STELARA 90mg 90mg / ml injection for pre-filled pen medication leaflet

STELARA 45 mg solution for injection in pre-filled pen

STELARA 90 mg solution for injection in pre-filled pen

STELARA 45 mg solution for injection in pre-filled pen

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

STELARA 90 mg solution for injection in pre-filled pen

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

Ustekinumab is a fully human IgG1κ monoclonal antibody to interleukin (IL)-12/23 produced in amurine myeloma cell line using recombinant DNA technology.

For the full list of excipients, see section 6.1.

STELARA 45 mg solution for injection in pre-filled pen

Solution for injection.

STELARA 90 mg solution for injection in pre-filled pen

Solution for injection.

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

Plaque psoriasis

STELARA 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).

Psoriatic arthritis (PsA)

STELARA, 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-modifyinganti-rheumatic drug (DMARD) therapy has been inadequate (see section 5.1).

Crohn’s Disease

STELARA 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.

STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerativecolitis who have had an inadequate response with, lost response to, or were intolerant to eitherconventional therapy or a biologic.

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

Plaque psoriasis

The recommended posology of STELARA 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 STELARA 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).

STELARA has not been studied in these patient populations. No dose recommendations can be made.

The safety and efficacy of STELARA in children with psoriasis less than 6 years of age or in childrenwith psoriatic arthritis less than 18 years of age have not yet been established. The pre-filled pen hasnot been studied in the paediatric population and is not recommended for use in paediatric patients.

See section 4.2 of the pre-filled syringe SmPC for posology and method of adminstation in paediaticpatients 6 years and older with psoriasis.

Crohn’s Disease and Ulcerative Colitis

In the treatment regimen, the first dose of STELARA is administered intravenously. For the posologyof the intravenous dosing regimen, see section 4.2 of the STELARA 130 mg Concentrate for solutionfor infusion SmPC.

The first subcutaneous administration of 90 mg STELARA 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 STELARA. Inpatients who have responded to treatment with STELARA, corticosteroids may be reduced ordiscontinued in accordance with standard of care.

In Crohn’s disease or Ulcerative Colitis, if therapy is interrupted, resumption of treatment withsubcutaneous dosing every 8 weeks is safe and effective.

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

STELARA has not been studied in these patient populations. No dose recommendations can be made.

The safety and efficacy of STELARA for the treatment of Crohn’s disease in paediatric patientsweighing less than 40 kg or ulcerative colitis in children less than 18 years have not yet beenestablished. No data are available. The pre-filled pen has not been studied in the paediatric populationand is not recommended for use in paediatric patients. See section 4.2 of the Concentrate for solutionfor infusion and pre-filled syringe SmPC for posology and method of administration in paediatricpatients weighing at least 40 kg with Crohn’s disease.

STELARA 45 mg and 90 mg pre-filled pens are for subcutaneous injection only. If possible, areas ofthe skin that show psoriasis should be avoided as injection sites.

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

STELARA 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 STELARA 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 tradename and the batchnumber of 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 STELARA (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 STELARA in patients with a chronicinfection or a history of recurrent infection (see section 4.3).

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

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

STELARA should be monitored closely for signs and symptoms of active tuberculosis during andafter treatment.

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 STELARAshould not be administered until the infection resolves.

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Somepatients who received STELARA 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 STELARA. Thus, caution should beexercised when considering the use of STELARA 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

STELARA 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 STELARA in a post-marketing observational study.

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

Latex sensitivity

The needle cover inside the bottom cap of the pre-filled pen is manufactured from dry natural rubber(a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin(BCG)) should not be given concurrently with STELARA. Specific studies have not been conductedin patients 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 STELARA. Before live viralor live bacterial vaccination, treatment with STELARA should be withheld for at least 15 weeks afterthe 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 STELARA may receive concurrent inactivated or non-live vaccinations.

Long term treatment with STELARA 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 STELARA 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 STELARA. In Crohn’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of STELARA. Caution should be exercised whenconsidering concomitant use of other immunosuppressants and STELARA or when transitioning fromother immunosuppressive biologics (see section 4.5).

Immunotherapy

STELARA has not been evaluated in patients who have undergone allergy immunotherapy. It is notknown whether STELARA 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. STELARA 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 STELARA wereobserved 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

STELARA contains 0.04 mg (90 mg/1.0mL) 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 STELARA.

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 STELARA 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 STELARA. In Crohn’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of STELARA (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 to

STELARA 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 STELARA 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 STELARA must be made taking into account the benefit of breast-feeding to the childand the benefit of STELARA therapy to the woman.

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

STELARA 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 STELARA 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 STELARA 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 least 1year (3,648 patients). 2,194 patients with psoriasis, Crohn’s disease or ulcerative colitis were exposedfor atleast 4 years while 1,148 patients with psoriasis or Crohn’s disease were exposed for at least 5years.

