STEQEYMA 45mg 45mg / 0.5ml injection solution in pre-filled syringe medication leaflet

Steqeyma 45 mg solution for injection

Steqeyma 45 mg solution for injection in pre-filled syringe

Steqeyma 90 mg solution for injection in pre-filled syringe

Steqeyma 45 mg solution for injection

Each vial contains 45 mg ustekinumab in 0.5 mL.

Steqeyma 45 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 45 mg ustekinumab in 0.5 mL.

Steqeyma 90 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 90 mg ustekinumab in 1 mL.

Ustekinumab is a fully human IgGlκ monoclonal antibody to interleukin (IL)-12/23 produced in a

Chinese Hamster Ovary (CHO) cell line using recombinant DNA technology.

For the full list of excipients, see section 6.1.

Steqeyma 45 mg solution for injection

Solution for injection.

Steqeyma 45 mg solution for injection in pre-filled syringe

Solution for injection.

Steqeyma 90 mg solution for injection in pre-filled syringe

Solution for injection.

The solution is clear to slightly opalescent, colourless to pale yellow.

Plaque psoriasis

Steqeyma is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed torespond to, or who have a contraindication to, or are intolerant to other systemic therapies includingciclosporin, methotrexate (MTX) or PUVA (psoralen and ultraviolet A) (see section 5.1).

Steqeyma is indicated for the treatment of moderate to severe plaque psoriasis in children andadolescent patients from the age of 6 years and older, who are inadequately controlled by, or areintolerant to, other systemic therapies or phototherapies (see section 5.1).

Psoriatic arthritis (PsA)

Steqeyma, alone or in combination with MTX, is indicated for the treatment of active psoriaticarthritis in adult patients when the response to previous non-biological disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate (see section 5.1).

Crohn’s Disease

Steqeyma is indicated for the treatment of adult patients with moderately to severely active Crohn’sdisease who have had an inadequate response with, lost response to, or were intolerant to eitherconventional therapy or a TNFα antagonist or have medical contraindications to such therapies.

Steqeyma is intended for use under the guidance and supervision of physicians experienced in thediagnosis and treatment of conditions for which Steqeyma is indicated.

Plaque psoriasis

The recommended posology of Steqeyma is an initial dose of 45 mg administered subcutaneously,followed by a 45 mg dose 4 weeks later, and then every 12 weeks thereafter.

Consideration should be given to discontinuing treatment in patients who have shown no response upto 28 weeks of treatment.

Patients with body weight > 100 kg

For patients with a body weight > 100 kg the initial dose is 90 mg administered subcutaneously,followed by a 90 mg dose 4 weeks later, and then every 12 weeks thereafter. In these patients, 45 mgwas also shown to be efficacious. However, 90 mg resulted in greater efficacy (see section 5.1,

Table 4).

Psoriatic arthritis (PsA)

The recommended posology of Steqeyma is an initial dose of 45 mg administered subcutaneously,followed by a 45 mg dose 4 weeks later, and then every 12 weeks thereafter. Alternatively, 90 mg maybe used in patients with a body weight > 100 kg.

Consideration should be given to discontinuing treatment in patients who have shown no response upto 28 weeks of treatment.

No dose adjustment is needed for elderly patients (see section 4.4).

Ustekinumab has not been studied in these patient populations. No dose recommendations can bemade.

The safety and efficacy of ustekinumab in children with psoriasis less than 6 years of age or inchildren with psoriatic arthritis less than 18 years of age have not yet been established.

Paediatric plaque psoriasis (6 years and older)

The recommended dose of Steqeyma based on body weight is shown below (Tables 1 and 2).

Steqeyma should be administered subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

Table 1 Recommended dose of Steqeyma for paediatric psoriasis

Body weight at the time of dosing Recommended dose< 60 kg 0.75 mg/kg≥ 60 kg to ≤ 100 kg 45 mg> 100 kg 90 mg

To calculate the volume of injection (mL) for patients < 60 kg, use the following formula: body weight(kg) × 0.0083 (mL/kg) or see Table 2. The calculated volume should be rounded to the nearest 0.01mL and administered using a 1 mL graduated syringe. A 45 mg vial is available for paediatric patientswho need to receive less than the full 45 mg dose.

Table 2 Injection volumes of Steqeyma for paediatric psoriasis patients < 60 kg

Body weight at time of dosing(kg) Dose (mg) Volume of injection (mL)15 11.3 0.1216 12.0 0.1317 12.8 0.1418 13.5 0.1519 14.3 0.1620 15.0 0.1721 15.8 0.1722 16.5 0.1823 17.3 0.1924 18.0 0.2025 18.8 0.2126 19.5 0.2227 20.3 0.2228 21.0 0.2329 21.8 0.2430 22.5 0.2531 23.3 0.2632 24.0 0.2733 24.8 0.2734 25.5 0.2835 26.3 0.2936 27.0 0.3037 27.8 0.3138 28.5 0.3239 29.3 0.3240 30.0 0.3341 30.8 0.3442 31.5 0.3543 32.3 0.3644 33.0 0.3745 33.8 0.3746 34.5 0.3847 35.3 0.3948 36.0 0.4049 36.8 0.4150 37.5 0.4251 38.3 0.4252 39.0 0.4353 39.8 0.4454 40.5 0.4555 41.3 0.4656 42.0 0.4657 42.8 0.4758 43.5 0.4859 44.3 0.49

Consideration should be given to discontinuing treatment in patients who have shown no response upto 28 weeks of treatment.

Crohn’s Disease

In the treatment regimen, the first dose of Steqeyma is administered intravenously. For the posology ofthe intravenous dosing regimen, see section 4.2 of the Steqeyma 130 mg Concentrate for solution forinfusion SmPC.

The first subcutaneous administration of 90 mg Steqeyma should take place at week 8 after theintravenous dose. After this, dosing every 12 weeks is recommended.

Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, mayreceive a second subcutaneous dose at this time (see section 5.1).

Patients who lose response on dosing every 12 weeks may benefit from an increase in dosingfrequency to every 8 weeks (see section 5.1, section 5.2).

Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment(see section 5.1).

Consideration should be given to discontinuing treatment in patients who show no evidence oftherapeutic benefit 16 weeks after the IV induction dose or 16 weeks after switching to the 8-weeklymaintenance dose.

Immunomodulators and/or corticosteroids may be continued during treatment with Steqeyma. Inpatients who have responded to treatment with Steqeyma, corticosteroids may be reduced ordiscontinued in accordance with standard of care.

In Crohn’s disease, if therapy is interrupted, resumption of treatment with subcutaneous dosing every8 weeks is safe and effective.

No dose adjustment is needed for elderly patients (see section 4.4).

Ustekinumab has not been studied in these patient populations. No dose recommendations can bemade.

The safety and efficacy of ustekinumab in treatment of Crohn’s disease in children less than 18 yearshave not yet been established. No data are available.

Steqeyma 45 mg vials or 45 mg and 90 mg pre-filled syringes are for subcutaneous injection only. Ifpossible, areas of the skin that show psoriasis should be avoided as injection sites.

After proper training in subcutaneous injection technique, patients or their caregivers may inject

Steqeyma if a physician determines that it is appropriate. However, the physician should ensureappropriate follow-up of patients. Patients or their caregivers should be instructed to inject theprescribed amount of Steqeyma according to the directions provided in the package leaflet.

Comprehensive instructions for administration are given in the package leaflet.

For further instructions on preparation and special precautions for handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important, active infection (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.

Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections.

In clinical studies and a post-marketing observational study in patients with psoriasis, seriousbacterial, fungal, and viral infections have been observed in patients receiving ustekinumab (seesection 4.8).

Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections(including atypical mycobacterial infection, listeria meningitis, pneumonia legionella, andnocardiosis), opportunistic fungal infections, opportunistic viral infections (including encephalitiscaused by herpes simplex 2), and parasitic infections (including ocular toxoplasmosis) have beenreported in patients treated with ustekinumab.

Caution should be exercised when considering the use of Steqeyma in patients with a chronic infectionor a history of recurrent infection (see section 4.3).

Prior to initiating treatment with Steqeyma, patients should be evaluated for tuberculosis infection.

Steqeyma must not be given to patients with active tuberculosis (see section 4.3). Treatment of latenttuberculosis infection should be initiated prior to administering Steqeyma. Anti-tuberculosis therapyshould also be considered prior to initiation of Steqeyma in patients with a history of latent or activetuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving

Steqeyma should be monitored closely for signs and symptoms of active tuberculosis during and aftertreatment.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infectionoccur. If a patient develops a serious infection, the patient should be closely monitored and Steqeymashould not be administered until the infection resolves.

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Somepatients who received ustekinumab in clinical studies and in a post-marketing observational study inpatients with psoriasis developed cutaneous and non-cutaneous malignancies (see section 4.8). Therisk of malignancy may be higher in psoriasis patients who have been treated with other biologicsduring the course of their disease.

No studies have been conducted that include patients with a history of malignancy or that continuetreatment in patients who develop malignancy while receiving ustekinumab. Thus, caution should beexercised when considering the use of Steqeyma in these patients.

All patients, in particular those greater than 60 years of age, patients with a medical history ofprolonged immunosuppressant therapy or those with a history of PUVA treatment, should bemonitored for the appearance of skin cancer (see section 4.8).

Systemic and respiratory hypersensitivity reactions

Systemic

Serious hypersensitivity reactions have been reported in the postmarketing setting, in some casesseveral days after treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or otherserious hypersensitivity reaction occurs, appropriate therapy should be instituted and administration of

Steqeyma should be discontinued (see section 4.8).

Respiratory

Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia havebeen reported during post-approval use of ustekinumab. Clinical presentations included cough,dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have includedrespiratory failure and prolonged hospitalisation. Improvement has been reported after discontinuationof ustekinumab and also, in some cases, administration of corticosteroids. If infection has beenexcluded and diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment (seesection 4.8).

Cardiovascular events including myocardial infarction and cerebrovascular accident have beenobserved in patients with psoriasis exposed to ustekinumab in a post-marketing observational study.

Risk factors for cardiovascular disease should be regularly assessed during treatment with Steqeyma.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin(BCG)) should not be given concurrently with Steqeyma. Specific studies have not been conducted inpatients who had recently received live viral or live bacterial vaccines. No data are available on thesecondary transmission of infection by live vaccines in patients receiving ustekinumab. Before liveviral or live bacterial vaccination, treatment with Steqeyma should be withheld for at least 15 weeksafter the last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the

Summary of Product Characteristics for the specific vaccine for additional information and guidanceon concomitant use of immunosuppressive agents post-vaccination.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumabis not recommended for twelve months following birth or until ustekinumab infant serum levels areundetectable (see sections 4.5 and 4.6). If there is a clear clinical benefit for the individual infant,administration of a live vaccine might be considered at an earlier timepoint, if infant ustekinumabserum levels are undetectable.

Patients receiving Steqeyma may receive concurrent inactivated or non-live vaccinations.

Long term treatment with ustekinumab does not suppress the humoral immune response topneumococcal polysaccharide or tetanus vaccines (see section 5.1).

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants,including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies,concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of ustekinumab. Caution should be exercised whenconsidering concomitant use of other immunosuppressants and Steqeyma or when transitioning fromother immunosuppressive biologics (see section 4.5).

Immunotherapy

Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy. It is notknown whether ustekinumab may affect allergy immunotherapy.

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment(see section 4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptomsthat may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course oftheir disease. As part of the monitoring of the patient’s psoriasis, physicians should be alert forsymptoms of erythrodermic psoriasis or exfoliative dermatitis. If these symptoms occur, appropriatetherapy should be instituted. Steqeyma should be discontinued if a drug reaction is suspected.

Lupus-related conditions

Cases of lupus-related conditions have been reported in patients treated with ustekinumab, includingcutaneous lupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposedareas of the skin or if accompanied by arthralgia, the patient should seek medical attention promptly. Ifthe diagnosis of a lupus-related condition is confirmed, ustekinumab should be discontinued andappropriate treatment initiated.

No overall differences in efficacy or safety in patients age 65 and older who received ustekinumabwere observed compared to younger patients in clinical studies in approved indications, however thenumber of patients aged 65 and older is not sufficient to determine whether they respond differentlyfrom younger patients. Because there is a higher incidence of infections in the elderly population ingeneral, caution should be used in treating the elderly.

Polysorbate 80

Steqeyma contains 0.04 mg (90 mg/1.0 mL) or 0.02 mg (45 mg/0.5 mL) of polysorbate 80 (E433) ineach dosage unit which is equivalent to 0.04 mg/mL. Polysorbates may cause allergic reactions.

Live vaccines should not be given concurrently with Steqeyma.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumabis not recommended for twelve months following birth or until ustekinumab infant serum levels areundetectable (see sections 4.4 and 4.6). If there is a clear clinical benefit for the individual infant,administration of a live vaccine might be considered at an earlier timepoint, if infant ustekinumabserum levels are undetectable.

In the population pharmacokinetic analyses of the phase 3 studies, the effect of the most frequentlyused concomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen,acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab wasexplored. There were no indications of an interaction with these concomitantly administered medicinalproducts. The basis for this analysis was that at least 100 patients (> 5% of the studied population)were treated concomitantly with these medicinal products for at least 90% of the study period. Thepharmacokinetics of ustekinumab was not impacted by concomitant use of MTX, NSAIDs,6-mercaptopurine, azathioprine and oral corticosteroids in patients with psoriatic arthritis, Crohn’sdisease or ulcerative colitis, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritisor Crohn’s disease or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) inpatients with ulcerative colitis.

The results of an in vitro study and a phase 1 study in subjects with active Crohn’s disease do notsuggest the need for dose adjustments in patients who are receiving concomitant CYP450 substrates(see section 5.2).

In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants,including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies,concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of ustekinumab. (see section 4.4).

Women of childbearing potential should use effective methods of contraception during treatment andfor at least 15 weeks after treatment.

Data from a moderate number of prospectively collected pregnancies following exposure toustekinumab with known outcomes, including more than 450 pregnancies exposed during the firsttrimester, do not indicate an increased risk of major congenital malformations in the newborn.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryonic/foetal development, parturition or postnatal development (see section 5.3).

However, the available clinical experience is limited. As a precautionary measure, it is preferable toavoid the use of Steqeyma in pregnancy.

Ustekinumab crosses the placenta and has been detected in the serum of infants born to female patientstreated with ustekinumab during pregnancy. The clinical impact of this is unknown, however, the riskof infection in infants exposed in utero to ustekinumab may be increased after birth.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumabis not recommended for twelve months following birth or until ustekinumab infant serum levels areundetectable (see sections 4.4 and 4.5). If there is a clear clinical benefit for the individual infant,administration of a live vaccine might be considered at an earlier timepoint, if infant ustekinumabserum levels are undetectable.

Limited data from published literature suggests that ustekinumab is excreted in human breast milk invery small amounts. It is not known if ustekinumab is absorbed systemically after ingestion. Becauseof the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether todiscontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinuetherapy with Steqeyma must be made taking into account the benefit of breast-feeding to the child andthe benefit of Steqeyma therapy to the woman.

The effect of ustekinumab on human fertility has not been evaluated (see section 5.3).

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

The most common adverse reactions (> 5%) in controlled periods of the adult psoriasis, psoriaticarthritis, Crohn’s disease and ulcerative colitis clinical studies with ustekinumab were nasopharyngitisand headache. Most were considered to be mild and did not necessitate discontinuation of studytreatment. The most serious adverse reaction that has been reported for ustekinumab is serioushypersensitivity reactions including anaphylaxis (see section 4.4). The overall safety profile wassimilar for patients with psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis.

The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 andphase 3 studies in 6 710 patients (4 135 with psoriasis and/or psoriatic arthritis, 1 749 with Crohn’sdisease and 826 patients with ulcerative colitis). This includes exposure to ustekinumab in thecontrolled and non-controlled periods of the clinical studies in patients with psoriasis, psoriaticarthritis, Crohn’s disease or ulcerative colitis for at least 6 months (4 577 patients) or at least1 year (3 648 patients). 2 194 patients with psoriasis, Crohn’s disease or ulcerative colitis wereexposed for at least 4 years while 1 148 patients with psoriasis or Crohn’s disease were exposed for atleast 5 years .

Table 3 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohn’s disease andulcerative colitis clinical studies as well as adverse reactions reported from post-marketing experience.

The adverse reactions are classified by System Organ Class and frequency, using the followingconvention: 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 (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 3 List of adverse reactions

System Organ Class Frequency: Adverse reaction

Infections and infestations Common: Upper respiratory tract infection, nasopharyngitis, sinusitis

Uncommon: Cellulitis, dental infections, herpes zoster, lower respiratorytract infection, viral upper respiratory tract infection, vulvovaginal mycoticinfection

Immune system disorders Uncommon: Hypersensitivity reactions (including rash, urticaria)

Rare: Serious hypersensitivity reactions (including anaphylaxis,angioedema)

Psychiatric disorders Uncommon: Depression

Nervous system disorders Common: Dizziness, headache

Uncommon: Facial palsy

Respiratory, thoracic and Common: Oropharyngeal painmediastinal disorders Uncommon: Nasal congestion

Rare: Allergic alveolitis, eosinophilic pneumonia

Very rare: Organising pneumonia*

Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue Common: Pruritusdisorders Uncommon: Pustular psoriasis, skin exfoliation, acne

Rare: Exfoliative dermatitis, hypersensitivity vasculitis

Very rare: Bullous pemphigoid, cutaneous lupus erythematosus

Musculoskeletal and connective Common: Back pain, myalgia, arthralgiatissue disorders Very rare: Lupus-like syndrome

General disorders and Common: Fatigue, injection site erythema, injection site painadministration site conditions Uncommon: Injection site reactions (including haemorrhage, haematoma,induration, swelling and pruritus), asthenia

* See section 4.4, Systemic and respiratory hypersensitivity reactions.

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn’s disease andulcerative colitis, the rates of infection or serious infection were similar between ustekinumab-treatedpatients and those treated with placebo. In the placebo-controlled period of these clinical studies, therate of infection was 1.36 per patient-year of follow-up in ustekinumab-treated patients, and 1.34 inplacebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up inustekinumab-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 inplacebo-treated patients (15 serious infections in 434 patient-years of follow-up) (see section 4.4).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis, Crohn’s disease andulcerative colitis clinical studies, representing 15 227 patient-years of ustekinumab exposure in6 710 patients, the median follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for

Crohn’s disease studies, and 2.3 years for ulcerative colitis studies. The rate of infection was 0.85 perpatient-year of follow-up in ustekinumab-treated patients, and the rate of serious infections was0.02 per patient-year of follow-up in ustekinumab-treated patients (289 serious infections in15 227 patient-years of follow-up) and serious infections reported included pneumonia, anal abscess,cellulitis, diverticulitis, gastroenteritis and viral infections.

In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid didnot develop tuberculosis.

In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerativecolitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years offollow-up) compared with 0.23 for placebo-treated patients (1 patient in 434 patient-years offollow-up). The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-upfor ustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 forplacebo-treated patients (2 patients in 433 patient-years of follow-up).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis, Crohn’s disease andulcerative colitis clinical studies, representing 15 205 patient-years of ustekinumab exposure in6 710 patients, the median follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for

Crohn’s disease studies and 2.3 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancers were reported in 76 patients in 15 205 patient-years of follow-up (incidence of0.50 per 100 patient-years of follow-up for ustekinumab-treated patients). The incidence ofmalignancies reported in ustekinumab-treated patients was comparable to the incidence expected inthe general population (standardised incidence ratio = 0.94 [95% confidence interval: 0.73, 1.18],adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal, and breast cancers. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up for ustekinumab-treated patients(69 patients in 15 165 patient-years of follow-up). The ratio of patients with basal versus squamouscell skin cancers (3:1) is comparable with the ratio expected in the general population (seesection 4.4).

During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of ustekinumab,rash and urticaria have each been observed in < 1% of patients (see section 4.4).

Paediatric patients 6 years and older with plaque psoriasis

The safety of ustekinumab has been studied in two phase 3 studies of paediatric patients with moderateto severe plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for upto 60 weeks and the second study was in 44 patients from 6 to 11 years of age treated for up to56 weeks. In general, the adverse events reported in these two studies with safety data up to 1 yearwere similar to those seen in previous studies in adults with plaque psoriasis.

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.

Single doses up to 6 mg/kg have been administered intravenously in clinical studies withoutdose-limiting toxicity. In case of overdose, it is recommended that the patient be monitored for anysigns or symptoms of adverse reactions and appropriate symptomatic treatment be institutedimmediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC05.

Steqeyma is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

Ustekinumab is a fully human IgGlκ monoclonal antibody that binds with specificity to the shared p40protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits thebioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptorprotein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that isalready bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute tocomplement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and

IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophagesand dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer(NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype,

IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL-12 and IL-23 hasbeen associated with immune mediated diseases, such as psoriasis, psoriatic arthritis and Crohn’sdisease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects inpsoriasis, psoriatic arthritis and Crohn’s disease through interruption of the Th1 and Th17 cytokinepathways, which are central to the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatorymarkers including C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, whichwere then maintained throughout the maintenance phase. CRP was assessed during the study extensionand the reductions observed during maintenance were generally sustained through week 252.

During the long term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated withustekinumab for at least 3.5 years mounted similar antibody responses to both pneumococcalpolysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similarproportions of adult patients developed protective levels of anti-pneumococcal and anti-tetanusantibodies and antibody titres were similar among ustekinumab-treated and control patients.

Plaque psoriasis (Adults)

The safety and efficacy of ustekinumab was assessed in 1 996 patients in two randomised,double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis and whowere candidates for phototherapy or systemic therapy. In addition, a randomised, blinded assessor,active-controlled study compared ustekinumab and etanercept in patients with moderate to severeplaque psoriasis who had had an inadequate response to, intolerance to, or contraindication tociclosporin, MTX, or PUVA.

Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of these patients were either non-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised toustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 and followed by the same dose every12 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receiveustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16 followed by dosing every 12 weeks. Patientsoriginally randomised to ustekinumab who achieved Psoriasis Area and Severity Index 75 response(PASI improvement of at least 75% relative to baseline) at both Weeks 28 and 40 were re-randomisedto receive ustekinumab every 12 weeks or to placebo (i.e., withdrawal of therapy). Patients who werere-randomised to placebo at week 40 reinitiated ustekinumab at their original dosing regimen whenthey experienced at least a 50% loss of their PASI improvement obtained at week 40. All patients werefollowed for up to 76 weeks following first administration of study treatment.

Psoriasis Study 2 (PHOENIX 2) evaluated 1 230 patients. 61% of these patients were eithernon-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised toustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at16 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receiveustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. All patients were followed for up to52 weeks following first administration of study treatment.

Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis whoinadequately responded to, were intolerant to, or had a contraindication to other systemic therapy andcompared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab andetanercept. During the 12-week active-controlled portion of the study, patients were randomised toreceive etanercept (50 mg twice a week), ustekinumab 45 mg at Weeks 0 and 4, or ustekinumab 90 mgat Weeks 0 and 4.

Baseline disease characteristics were generally consistent across all treatment groups in Psoriasis

Studies 1 and 2 with a median baseline PASI score from 17 to 18, median baseline Body Surface Area(BSA) ≥ 20, and median Dermatology Life Quality Index (DLQI) range from 10 to 12. Approximatelyone third (Psoriasis Study 1) and one quarter (Psoriasis Study 2) of subjects had Psoriatic Arthritis(PsA). Similar disease severity was also seen in Psoriasis Study 3.

The primary endpoint in these studies was the proportion of patients who achieved PASI 75 responsefrom baseline at week 12 (see Tables 4 and 5).

Table 4 Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis

Study 2 (PHOENIX 2)

Week 12 Week 282 doses (week 0 and week 4) 3 doses (week 0, week 4and week 16)

PBO 45 mg 90 mg 45 mg 90 mg

Psoriasis Study 1

Number of patients randomised 255 255 256 250 243

PASI 50 response N (%) 26 (10%) 213 (84%)a 220 (86%)a 228 (91%) 234 (96%)

PASI 75 response N (%) 8 (3%) 171 (67%)a 170 (66%)a 178 (71%) 191 (79%)

PASI 90 response N (%) 5 (2%) 106 (42%)a 94 (37%)a 123 (49%) 135 (56%)

PGAb of cleared or minimal N(%) 10 (4%) 151 (59%)a 156 (61%)a 146 (58%) 160 (66%)

Number of patients ≤ 100 kg 166 168 164 164 153

PASI 75 response N (%) 6 (4%) 124 (74%) 107 (65%) 130 (79%) 124 (81%)

Number of patients > 100 kg 89 87 92 86 90

PASI 75 response N (%) 2 (2%) 47 (54%) 63 (68%) 48 (56%) 67 (74%)

Psoriasis Study 2

Number of patients randomised 410 409 411 397 400

PASI 50 response N (%) 41 (10%) 342 (84%)a 367 (89%)a 369 (93%) 380 (95%)

PASI 75 response N (%) 15 (4%) 273 (67%)a 311 (76%)a 276 (70%) 314 (79%)

PASI 90 response N (%) 3 (1%) 173 (42%)a 209 (51%)a 178 (45%) 217 (54%)

PGAb of cleared or minimal N(%) 18 (4%) 277 (68%)a 300 (73%)a 241 (61%) 279 (70%)

Number of patients ≤ 100 kg 290 297 289 287 280

PASI 75 response N (%) 12 (4%) 218 (73%) 225 (78%) 217 (76%) 226 (81%)

Number of patients > 100 kg 120 112 121 110 119

PASI 75 response N (%) 3 (3%) 55 (49%) 86 (71%) 59 (54%) 88 (74%)a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with placebo (PBO).b PGA = Physician Global Assessment

Table 5 Summary of clinical response at week 12 in Psoriasis Study 3 (ACCEPT)

Psoriasis Study 3

Etanercept 24 doses Ustekinumab(50 mg twice a week) 2 doses (week 0 and week 4)45 mg 90 mg

Number of patients randomised 347 209 347

PASI 50 response N (%) 286 (82%) 181 (87%) 320 (92%)a

PASI 75 response N (%) 197 (57%) 141 (67%)b 256 (74%)a

PASI 90 response N (%) 80 (23%) 76 (36%)a 155 (45%)a

PGA of cleared or minimal N (%) 170 (49%) 136 (65%)a 245 (71%)a

Number of patients ≤ 100 kg 251 151 244

PASI 75 response N (%) 154 (61%) 109 (72%) 189 (77%)

Number of patients > 100 kg 96 58 103

PASI 75 response N (%) 43 (45%) 32 (55%) 67 (65%)a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with etanercept.b p = 0.012 for ustekinumab 45 mg in comparison with etanercept.

In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatmentcompared with treatment withdrawal (p < 0.001). Similar results were seen with each dose ofustekinumab. At 1 year (week 52), 89% of patients re-randomised to maintenance treatment were

PASI 75 responders compared with 63% of patients re-randomised to placebo (treatment withdrawal)(p < 0.001). At 18 months (week 76), 84% of patients re-randomised to maintenance treatment were

PASI 75 responders compared with 19% of patients re-randomised to placebo (treatment withdrawal).

At 3 years (week 148), 82% of patients re-randomised to maintenance treatment were PASI 75responders. At 5 years (week 244), 80% of patients re-randomised to maintenance treatment were

PASI 75 responders.

In patients re-randomised to placebo, and who reinitiated their original ustekinumab treatment regimenafter loss of ≥ 50% of PASI improvement 85% regained PASI 75 response within 12 weeks afterre-initiating therapy.

In Psoriasis Study 1, at week 2 and week 12, significantly greater improvements from baseline weredemonstrated in the DLQI in each ustekinumab treatment group compared with placebo. Theimprovement was sustained through week 28. Similarly, significant improvements were seen in

Psoriasis Study 2 at week 4 and 12, which were sustained through week 24. In Psoriasis Study 1,improvements in nail psoriasis (Nail Psoriasis Severity Index), in the physical and mental componentsummary scores of the SF-36 and in the Itch Visual Analogue Scale (VAS) were also significant ineach ustekinumab treatment group compared with placebo. In Psoriasis Study 2, the Hospital Anxietyand Depression Scale (HADS) and Work Limitations Questionnaire (WLQ) were also significantlyimproved in each ustekinumab treatment group compared with placebo.

Psoriatic arthritis (PsA) (Adults)

Ustekinumab has been shown to improve signs and symptoms, physical function and health-relatedquality of life, and reduce the rate of progression of peripheral joint damage in adult patients withactive PsA.

The safety and efficacy of ustekinumab was assessed in 927 patients in two randomised, double-blind,placebo-controlled studies in patients with active PsA (≥ 5 swollen joints and ≥ 5 tender joints) despitenon-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy.

Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of

PsA were enrolled, including polyarticular arthritis with no evidence of rheumatoid nodules (39%),spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distalinterphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients inboth studies had enthesitis and dactylitis at baseline, respectively. Patients were randomised to receivetreatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed byevery 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX(≤ 25 mg/week).

In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of the patients,respectively, had been previously treated with DMARDs. In Study 1 previous treatment with anti-tumour necrosis factor (TNF)α agent was not allowed. In Study 2, the majority of patients (58%,n = 180) had been previously treated with one or more anti-TNFα agent(s), of whom over 70% haddiscontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.

Signs and symptoms

Treatment with ustekinumab resulted in significant improvements in the measures of disease activitycompared to placebo at week 24. The primary endpoint was the percentage of patients who achieved

American College of Rheumatology (ACR) 20 response at week 24. The key efficacy results areshown in Table 6 below.

Table 6 Number of patients who achieved clinical response in Psoriatic arthritis Study 1(PSUMMIT I) and Study 2 (PSUMMIT II) at week 24

Psoriatic arthritis Study 1 Psoriatic arthritis Study 2

PBO 45 mg 90 mg PBO 45 mg 90 mg

Number of patientsrandomised 206 205 204 104 103 105

ACR 20 a aresponse, N (%) 47 (23%) 87 (42%) 101 (50%) 21 (20%) 45 (44%)a 46 (44%)a

ACR 50 a aresponse, N (%) 18 (9%) 51 (25%) 57 (28%) 7 (7%) 18 (17%)b 24 (23%)a

ACR 70 aresponse, N (%) 5 (2%) 25 (12%) 29 (14%)a 3 (3%) 7 (7%)c 9 (9%)c

Number of patientswith 3% BSAd 146 145 149 80 80 81≥

PASI 75response, N (%) 16 (11%) 83 (57%)a 93 (62%)a 4 (5%) 41 (51%)a 45 (56%)a

PASI 90response, N (%) 4 (3%) 60 (41%)a 65 (44%)a 3 (4%) 24 (30%)a 36 (44%)a

Combined PASI 75and ACR 20 8 (5%) 40 (28%)a 62 (42%)a 2 (3%) 24 (30%)a 31 (38%)aresponse, N (%)

Number of patients≤ 100 kg 154 153 154 74 74 73

ACR 20response, N (%) 39 (25%) 67 (44%) 78 (51%) 17 (23%) 32 (43%) 34 (47%)

Number of patientswith 3% BSAd 105 105 111 54 58 57≥

PASI 75response, N (%) 14 (13%) 64 (61%) 73 (66%) 4 (7%) 31 (53%) 32 (56%)

Number of patients> 100 kg 52 52 50 30 29 31

ACR 20response, N (%) 8 (15%) 20 (38%) 23 (46%) 4 (13%) 13 (45%) 12 (39%)

Number of patientswith 3% BSAd 41 40 38 26 22 24≥

PASI 75response, N (%) 2 (5%) 19 (48%) 20 (53%) 0 10 (45%) 13 (54%)a p < 0.001b p < 0.05c p = NSd Number of patients with ≥ 3% BSA psoriasis skin involvement at baseline

ACR 20, 50 and 70 responses continued to improve or were maintained through week 52 (PsA Study 1and 2) and week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at week 100 were achieved by57% and 64%, for 45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at week 52 wereachieved by 47% and 48%, for 45 mg and 90 mg, respectively.

The proportion of patients achieving a modified PsA response criteria (PsARC) response was alsosignificantly greater in the ustekinumab groups compared to placebo at week 24. PsARC responseswere maintained through weeks 52 and 100. A higher proportion of patients treated with ustekinumabwho had spondylitis with peripheral arthritis as their primary presentation, demonstrated 50 and70 percent improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scorescompared with placebo at week 24.

Responses observed in the ustekinumab treated groups were similar in patients receiving and notreceiving concomitant MTX, and were maintained through weeks 52 and 100. Patients previouslytreated with anti-TNFα agents who received ustekinumab achieved a greater response at week 24 thanpatients receiving placebo (ACR 20 response at week 24 for 45 mg and 90 mg was 37% and 34%,respectively, compared with placebo 15%; p < 0.05), and responses were maintained through week 52.

For patients with enthesitis and/or dactylitis at baseline, in PsA Study 1 significant improvement inenthesitis and dactylitis score was observed in the ustekinumab groups compared with placebo atweek 24. In PsA Study 2 significant improvement in enthesitis score and numerical improvement (notstatistically significant) in dactylitis score was observed in the ustekinumab 90 mg group comparedwith placebo at week 24. Improvements in enthesitis score and dactylitis score were maintainedthrough weeks 52 and 100.

Radiographic Response

Structural damage in both hands and feet was expressed as change in total van der Heijde-Sharp score(vdH-S score), modified for PsA by addition of hand distal interphalangeal joints, compared tobaseline. A pre-specified integrated analysis combining data from 927 subjects in both PsA Study 1and 2 was performed. Ustekinumab demonstrated a statistically significant decrease in the rate ofprogression of structural damage compared to placebo, as measured by change from baseline toweek 24 in the total modified vdH-S score (mean ± SD score was 0.97 ± 3.85 in the placebo groupcompared with 0.40 ± 2.11 and 0.39 ± 2.40 in the ustekinumab 45 mg (p < 0.05) and 90 mg(p < 0.001) groups, respectively). This effect was driven by PsA Study 1. The effect is considereddemonstrated irrespective of concomitant MTX use, and was maintained through Weeks 52(integrated analysis) and 100 (PsA Study 1).

Ustekinumab-treated patients showed significant improvement in physical function as assessed by the

Disability Index of the Health Assessment Questionnaire (HAQ-DI) at week 24. The proportion ofpatients achieving a clinically meaningful ≥ 0.3 improvement in HAQ-DI score from baseline was alsosignificantly greater in the ustekinumab groups when compared with placebo. Improvement in

HAQ-DI score from baseline was maintained through Weeks 52 and 100.

There was significant improvement in DLQI scores in the ustekinumab groups as compared withplacebo at week 24, which was maintained through weeks 52 and 100. In PsA Study 2 there was asignificant improvement in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)scores in the ustekinumab groups when compared with placebo at week 24. The proportion of patientsachieving a clinically significant improvement in fatigue (4 points in FACIT-F) was also significantlygreater in the ustekinumab groups compared with placebo. Improvements in FACIT scores weremaintained through week 52.

The European Medicines Agency has deferred the obligation to submit the results of studies withustekinumab in one or more subsets of the paediatric population with juvenile idiopathic arthritis (seesection 4.2 for information on paediatric use).

Ustekinumab has been shown to improve signs and symptoms, and health-related quality of life inpaediatric patients 6 years and older with plaque psoriasis.

Adolescent patients (12-17 years)

The efficacy of ustekinumab was studied in 110 paediatric patients aged 12 to 17 years with moderateto severe plaque psoriasis in a multicentre, phase 3, randomised, double-blind, placebo-controlledstudy (CADMUS). Patients were randomised to receive either placebo (n = 37), or the recommendeddose of ustekinumab (see section 4.2; n = 36) or half of the recommended dose of ustekinumab(n = 37) by subcutaneous injection at Weeks 0 and 4 followed by every 12 week (q12w) dosing. Atweek 12, placebo-treated patients crossed over to receive ustekinumab.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates forsystemic therapy or phototherapy, were eligible for the study. Approximately 60% of the patients hadprior exposure to conventional systemic therapy or phototherapy. Approximately 11% of the patientshad prior exposure to biologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) orminimal (1) at week 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in

Children’s Dermatology Life Quality Index (CDLQI), change from baseline in the total scale score of

PedsQL (Paediatric Quality of Life Inventory) at week 12. At week 12, subjects treated withustekinumab showed significantly greater improvement in their psoriasis and health-related quality oflife compared with placebo (Table 7).

All patients were followed for efficacy for up to 52 weeks following first administration of studyagent. The proportion of patients with a PGA score of cleared (0) or minimal (1) and the proportionachieving PASI 75 showed separation between the ustekinumab treated group and placebo at the firstpost-baseline visit at week 4, reaching a maximum by week 12. Improvements in PGA, PASI, CDLQIand PedsQL were maintained through week 52 (Table 7).

Table 7 Summary of primary and secondary endpoints at week 12 and week 52

Paediatric psoriasis study (CADMUS) (Age 12-17)

Week 12 Week 52

Placebo Recommended dose of Recommended dose of

Ustekinumab Ustekinumab

N (%) N (%) N (%)

Patients randomised 37 36 35

PGA

PGA of cleared (0) or aminimal (1) 2 (5.4%) 25 (69.4%) 20 (57.1%)

PGA of Cleared (0) 1 (2.7%) 17 (47.2%)a 13 (37.1%)

PASI

PASI 75 responders 4 (10.8%) 29 (80.6%)a 28 (80.0%)

PASI 90 responders 2 (5.4%) 22 (61.1%)a 23 (65.7%)

PASI 100 responders 1 (2.7%) 14 (38.9%)a 13 (37.1%)

CDLQI

CDLQI of 0 or 1b 6 (16.2%) 18 (50.0%)c 20 (57.1%)

PedsQL

Change from baseline Mean e(SD)d 3.35 (10.04) 8.03 (10.44) 7.26 (10.92)a p < 0.001b CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality oflife in the paediatric population. CDLQI of 0 or 1 indicates no effect on child’s quality of life.c p = 0.002d PedsQL: The PedsQL Total Scale Score is a general health-related quality of life measure developed for use in childrenand adolescent populations. For the placebo group at week 12, N = 36e p = 0.028

During the placebo-controlled period through week 12, the efficacy of both the recommended and halfof the recommended dose groups were generally comparable at the primary endpoint (69.4% and67.6% respectively) although there was evidence of a dose response for higher level efficacy criteria(e.g. PGA of cleared (0), PASI 90). Beyond week 12, efficacy was generally higher and bettersustained in the recommended dose group compared with half of the recommended dosage group inwhich a modest loss of efficacy was more frequently observed toward the end of each 12 week dosinginterval. The safety profiles of the recommended dose and half of the recommended dose werecomparable.

Children (6-11 years)

The efficacy of ustekinumab was studied in 44 paediatric patients aged 6 to 11 years with moderate tosevere plaque psoriasis in an open label, single-arm, multicentre, phase 3, study (CADMUS Jr.).

Patients were treated with the recommended dose of ustekinumab (see section 4.2; n = 44) bysubcutaneous injection at weeks 0 and 4 followed by every 12 week (q12w) dosing.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates forsystemic therapy or phototherapy, were eligible for the study. Approximately 43% of the patients hadprior exposure to conventional systemic therapy or phototherapy. Approximately 5% of the patientshad prior exposure to biologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) orminimal (1) at week 12. Secondary endpoints included PASI 75, PASI 90, and change from baselinein Children’s Dermatology Life Quality Index (CDLQI) at week 12. At week 12, subjects treated withustekinumab showed clinically meaningful improvements in their psoriasis and health-related qualityof life (Table 8).

All patients were followed for efficacy for up to 52 weeks following first administration of studyagent. The proportion of patients with a PGA score of cleared (0) or minimal (1) at week 12 was77.3%. Efficacy (defined as PGA 0 or 1) was observed as early as the first post-baseline visit atweek 4 and the proportion of subjects who achieved a PGA score of 0 or 1 increased through week 16and then remained relatively stable through week 52. Improvements in PGA, PASI, and CDLQI weremaintained through week 52 (Table 8).

Table 8 Summary of primary and secondary endpoints at week 12 and week 52

Paediatric psoriasis study (CADMUS Jr.) (Age 6-11)

Week 12 Week 52

Recommended dose of Recommended dose of

Ustekinumab Ustekinumab

N(%) N(%)

Patients enrolled 44 41

PGA

PGA of cleared (0) or minimal (1) 34 (77.3%) 31 (75.6%)

PGA of cleared (0) 17 (38.6%) 23 (56.1%)

PASI

PASI 75 responders 37 (84.1%) 36 (87.8%)

PASI 90 responders 28 (63.6%) 29 (70.7%)

PASI 100 responders 15 (34.1%) 22 (53.7%)

CDLQIa

Patients with a CDLQI >1 atbaseline (N = 39) (N = 36)

CDLQI of 0 or 1 24 (61.5%) 21 (58.3%)a CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality oflife in the paediatric population. CDLQI of 0 or 1 indicates no effect on child’s quality of life.

Crohn’s Disease

The safety and efficacy of ustekinumab was assessed in three randomised, double-blind, placebo-controlled, multicentre studies in adult patients with moderately to severely active Crohn’s disease(Crohn’s Disease Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical development programconsisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 weeksubcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks oftherapy.

The induction studies included 1 409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primaryendpoint for both induction studies was the proportion of subjects in clinical response (defined as areduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analysedthrough week 8 for both studies. Concomitant doses of oral corticosteroids, immunomodulators,aminosalicylates and antibiotics were permitted and 75% of patients continued to receive at least oneof these medications. In both studies, patients were randomised to receive a single intravenousadministration of either the recommended tiered dose of approximately 6 mg/kg (see section 4.2 of the

Steqeyma 130 mg Concentrate for solution for infusion SmPC), a fixed dose of 130 mg ustekinumab,or placebo at week 0.

Patients in UNITI-1 had failed or were intolerant to prior anti-TNFα therapy. Approximately 48% ofthe patients had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies.

In this study, 29.1% of the patients had an inadequate initial response (primary non-responders),69.4% responded but lost response (secondary non-responders), and 36.4% were intolerant toanti-TNFα therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids orimmunomodulators, and were either anti-TNF-α naïve (68.6%) or had previously received but notfailed anti-TNFα therapy (31.4%).

In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical responseand remission in the ustekinumab treated group compared to placebo (Table 9). Clinical response andremission were significant as early as week 3 in ustekinumab treated patients and continued toimprove through week 8. In these induction studies, efficacy was higher and better sustained in thetiered dose group compared to the 130 mg dose group, and tiered dosing is therefore the recommendedintravenous induction dose.

Table 9 Induction of Clinical Response and Remission in UNITI-1 and UNITI-2

UNITI-1* UNITI-2**

Recommended Recommended

Placebo dose of Placebo dose of

N = 247 ustekinumab N = 209 ustekinumab

N = 249 N = 209

Clinical Remission, week 8 18 (7.3%) 52 (20.9%)a 41 (19.6%) 84 (40.2%)a

Clinical Response (100 point),week 6 53 (21.5%) 84 (33.7%)b 60 (28.7%) 116 (55.5%)a

Clinical Response (100 point),week 8 50 (20.2%) 94 (37.8%)a 67 (32.1%) 121 (57.9%)a70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a70 Point Response, week 6 75 (30.4%) 109 (43.8%)b 81 (38.8%) 135 (64.6%)a

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least100 points or being in clinical remission70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failuresa p < 0.001b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical responseat week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomisedto receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mgustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance posology, seesection 4.2).

Significantly higher proportions of patients maintained clinical remission and response in theustekinumab treated groups compared to the placebo group at week 44 (see Table 10).

Table 10 Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeksfrom initiation of the induction dose)90 mg 90 mg

Placebo* ustekinumab ustekinumab

N = 131† every 8 weeks every 12 weeks

N = 128† N = 129†

Clinical Remission 36% 53%a 49%b

Clinical Response 44% 59%b 58%b

Corticosteroid-Free Clinical Remission 30% 47%a 43%c

Clinical Remission in patients:

in remission at the start of maintenancetherapy 46% (36/79) 67% (52/78)a 56% (44/78)who entered from study CRD3002‡ 44% (31/70) 63% (45/72)c 57% (41/72)who are Anti-TNFα naïve 49% (25/51) 65% (34/52)c 57% (30/53)who entered from study CRD3001§ 26% (16/61) 41% (23/56) 39% (22/57)

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points orbeing in clinical remission

* The placebo group consisted of patients who were in response to ustekinumab and were randomised to receive placebo atthe start of maintenance therapy.† Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy‡ Patients who failed conventional therapy but not anti-TNFα therapy§ Patients who are anti-TNFα refractory/intoleranta p < 0.01b p < 0.05c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every12 weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of responsewas defined as a CDAI score ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline.

In these patients, clinical remission was achieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and

UNITI-2 induction studies (476 patients) entered into the non-randomised portion of the maintenancestudy (IM-UNITI) and received a 90 mg subcutaneous injection of ustekinumab at that time.

Eight weeks later, 50.5% of the patients achieved clinical response and continued to receivemaintenance dosing every 8 weeks; among these patients with continued maintenance dosing, amajority maintained response (68.1%) and achieved remission (50.2%) at week 44, at proportions thatwere similar to the patients who initially responded to ustekinumab induction.

Of 131 patients who responded to ustekinumab induction, and were randomised to the placebo groupat the start of the maintenance study, 51 subsequently lost response and received 90 mg ustekinumabsubcutaneously every 8 weeks. The majority of patients who lost response and resumed ustekinumabdid so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinicalresponse and 39.2% percent achieved clinical remission 16 weeks after receiving the firstsubcutaneous dose of ustekinumab.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatmentin a study extension. Among the 567 patients who entered on and were treated with ustekinumab in thestudy extension, clinical remission and response were generally maintained through week 252 for bothpatients who failed TNF-therapies and those who failed conventional therapies.

No new safety concerns were identified in this study extension with up to 5 years of treatment inpatients with Crohn’s Disease.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopicdisease activity in a substudy. The primary endpoint was change from baseline in Simplified

Endoscopic Disease Severity Score for Crohn’s Disease (SES-CD), a composite score across5 ileo-colonic segments of presence/size of ulcers, proportion of mucosal surface covered by ulcers,proportion of mucosal surface affected by any other lesions and presence/type of narrowing/strictures.

At week 8, after a single intravenous induction dose, the change in SES-CD score was greater in theustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, meanchange = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) ofustekinumab-treated patients achieved a fistula response over 44 weeks (defined as ≥ 50% reductionfrom baseline of the induction study in the number of draining fistulas) compared to 5/11 (45.5%)exposed to placebo.

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and

SF-36 questionnaires. At week 8, patients receiving ustekinumab showed statistically significantlygreater and clinically meaningful improvements on IBDQ total score and SF-36 Mental Component

Summary Score in both UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in

UNITI-2, when compared to placebo. These improvements were generally better maintained inustekinumab-treated patients in the IM-UNITI study through week 44 when compared to placebo.

Improvement in health-related quality of life was generally maintained during the extension throughweek 252.

Antibodies to ustekinumab may develop during ustekinumab treatment and most are neutralising. Theformation of anti-ustekinumab antibodies is associated with both increased clearance and reducedefficacy of ustekinumab, except in patients with Crohn’s disease where no reduced efficacy wasobserved. There is no apparent correlation between the presence of anti-ustekinumab antibodies andthe occurrence of injection site reactions.

The European Medicines Agency has deferred the obligation to submit the results of studies withustekinumab in one or more subsets of the paediatric population in Crohn’s Disease (see section 4.2for information on paediatric use).

The median time to reach the maximum serum concentration (tmax) was 8.5 days after a single 90 mgsubcutaneous administration in healthy subjects. The median tmax values of ustekinumab following asingle subcutaneous administration of either 45 mg or 90 mg in patients with psoriasis werecomparable to those observed in healthy subjects.

The absolute bioavailability of ustekinumab following a single subcutaneous administration wasestimated to be 57.2% in patients with psoriasis.

Median volume of distribution during the terminal phase (Vz) following a single intravenousadministration to patients with psoriasis ranged from 57 to 83 mL/kg.

The exact metabolic pathway for ustekinumab is unknown.

Median systemic clearance (CL) following a single intravenous administration to patients withpsoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab wasapproximately 3 weeks in patients with psoriasis, psoriatic arthritis or Crohn’s disease, ranging from15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokineticanalysis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 l/dayand 15.7 l, respectively, in patients with psoriasis. The CL/F of ustekinumab was not impacted bygender. Population pharmacokinetic analysis showed that there was a trend towards a higher clearanceof ustekinumab in patients who tested positive for antibodies to ustekinumab.

Dose linearity

The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximatelydose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kgto 4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately24 mg to 240 mg in patients with psoriasis.

Single dose versus multiple doses

Serum concentration-time profiles of ustekinumab were generally predictable after single or multiplesubcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations ofustekinumab were achieved by week 28 after initial subcutaneous doses at Weeks 0 and 4 followed bydoses every 12 weeks. The median steady-state trough concentration ranged from 0.21 μg/mL to0.26 μg/mL (45 mg) and from 0.47 μg/mL to 0.49 μg/mL (90 mg). There was no apparentaccumulation in serum ustekinumab concentration over time when given subcutaneously every12 weeks.

In patients with Crohn’s disease, following an intravenous dose of ~6 mg/kg, starting at week 8,subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks.

Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. Inpatients with Crohn’s disease, median steady-state trough concentrations ranged from 1.97 μg/mL to2.24 μg/mL and from 0.61 μg/mL to 0.76 μg/mL for 90 mg ustekinumab every 8 weeks or every12 weeks respectively. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumabevery 8 weeks were associated with higher clinical remission rates as compared to the steady-statetrough levels following 90 mg every 12 weeks.

Impact of weight on pharmacokinetics

In a population pharmacokinetic analysis using data from patients with psoriasis, body weight wasfound to be the most significant covariate affecting the clearance of ustekinumab. The median CL/F inpatients with weight > 100 kg was approximately 55% higher compared to patients with weight≤ 100 kg. The median V/F in patients with weight > 100 kg was approximately 37% higher ascompared to patients with weight ≤ 100 kg. The median trough serum concentrations of ustekinumabin patients with higher weight (> 100 kg) in the 90 mg group were comparable to those in patients withlower weight (≤ 100 kg) in the 45 mg group. Similar results were obtained from a confirmatorypopulation pharmacokinetic analysis using data from patients with psoriatic arthritis.

Dosing frequency adjustment

In patients with Crohn’s disease, based on observed data and population PK analyses, randomisedsubjects who lost response to treatment had lower serum ustekinumab concentrations over timecompared with subjects who did not lose response. In Crohn’s disease, dose adjustment from 90 mgevery 12 weeks to 90 mg every 8 weeks was associated with an increase in trough serum ustekinumabconcentrations and an accompanying increase in efficacy.

No pharmacokinetic data are available in patients with impaired renal or hepatic function.

No specific studies have been conducted in elderly patients.

The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asianpatients with psoriasis.

In patients with Crohn’s disease, variability in ustekinumab clearance was affected by body weight,serum albumin level, sex, and antibody to ustekinumab status while body weight was the maincovariate affecting the volume of distribution. Additionally in Crohn’s disease, clearance was affectedby C-reactive protein, TNF antagonist failure status and race (Asian versus non-Asian). The impact ofthese covariates was within ±20% of the typical or reference value of the respective PK parameter,thus dose adjustment is not warranted for these covariates. Concomitant use of immunomodulators didnot have a significant impact on ustekinumab disposition.

In the population pharmacokinetic analysis, there were no indications of an effect of tobacco oralcohol on the pharmacokinetics of ustekinumab.

Serum ustekinumab concentrations in paediatric psoriasis patients 6 to 17 years of age, treated with therecommended weight-based dose were generally comparable to those in the adult psoriasis populationtreated with the adult dose. Serum ustekinumab concentrations in paediatric psoriasis patients12-17 years of age (CADMUS) treated with half of the recommended weight-based dose weregenerally lower than those in adults.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitrostudy using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did notalter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).

A phase 1, open-label, drug interaction study, Study CNTO1275CRD1003, was conducted to evaluatethe effect of ustekinumab on cytochrome P450 enzyme activities following induction and maintenancedosing in patients with active Crohn’s disease (n=18). No clinically significant changes in exposure ofcaffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate),dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when usedconcomitantly with ustekinumab at the approved recommended dosing in patients with Crohn’sdisease (see section 4.5).

Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies ofrepeated-dose toxicity and developmental and reproductive toxicity, including safety pharmacologyevaluations. In developmental and reproductive toxicity studies in cynomolgus monkeys, neitheradverse effects on male fertility indices nor birth defects or developmental toxicity were observed. Noadverse effects on female fertility indices were observed using an analogous antibody to IL-12/23 inmice.

Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalentdose intended to be administered to psoriasis patients and resulted in peak serum concentrations inmonkeys that were more than 100-fold higher than observed in humans.

Carcinogenicity studies were not performed with ustekinumab due to the lack of appropriate modelsfor an antibody with no cross-reactivity to rodent IL-12/23 p40.

L-histidine

L-histidine monohydrochloride monohydrate

Polysorbate 80 (E433)

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Steqeyma 45 mg solution for injection1 year

Individual vials may be stored at room temperature up to 30 °C for a maximum single period of up to15 days in the original carton in order to protect from light. Record the date when the vial is firstremoved from the refrigerator and the discard date in the space provided on the outer carton. Thediscard date must not exceed the original expiry date printed on the carton. Once a vial has been storedat room temperature (up to 30 °C), it should not be returned to the refrigerator. Discard the vial if notused within 15 days at room temperature storage or by the original expiry date, whichever is earlier.

Steqeyma 45 mg solution for injection in pre-filled syringe3 years

Steqeyma 90 mg solution for injection in pre-filled syringe3 years

Individual pre-filled syringes may be stored at room temperature up to 30 °C for a maximum singleperiod of up to 31 days in the original carton in order to protect from light. Record the date when thepre-filled syringe is first removed from the refrigerator and the discard date in the space provided onthe outer carton. The discard date must not exceed the original expiry date printed on the carton. Oncea syringe has been stored at room temperature (up to 30 °C), it should not be returned to therefrigerator. Discard the syringe if not used within 31 days at room temperature storage or by theoriginal expiry date, whichever is earlier.

Store in a refrigerator (2 °C - 8 °C). Do not freeze.

Keep the vial or pre-filled syringe in the outer carton in order to protect from light.

If needed, individual pre-filled syringes or vials may be stored at room temperature up to 30 °C (seesection 6.3).

Steqeyma 45 mg solution for injection0.5 mL solution in a type I glass 3 mL vial closed with a coated butyl rubber stopper.

Steqeyma 45 mg solution for injection in pre-filled syringe0.5 mL solution in a type I glass 1 mL syringe with a staked hypodermic stainless steel needle and aflexible needle shield made of styrene-butadien rubber. The syringe is fitted with a safety guard thatautomatically shields the needle after dose administration.

Steqeyma 90 mg solution for injection in pre-filled syringe1 mL solution in a type I glass 1 mL syringe with a staked hypodermic stainless steel needle and aflexible needle shield made of styrene-butadien rubber. The syringe is fitted with a safety guard thatautomatically shields the needle after dose administration.

Steqeyma is available in a pack of 1 vial or pre-filled syringe.

The solution in the Steqeyma vial or pre-filled syringe should not be shaken. The solution should bevisually inspected for particulate matter or discolouration prior to subcutaneous administration. Thesolution is clear to slightly opalescent, colourless to pale yellow and may contain a few smalltranslucent or white particles of protein. This appearance is not unusual for proteinaceous solutions.

The medicinal product should not be used if the solution is discoloured or cloudy, or if foreignparticulate matter is present. Before administration, Steqeyma should be allowed to reach roomtemperature (approximately half an hour). Detailed instructions for administration are provided in thepackage leaflet.

Steqeyma does not contain preservatives; therefore any unused medicinal product remaining in thevial or the syringe should not be used. Steqeyma is supplied as a sterile, single-use vial or single-usepre-filled syringe. The syringe, needle and vial must never be re-used. Any unused medicinal productor waste material should be disposed of in accordance with local requirements.

When using the single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch (13 mm) needle isrecommended.

Celltrion Healthcare Hungary Kft.1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Steqeyma 45 mg solution for injection

EU/1/24/1844/004

Steqeyma 45 mg solution for injection in pre-filled syringe

EU/1/24/1844/001

Steqeyma 90 mg solution for injection in pre-filled syringe

EU/1/24/1844/002

Date of first authorisation: 22 Aug 2024

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

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