SPEVIGO 450mg concentrate for solution for infusion medication leaflet

Spevigo 450 mg concentrate for solution for infusion

Each vial contains 450 mg spesolimab in 7.5 mL.

Each mL of concentrate for solution for infusion contains 60 mg spesolimab.

After dilution, each mL of the solution contains 9 mg spesolimab (see section 6.6).

Spesolimab is produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Clear to slightly opalescent, colourless to slightly brownish-yellow solution.

Spevigo is indicated for the treatment of generalised pustular psoriasis (GPP) flares in adults andadolescents from 12 years of age as monotherapy.

Treatment should be initiated and supervised by physicians experienced in the management of patientswith inflammatory skin diseases.

Treatment can be initiated with the pre-filled syringe as a subcutaneous injection to prevent GPP flares(see Spevigo 150 mg solution for injection in pre-filled syringe Summary of Product Characteristics)or with an intravenous dose of spesolimab to treat a GPP flare.

The recommended dose for GPP flare treatment in adults and adolescents from 12 years of age andweighing at least 40 kg is a single dose of 900 mg (two vials of 450 mg) administered as anintravenous infusion. If flare symptoms persist, an additional 900 mg dose may be administered1 week after the initial dose.

Spevigo has not been studied in patients weighing less than 40 kg. Based on pharmacokineticmodelling and simulation, the recommended dose for adolescents from 12 years of age weighing≥ 30 and < 40 kg is a single dose of 450 mg (one vial of 450 mg) administered as an intravenousinfusion (see section 5.2). If flare symptoms persist, an additional 450 mg dose (one vial of 450 mg)may be administered 1 week after the initial dose.

Clinical data for treatment of subsequent flares is very limited (see section 4.4).

Clinical data for concomitant use of other GPP treatments with spesolimab is limited. Spesolimabshould not be used in combination with other GPP treatments, e.g. systemic immunosuppressants, totreat a flare (see sections 4.4 and 4.5).

No dose adjustment is required.

Spesolimab has not been formally studied in these patient populations. These conditions are generallynot expected to have any clinically relevant impact on the pharmacokinetics of monoclonal antibodiesand no dose adjustments are considered necessary.

The safety and efficacy of spesolimab in children less than 12 years of age has not been established.

No data are available.

This medicinal product is for intravenous infusion only. It should not be administered as anintravenous push or bolus.

Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, it is administered as acontinuous intravenous infusion through an intravenous line containing a sterile, non-pyrogenic, lowprotein binding in-line filter (pore size of 0.2 micron) over 90 minutes. No other infusion should beadministered in parallel via the same intravenous access.

In the event that the infusion is slowed or temporarily stopped, the total infusion time (including stoptime) should not exceed 180 minutes (see section 4.4).

For instructions on dilution of the medicinal product before administration, see section 6.6.

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients listed insection 6.1 (see section 4.4).

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Spesolimab may increase the risk of infections (see section 4.8).

In patients with a chronic infection or a history of recurrent infection, the potential risks and expectedclinical benefits of treatment should be considered prior to prescribing spesolimab. Treatment withspesolimab should not be initiated in patients with any clinically important active infection until theinfection resolves or is adequately treated. Patients should be instructed to seek medical advice if signsor symptoms of clinically important infection occur after treatment with spesolimab.

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment with spesolimab, patients should be evaluated for tuberculosis (TB)infection. Spesolimab is contraindicated to patients with active TB infection (see section 4.3).

Anti-TB therapy should be considered prior to initiating spesolimab treatment in patients with latent

TB, a history of TB or possible previous exposure to people with active tuberculosis in whom anadequate course of treatment cannot be confirmed. After spesolimab treatment, patients should bemonitored for signs and symptoms of active TB.

Hypersensitivity and infusion-related reactions

Hypersensitivity and infusion-related reactions may occur with monoclonal antibodies such asspesolimab. Hypersensitivity may include immediate reactions such as anaphylaxis and delayedreactions such as drug reaction with eosinophilia and systemic symptoms (DRESS).

Immediate hypersensitivity reactions, including anaphylactic reactions have been reported in patientstreated with spesolimab (see section 4.8).

If a patient develops signs of anaphylaxis or other serious hypersensitivity, spesolimab treatmentshould be discontinued immediately and appropriate treatment should be initiated (see section 4.3).

If a patient develops mild or moderate hypersensitivity during an intravenous infusion or otherinfusion-related reactions, treatment should be stopped and appropriate medical therapy should beconsidered (e.g., systemic anti-histamines and/or corticosteroids). Upon resolution of the reaction, theinfusion may be restarted at a slower infusion rate with gradual increase to complete the infusion (seesection 4.2).

Use in patients with an immediate, life-threatening GPP flare

There is no experience from the use of spesolimab in patients with an immediate, life-threatening flareof GPP or a flare requiring intensive care treatment.

Concomitant use with other GPP treatments

The safety and efficacy of spesolimab in combination with immunosuppressants, including biologics,have not been evaluated systematically (see section 4.5). In the GPP flare treatment clinical study,there was a washout period for most other treatments (biologics, other systemic immunomodulatingtreatments), while some treatments were discontinued before initiation of spesolimab treatment withno washout period required (methotrexate, cyclosporine, retinoids, topical treatments) (seesection 5.1).

Concomitant use of other immunosuppressants and spesolimab is not recommended. At initiation ofspesolimab treatment, other GPP treatments should be stopped and other treatments (e.g. withsystemic immunosuppressants) should not be used concomitantly to treat the flare.

Very limited efficacy and safety data are available for re-treatment with spesolimab for a subsequentnew flare. In Effisayil 1, five patients received re-treatment for a subsequent new flare and werefollowed up for a minimum of 8 weeks.

It is unknown whether spesolimab affects the efficacy of vaccines.

No data are available on the potential secondary transmission of infection by live vaccines in patientsreceiving spesolimab (see section 4.5). The interval between live vaccinations and initiation ofspesolimab therapy should be at least 4 weeks. Live vaccines should not be administered for at least16 weeks after treatment with spesolimab.

For additional information regarding immunisation prior starting the treatment for preventing GPPflares, see Spevigo 150 mg solution for injection in pre-filled syringe Summary of Product

Characteristics.

The potential for peripheral neuropathy with spesolimab is unknown. Cases of peripheral neuropathyhave been reported in clinical trials with spesolimab. Physicians should be vigilant for symptomspotentially indicative of new-onset peripheral neuropathy.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium free’.

No interaction studies have been performed. In GPP patients, spesolimab is not expected to causecytokine-mediated CYP interactions as a perpetrator.

Live vaccines should not be given concurrently with spesolimab (see section 4.4).

There is limited experience from the concomitant use of spesolimab with immunosuppressants in GPPpatients (see section 4.4).

There are no or limited data from the use of spesolimab in pregnant women. Non-clinical studies usinga surrogate, mouse specific anti-IL36R monoclonal antibody do not indicate direct or indirect harmfuleffects with respect to reproductive toxicity (see section 5.3). Human immunoglobulin (IgG) is knownto cross the placental barrier. As a precautionary measure, it is preferable to avoid the use ofspesolimab during pregnancy.

No data are present on excretion of spesolimab in human milk. In humans, excretion of IgG antibodiesin milk occurs during the first few days after birth, which is decreasing to low concentrations soonafterwards. Consequently, transfer of IgG antibodies to the newborns through milk, may happenduring the first few days. In this short period, a risk to the breastfed child cannot be excluded.

Afterwards, spesolimab can be used during breastfeeding if clinically needed. If treatment wasdiscontinued before the last trimester of pregnancy, breastfeeding can be started immediately afterbirth.

There are no data available on the effect of spesolimab on human fertility. Studies in mice using asurrogate, mouse specific anti-IL36R monoclonal antibody, do not indicate direct or indirect harmfuleffects with respect to fertility from antagonism of IL36R (see section 5.3).

Spevigo has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions are infections (17.1%) with urinary tract infectionreported as serious in 1 patient (2.9%) (see Description of selected adverse reactions).

Table 1 provides a list of the adverse reactions reported in clinical trials as well as in the post-marketing setting. The adverse reactions are listed by MedDRA System Organ Class (SOC) andfrequency category using the following convention: very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), notknown (frequency cannot be estimated from the available data).

Table 1: Adverse reactions

System organ class Adverse reactions Frequencies

Infections and infestations Infectiona) Very common

Immune system disorders Hypersensitivityb) Not known

Skin and subcutaneous tissue Pruritus Commondisorders

General disorders and Injection site reactions Very commonc)administration site conditions Fatigue Commona) The most commonly reported infections were Urinary tract infection (Common) and Upperrespiratory tract infection (Very common)b) Derived from open-label extension trials and post-marketing experiencec) Not reported in Effisayil 1

During the 1-week placebo-controlled period in Effisayil 1, infections were reported in 17.1% ofpatients treated with spesolimab compared with 5.6% of patients treated with placebo. In Effisayil 1,serious infection (urinary tract infection) was reported in 1 patient (2.9%) in the spesolimab group andno patient in the placebo group. During the placebo-controlled period of up to 48 weeks in Effisayil 2,infections were reported in 33.3% of patients treated with Spevigo and 33.3% of patients treated withplacebo. In Effisayil 2, serious infections were reported in 3 patients (3.2%) in the Spevigo group andno patient in the placebo group.

Infections observed in clinical trials with spesolimab were generally mild to moderate with no distinctpattern regarding pathogen or type of infection.

Hypersensitivity comprises immediate systemic hypersensitivity reactions, including anaphylacticreaction. Immediate systemic hypersensitivity reactions have been reported in open-label extensiontrials and the post-marketing setting.

Injection site reactions include erythema, swelling, pain, induration, warmth, exfoliation, papule,pruritus, rash, and urticaria at the injection site. Injection site reactions were typically mild to moderatein severity.

The available data for adolescents are limited. 8 adolescent patients with GPP, 14 to 17 years of age,were enrolled in trial Effisayil 2 (see section 5.1). Overall, the safety profile in adolescents treatedwith spesolimab (n = 6) was consistent with the safety profile in adults and no new safety concernshave been identified.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of spesolimab administered in clinical trials was 1 200 mg intravenously orsubcutaneously. Adverse reactions observed in subjects receiving single or repeated doses up to1 200 mg were consistent with the known safety profile of spesolimab.

In the event of overdose, it is recommended that the patient be monitored for any signs or symptomsof adverse reactions and symptomatic treatment be instituted as appropriate.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC22

Spesolimab is a humanised antagonistic monoclonal immunoglobulin G1 (IgG1) antibody blockinghuman interleukin 36 receptor (IL36R) signalling. Binding of spesolimab to IL36R prevents thesubsequent activation of IL36R by its ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory pathways.

Following treatment with intravenous spesolimab in patients with GPP, reduced levels of C-reactiveprotein (CRP), IL6, T helper cell (Th1/Th17) mediated cytokines, keratinocyte-mediated inflammationmarkers, neutrophilic mediators, and proinflammatory cytokines were observed in serum and skin atweek 1 compared to baseline and were associated with a decrease in clinical severity. These reductionsin biomarkers became more pronounced at the last measurement at week 8 in Effisayil 1.

Effisayil 1 (1368-0013)

A randomised, double-blind, placebo-controlled study (Effisayil 1) was conducted to evaluate theclinical efficacy and safety of spesolimab in adult patients with flares of Generalised Pustular Psoriasis(GPP), as diagnosed per European Rare And Severe Psoriasis Expert Network (ERASPEN) criteria,regardless of IL36RN mutation status. Patients were randomised if they had a flare of GPP ofmoderate-to-severe intensity, as defined by a Generalised Pustular Psoriasis Physician Global

Assessment (GPPGA) total score (which ranges from 0 [clear] to 4 [severe]) of at least 3 (moderate),presence of fresh pustules (new appearance or worsening of pustules), GPPGA pustulation sub scoreof at least 2 (mild), and at least 5% of body surface area covered with erythema and the presence ofpustules. Patients were required to discontinue systemic and topical therapy for GPP prior torandomisation (see Table 2). Patients with an immediate life-threatening flare of GPP or requiringintensive care treatment were excluded from the study.

Table 2: Minimum time between discontinuation of restricted medications for GPP treatment andrandomisation (Effisayil 1)*

Duration of washout period Medications or class of medications2 months adalimumab, alemtuzumab, briakinumab, brodalumab, efalizumab,guselkumab, infliximab, ixekizumab, natalizumab, risankizumab,rituximab, secukinumab, tildrakizumab, ustekinumab, visilizumab,investigational products for psoriasis (non biologics)6 weeks etanercept30 days systemic immunomodulatory treatments (e.g. corticosteroids**,cyclophosphamide), tofacitinib, apremilast; other systemic psoriasistreatments (e.g. fumarates), any investigational device or product(excluding psoriasis products); photochemotherapy (e.g. PUVA);granulocytes and monocytes adsorptive apharesis7 days anakinra

* No treatment initiation 1 week prior to randomisation: phototherapy (e.g. UVA, UVB), topical treatment forpsoriasis or any other skin condition (e.g. topical corticosteroids, topical vitamin D analogues, tar, anthralin,topical retinoids); no treatment initiation 2 weeks prior to randomisation, no dose escalation within 2 weeks priorto randomisation, and had to be discontinued prior to receiving the first dose: methotrexate, cyclosporine,retinoids.

** No restriction on inhaled corticosteroids to treat asthma or corticosteroid drops administered in the eye or ear.

The primary endpoint of the study was the proportion of patients with a GPPGA pustulation sub scoreof 0 (indicating no visible pustules) at week 1 after treatment. The key secondary endpoint of the studywas the proportion of patients with a GPPGA total score of 0 or 1 (clear or almost clear skin) atweek 1. For the GPPGA pustulation sub score of 0 and the GPPGA total score of 0/1, non-responderimputation was used to handle the occurrence of escape (treatment at the investigator’s choice if thedisease worsened) and rescue (single 900 mg dose of intravenous spesolimab) medication use andmissing data.

A total of 53 patients were randomised (2:1) to receive a single intravenous dose of 900 mgspesolimab (n = 35) or placebo (n = 18). Patients in either treatment arm who still experienced flaresymptoms at week 1 were eligible to receive a single intravenous dose of open-label 900 mgspesolimab, resulting in 12 patients (34%) in the spesolimab arm receiving a second dose ofspesolimab and 15 patients (83%) in the placebo arm receiving one dose of spesolimab on day 8. Inaddition, 6 patients (4 spesolimab arm; 2 placebo arm) received flare treatment with a single 900 mgdose of intravenous spesolimab for reoccurrence of a flare after day 8.

The study population consisted of 32% men and 68% women. The mean age was 43 (range: 21 to69) years; 55% of patients were Caucasian and 45% were Asian. Most patients included in the studyhad a GPPGA pustulation sub score of 3 (43%) or 4 (36%), and patients had a GPPGA total score of3 (81%) or 4 (19%). 24.5% of patients had been previously treated with biologic therapy for GPP.

Primary and key secondary efficacy

At week 1, there was a statistically significant difference in the proportion of patients achieving a

GPPGA pustulation sub score of 0 (indicating no visible pustules) and GPPGA total score of 0 or 1(clear or almost clear skin) in the spesolimab arm compared with placebo (see Table 3).

Table 3: GPPGA pustulation sub score and GPPGA total score at week 1 (Effisayil 1)

Placebo Spesolimab 900 mg i.v.

Number of Patients analysed 18 35

Patients achieving a GPPGA pustulation sub 1 (5.6) 19 (54.3)score of 0, n (%)p-value* 0.0004

Patients achieving a GPPGA total score of 0 2 (11.1) 15 (42.9)or 1, n (%)p-value* 0.0118

GPPGA = Generalised Pustular Psoriasis Physician Global Assessment; i.v. = intravenous

* One-sided p-value

For both the primary and the key secondary endpoint, treatment effect was observed for all patientsregardless of the IL36RN mutation status.

Effisayil 2 (1368-0027)

A randomised, double-blind, placebo-controlled phase II b study (Effisayil 2) evaluated the efficacyand safety of spesolimab for subcutaneous administration in adult and adolescent patients with ahistory of GPP, as diagnosed per ERASPEN criteria, regardless of IL36RN mutation status, and withat least two GPP flares of moderate-to-severe intensity in the past. Patients were randomised if theyhad a GPPGA total score of 0 or 1 at screening and randomisation. Patients were required todiscontinue systemic and topical therapy for GPP prior to or at randomisation. These patients musthave had a history of flaring while on concomitant treatment for GPP or a history of flaring upon dosereduction or discontinuation of these concomitant medications.

The primary endpoint of the study was the time to the first GPP flare up to week 48 (defined by a

GPPGA pustulation subscore of ≥ 2 and an increase in GPPGA total score by ≥ 2 from baseline). Thekey secondary endpoint of the study was the occurrence of at least one GPP flare up to week 48.

Additional secondary endpoints at week 48 were the time to the first worsening of Psoriasis Symptom

Scale (PSS) and Dermatology Quality of Life Index (DLQI) defined as a 4-point increase in total scorefrom baseline.

A total of 123 patients were randomised (1:1:1:1) to receive one of the four treatments (see Table 4).

Table 4: Treatment arms in Effisayil 2

Loading dose Subsequent dosesspesolimab 600 mg subcutaneously 300 mg subcutaneously every 4 weeksspesolimab 600 mg subcutaneously 300 mg subcutaneously every 12 weeksspesolimab 300 mg subcutaneously 150 mg subcutaneously every 12 weeks

Placebo subcutaneous treatment subcutaneous treatment every 4 weeks

The study population consisted of 38.2% men and 61.8% women. The mean age was 40.4 (range:

14 to 75) years with 8 (6.5%) adolescent patients (2 per treatment arm); 64.2% of patients were Asianand 35.8% were Caucasian. Patients included in the study had a GPPGA pustulation sub score of1 (28.5%) or 0 (71.5%), and patients had a GPPGA total score of 1 (86.2%) or 0 (13.8%). At the timeof randomisation, 74.8% of patients were treated with systemic therapy for GPP, which wasdiscontinued at the start of the randomised study treatment.

While 3 dosing regimens were studied in Effisayil 2, the recommended dosing regimen for GPP flareprevention is a subcutaneous loading dose of 600 mg spesolimab followed by 300 mg subcutaneoustreatment administered every 4 weeks (see section 4.2). The results summarised below are those forthe recommended dosing regimen.

Patients who experienced a flare were eligible to receive up to two open-label, intravenous doses of900 mg spesolimab (see section 4.2). 2 (6.7%) patients in the spesolimab arm for the recommendeddose and 15 (48.4%) patients in the placebo arm received intravenous flare treatment.

Treatment with the recommended spesolimab dose compared to placebo resulted in statisticallysignificant improvement based on the primary and key secondary endpoint (see Table 5).

Table 5: Time to the first GPP flare and occurrence of at least one GPP flare up to week 48(Effisayil 2)

Recommended spesolimab

Placebodose

Number of patients analysed, N 31 30

Patients with GPP flares, N (%)* 16 (51.6) 3 (10.0)

Hazard ratio (HR)** for the time to the 0.16first flare vs placebo (95% CI) (0.05, 0.54)p-value*** 0.0005

Risk difference for GPP flare -39.0%occurrence vs placebo (95% CI) (-62.1, -15.9)p-value**** 0.0013

* The use of intravenous spesolimab treatment or investigator-prescribed standard of care to treat GPPworsening were considered as onset of GPP flare

** Cox regression model stratified by the use of systemic GPP medications at randomisation

*** Log-rank test stratified by the use of systemic GPP medications at randomisation, one-sided p-value

**** Cochran-Mantel-Haenszel test after multiple imputation, stratified by the use of systemic GPP medicationsat randomisation, one-sided p-value

The efficacy of the subcutaneous recommended spesolimab dose compared with placebo was observedshortly after randomisation and was maintained up to week 48 (see Figure 1).

Figure 1: Time to the first GPP flare up to week 48 (Effisayil 2)

For both primary and key secondary endpoint, treatment effect was observed for all patients regardlessof the IL36RN mutation status.

One adolescent patient in the placebo arm received investigator-prescribed standard of care to treat

GPP worsening and was considered to have a GPP flare. No adolescent patient in the recommendedspesolimab dose arm experienced a GPP flare.

The prevention of GPP worsening in terms of PSS, and DLQI was also observed, as shown by thehazard ratios for PSS 0.42 (95% CI 0.20, 0.91) and for DLQI 0.26 (95% CI 0.11, 0.62).

In patients with GPP treated with intravenous spesolimab in Effisayil 1, 46% of patients developed

ADAs. A majority of ADA-positive subjects also developed neutralising antibodies. In Effisayil 2,following multiple subcutaneous doses of spesolimab, 41% of the patients developed ADAs. Amajority of ADA-positive subjects also developed neutralising antibodies.

Clearance of spesolimab increased along with increasing ADA titers.

As the majority of patients did not experience a subsequent new flare in Effisayil 1, the data onre-treatment of patients with ADA (n = 4) is limited. It is currently unknown if there is a correlationbetween the presence of ADA to spesolimab and maintenance of efficacy for flare treatment. Aftersubcutaneous administration of spesolimab in Effisayil 2, there was no apparent impact of ADApresence on efficacy or safety.

The European Medicines Agency has waived the obligation to submit the results of studies with

Spevigo in the paediatric population younger than 12 years of age in the treatment of generalisedpustular psoriasis (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

A population pharmacokinetic model was developed based on data collected from healthy subjects,patients with GPP and patients with other diseases. After a single intravenous dose of 900 mg, thepopulation PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical ADA-negativepatient with GPP were 4 750 (4 510, 4 970) µg·day/mL and 238 (218, 256) µg/mL, respectively. Aftera 600 mg subcutaneous loading dose of spesolimab followed by 300 mg spesolimab subcutaneouslyevery 4 weeks, the mean (CV%) steady-state trough concentration ranged from 33.4 µg/mL (37.6%) to42.3 µg/mL (43.0%).

Following subcutaneous single dose administration of spesolimab in healthy volunteers, peak plasmaconcentrations were achieved between 5.5 to 7.0 days after dosing. After subcutaneous administrationin the abdomen, absolute bioavailability was slightly higher at higher doses with estimated values of58%, 65%, and 72% at 150 mg, 300 mg, and 600 mg, respectively. Based on limited data, absolutebioavailability in the thigh was approximately 85% following a subcutaneous dose of 300 mgspesolimab.

Based on the population pharmacokinetic analysis, the typical volume of distribution at steady statewas 6.4 L.

The metabolic pathway of spesolimab has not been characterised. As a humanised IgG1 monoclonalantibody, spesolimab is expected to be degraded into small peptides and amino acids via catabolicpathways in a manner similar to endogenous IgG.

In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab clearance(95% CI) in a typical ADA-negative patient with GPP, weighing 70 kg was 0.184 L/day. Theterminal-half-life was 25.5 days.

When administered intravenously, spesolimab exhibited linear pharmacokinetics with dose-proportional increase in exposure across single dose ranges of 0.3 to 20 mg/kg. Both clearance (CL)and terminal half-life were independent of dose. Following subcutaneous single dose administration,spesolimab exposure increased slightly more than dose-proportionally across the dose range of 150 mgto 600 mg due to slightly increased bioavailability at higher doses.

Spesolimab concentrations were lower in subjects with higher body weight and higher in subjects withlower body weight. Spesolimab has not been studied in patients with GPP weighing more than 164 kg.

Based on pharmacokinetic modelling and simulation, the recommended dose for adolescents from12 years of age weighing ≥ 30 and < 40 kg is half the recommended dose than for adults andadolescents from 12 years of age and weighing at least 40 kg (see section 4.2).

The exposure in patients weighing ≥ 30 and < 40 kg receiving the reduced dosing regimen is expectedto be comparable with those observed in GPP studies.

Elderly/gender/race

Based on population pharmacokinetic analyses, age, gender and race do not have a clinically relevanteffect on the pharmacokinetics of spesolimab.

As a monoclonal antibody, spesolimab is not expected to undergo hepatic or renal elimination. Noformal trial of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab wasconducted.

Population PK analysis did not identify mild hepatic impairment or mild or moderate renal impairmentas having an influence on the systemic exposure of spesolimab.

The pharmacokinetics of spesolimab in paediatric patients below the age of 14 years have not beenstudied.

The plasma pharmacokinetics of spesolimab observed in adolescents were consistent with thatobserved in adults.

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies.

Developmental and reproductive toxicity

Non-clinical studies conducted in mice using a surrogate antibody directed towards murine IL36R donot indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetaldevelopment or fertility.

Genotoxicity studies have not been conducted with spesolimab.

Carcinogenicity and mutagenicity studies have not been conducted with spesolimab.

Sodium acetate trihydrate (E262)

Glacial acetic acid (E260) (for pH adjustment)

Sucrose

Arginine hydrochloride

Polysorbate 20 (E432)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years.

From a microbiological point of view, once opened, the medicinal product should be diluted andinfused immediately.

Chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at2 °C to 30 °C.

From a microbiological point of view, the diluted solution for infusion should be used immediately. Ifnot used immediately, in use storage conditions are the responsibility of the user and would normallynot be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validatedaseptic conditions. For the time between preparation and start of administration the solution forinfusion should be protected from light following local standard procedures.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

Prior to use, the unopened vial may be kept at temperatures up to 30 °C for up to 24 hours, if stored inthe original package in order to protect from light.

For storage conditions after opening and dilution of the medicinal product, see section 6.3.

7.5 mL concentrate in a colourless 10 mL glass vial (type I glass), with a coated rubber stopper andaluminium crimp cap with blue plastic button.

Pack size of 2 vials.

This medicinal product is compatible with infusion sets composed of polyvinylchloride (PVC),polyethylene (PE), polypropylene (PP), polybutadiene and polyurethane (PUR), and in-line filtermembranes composed of polyethersulfone (PES, neutral and positively charged) and positivelycharged polyamide (PA).

* The vial should be visually inspected before use. If the solution is cloudy, discoloured, orcontains large or coloured particulates, the vial should be discarded.

* Spevigo is for single use only.

* Aseptic technique must be used to prepare the solution for infusion:

o For the recommended dose of 900 mg, draw and discard 15 mL from a 100 mLcontainer of sodium chloride 9 mg/mL (0.9%) solution for injection and replaceslowly with 15 mL spesolimab sterile concentrate (two vials of 450 mg/7.5 mL).

o For the recommended dose of 450 mg, draw and discard 7.5 mL from a 100 mLcontainer of sodium chloride 9 mg/mL (0.9%) solution for injection and replaceslowly with 7.5 mL spesolimab sterile concentrate (one vial of 450 mg/7.5 mL).

o Mix gently before use. The diluted spesolimab infusion solution should be usedimmediately.

* Spevigo must not be mixed with other medicinal products. A pre-existing intravenous line maybe used for administration of diluted spesolimab infusion solution, if the compatibilityinformation above is considered. The line must be flushed with sodium chloride 9 mg/mL(0.9%) solution for injection prior to and at the end of infusion. No other infusion should beadministered in parallel via the same intravenous access.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

EU/1/22/1688/001

Date of first authorisation: 09 December 2022

Date of latest renewal: 14 November 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.