Table 1 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 1: 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, lowerrespiratory tract infection, viral upper respiratory tract infection,vulvovaginal mycotic infection

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 exposure in 6,710 patients, themedian follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for Crohn’s diseasestudies and 2.3 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancerswere reported in 76 patients in 15,205 patient-years of follow-up (incidence of 0.50 per 100 patient-years of follow-up for ustekinumab-treated patients). The incidence of malignancies reported inustekinumab-treated patients was comparable to the incidence expected in the general population(standardised incidence ratio = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, genderand race). The most frequently observed malignancies, other than non-melanoma skin cancer, wereprostate, melanoma, colorectal, and breast cancers. The incidence of non-melanoma skin cancer was0.46 per 100 patient-years of follow-up for ustekinumab-treated patients (69 patients in15,165 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers(3:1) is comparable with the ratio expected in the general population (see section 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).

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.

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the sharedp40 protein 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-12R1 receptorprotein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that isalready bound to IL-12R1 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, Crohn’s diseaseand ulcerative colitis.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects inpsoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis through interruption of the Th1 and

Th17 cytokine pathways, 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.

In patients with ulcerative colitis, treatment with ustekinumab resulted in a decrease in inflammatorymarkers including CRP and fecal calprotectin during the induction phase, which was maintainedthroughout the maintenance phase and study extension through week 200.

During the long term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated with

STELARA 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 STELARA-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 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 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 2 and 3).

Table 2: Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2(PHOENIX 2)

Week 28

Week 123 doses (week 0, week 42 doses (week 0 and week 4)and week 16)

PBO 45 mg 90 mg 45 mg 90 mg

Psoriasis Study 1

Number of patients255 255 256 250 243randomised

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 N10 (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 patients410 409 411 397 400randomised

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 N18 (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 3: Summary of clinical response at week 12 in Psoriasis Study 3 (ACCEPT)

Psoriasis Study 3

Etanercept Ustekinumab24 doses 2 doses (week 0 and week 4)(50 mg twice a45 mg 90 mgweek)

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 withanti-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 4 below.

Table 4 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 ofpatients 206 205 204 104 103 105randomised

ACR 2047 (23%) 87 (42%)a 101 (50%)a 21 (20%) 45 (44%)a 46 (44%)aresponse, N (%)

ACR 5018 (9%) 51 (25%)a 57 (28%)a 7 (7%) 18 (17%)b 24 (23%)aresponse, N (%)

ACR 705 (2%) 25 (12%)a 29 (14%)a 3 (3%) 7 (7%)c 9 (9%)cresponse, N (%)

Number of patients146 145 149 80 80 81with ≥ 3% BSAd

PASI 7516 (11%) 83 (57%)a 93 (62%)a 4 (5%) 41 (51%)a 45 (56%)aresponse, N (%)

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

Combined

PASI 75 and8 (5%) 40 (28%)a 62 (42%)a 2 (3%) 24 (30%)a 31 (38%)a

ACR 20response, N (%)

Number of154 153 154 74 74 73patients ≤ 100 kg

ACR 2039 (25%) 67 (44%) 78 (51%) 17 (23%) 32 (43%) 34 (47%)response, N (%)

Number of patients105 105 111 54 58 57with ≥ 3% BSAd

PASI 7514 (13%) 64 (61%) 73 (66%) 4 (7%) 31 (53%) 32 (56%)response, N (%)

Number of52 52 50 30 29 31patients > 100 kg

ACR 208 (15%) 20 (38%) 23 (46%) 4 (13%) 13 (45%) 12 (39%)response, N (%)

Number of patients41 40 38 26 22 24with ≥ 3% BSAd

PASI 752 (5%) 19 (48%) 20 (53%) 0 10 (45%) 13 (54%)response, N (%)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. Thepre-filled pen has not been studied in the paediatric psoriasis population and is not recommended foruse by paediatric patients.

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

STELARA 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-TNF 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 to anti-

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 5). 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 5: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1* UNITI-2**

Placebo Recommende Placebo Recommende

N = 247 d dose of N = 209 d dose ofustekinumab 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 6).

Table 6: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks frominitiation of the induction dose)

Placebo* 90 mg 90 mgustekinumab ustekinumabevery 8 weeks every 12 weeks

N = 131†

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 maintenance 46% (36/79) 67% (52/78)a 56% (44/78)therapywho 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 pointsor being in clinical remission

* The placebo group consisted of patients who were in response to ustekinumab and were randomised to receive placeboat the 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/intolerant.a 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 across 5 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.

The safety and efficacy of ustekinumab was assessed in two randomised, double-blind, placebo-controlled, multicentre studies in adult patients with moderately to severely active ulcerative colitis(Mayo score 6 to 12; