Study Effisayil-2) Subcutaneous treatment with SPEVIGO was studied in Study Effisayil-2, a randomized, placebo-controlled, double-blind, parallel group study evaluating three dosages of SPEVIGO or placebo in subjects with generalized pustular psoriasis (GPP). Subjects were randomized (1:1:1:1) to receive a 600 mg loading dose (LD) of SPEVIGO followed by 300 mg every 4 weeks (n=30), one of two other dosages of SPEVIGO, or placebo (n=30) for up to 48 weeks . Subjects ranged in age from 14 to 75 years (mean age was 40 years); 64% of subjects were Asian and 36% were White; 62% of subjects were female.

Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for injection site reaction (including erythema, pain, swelling, induration, urticaria, and warmth at the injection site) was 31.6 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 12.7 for the placebo cohort. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for urinary tract infection was 18 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 0 for the placebo cohort. Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for pruritus was 8.8 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 0 for the placebo cohort.

Regarding the exposure-adjusted incidence rates for subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without a flare, the rate per 100-patient years for arthralgia was 13.3 for the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) compared to 6 for the placebo cohort. For subjects on randomized treatment prior to receiving rescue treatment for flare or completing trial without flare, there were 3 subjects who discontinued subcutaneous SPEVIGO in the subcutaneous SPEVIGO cohort (600 mg LD followed by 300 mg every 4 weeks) due to treatment emergent adverse events of psoriasis compared to no subjects in the placebo cohort who discontinued placebo for any treatment emergent adverse event. Safety In Study Effisayil-2 after flare In Effisayil-2, subjects who experienced a GPP flare and received at least one dose of an open-label single intravenous 900 mg dose of SPEVIGO were treated with open-label subcutaneous SPEVIGO 300 mg.

These subjects (n=19) received subcutaneous dosing at every 12 weeks which could have been increased to every 4 weeks based on GPPPGA total score or pustulation sub score increased by ≥1 from any previous OL maintenance visit. The reported safety profile of open-label subcutaneous SPEVIGO use after treatment of GPP flare with open-label intravenous SPEVIGO use was consistent with the safety profiles of use of SPEVIGO from Trial Effisayil-1 and randomized controlled data from Trial Effisayil-2. Clinical Development of Spesolimab-sbzo Guillain-Barre syndrome Among approximately 835 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 studies for unapproved indications.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of SPEVIGO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Immediate systemic hypersensitivity reactions, including anaphylaxis.

Pregnancy Risk Summary The limited data on the use of SPEVIGO in pregnant women are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. Human IgG is known to cross the placental barrier; therefore, SPEVIGO may be transmitted from the mother to the developing fetus. In an animal reproduction study, intravenous administration of a surrogate antibody against IL36R in mice during the period of organogenesis did not elicit any reproductive toxicity (see Data ). 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 Embryo-fetal development and pre- and postnatal development toxicity studies 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.

Pediatric Use The safety and effectiveness of SPEVIGO for the treatment of GPP have been established in pediatric patients 12 years of age and older and weighing at least 40 kg. Use of SPEVIGO for this indication is supported by data from a randomized, placebo-controlled study which included 6 pediatric subjects 14 to 17 years of age with a history of GPP treated with subcutaneous SPEVIGO (Study Effisayil-2) and evidence from an adequate and well-controlled study of intravenous SPEVIGO in adults with GPP (Study Effisayil-1), with additional pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric subjects 12 years of age and older and weighing 40 kg or more . The safety and effectiveness of SPEVIGO in pediatric patients younger than 12 years of age or in pediatric patients weighing less than 40 kg have not been established.

is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO. Reported hypersensitivity reactions have included drug reaction with eosinophilia and systemic symptoms (DRESS) and anaphylaxis . Severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO