4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Treatment can be initiated with the pre-filled syringe as a subcutaneous injection to prevent GPP flares (please refer to the Summary of Product Characteristics for Spevigo 150 mg and 300 mg solution for injection in pre-filled syringe) or with an intravenous dose of spesolimab to treat a GPP flare.

Posology

The recommended dose for GPP flare treatment in adults and adolescents from 12 years of age and weighing at least 40 kg is a single dose of 900 mg (two vials of 450 mg) administered as an intravenous infusion. If flare symptoms persist, an additional 900 mg dose may be administered 1 week after the initial dose.

Spevigo has not been studied in patients weighing less than 40 kg. Based on pharmacokinetic modelling 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 intravenous infusion (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. Spesolimab should not be used in combination with other GPP treatments, e.g. systemic immunosuppressants, to treat a flare (see sections 4.4 and 4.5).

Special populations

Elderly

No dose adjustment is required.

Renal or hepatic impairment

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

Paediatric population

The safety and efficacy of spesolimab in children less than 12 years of age has not been established. No data are available.

Method of administration

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

Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, it is administered 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. No other infusion should be administered in parallel via the same intravenous access.

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

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

4.3. Contraindications

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

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

4.4. Special warnings and precautions for use

Traceability

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

Infections

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 expected clinical benefits of treatment should be considered prior to prescribing spesolimab. Treatment with spesolimab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be instructed to seek medical advice if signs or 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 an adequate course of treatment cannot be confirmed. After spesolimab treatment, patients should be monitored for signs and symptoms of active TB.

Hypersensitivity and infusion-related reactions

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

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

If a patient develops signs of anaphylaxis or other serious hypersensitivity, spesolimab treatment should 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 other infusion-related reactions, treatment should be stopped and appropriate medical therapy should be considered (e.g., systemic anti-histamines 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 (see section 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 flare of 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 immunomodulating treatments), while some treatments were discontinued before initiation of spesolimab treatment with no washout period required (methotrexate, cyclosporine, retinoids, topical treatments) (see section 5.1).

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

Re‑treatment

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

Immunisations

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 patients receiving spesolimab (see section 4.5). The interval between live vaccinations and initiation of spesolimab therapy should be at least 4 weeks. Live vaccines should not be administered for at least 16 weeks after treatment with spesolimab.

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

Peripheral neuropathy

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

Excipients with known effect

Polysorbates

This medicine contains 3 mg of polysorbate 20 in each 7.5 ml vial. Polysorbates may cause allergic reactions.

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. In GPP patients, spesolimab is not expected to cause cytokine-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 GPP patients (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

No data are present on excretion of spesolimab in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, transfer of IgG antibodies to the newborns through milk, may happen during 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 was discontinued before the last trimester of pregnancy, breastfeeding can be started immediately after birth.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of 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) and frequency 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), not known (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 disorders

Pruritus

Common

General disorders and administration site conditions

Injection site reactions

Very commonc)

Fatigue

Common

a) The most commonly reported infections were Urinary tract infection (Common) and Upper respiratory tract infection (Very common)

b) Derived from open-label extension trials and post-marketing experience

c) Not reported in Effisayil 1

Description of selected adverse reactions

Infections

During the 1-week placebo-controlled period in Effisayil 1, infections were reported in 17.1% of patients 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 and no 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 with placebo. In Effisayil 2, serious infections were reported in 3 patients (3.2%) in the Spevigo group and no patient in the placebo group.

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

Hypersensitivity

Hypersensitivity comprises immediate systemic hypersensitivity reactions, including anaphylactic reaction. Immediate systemic hypersensitivity reactions have been reported in open-label extension trials and the post-marketing setting.

Injection site reactions

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 moderate in severity.

Paediatric population

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 treated with spesolimab (n = 6) was consistent with the safety profile in adults and no new safety concerns have been identified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest dose of spesolimab administered in clinical trials was 1 200 mg intravenously or subcutaneously. Adverse reactions observed in subjects receiving single or repeated doses up to 1 200 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 symptoms of adverse reactions and symptomatic treatment be instituted as appropriate.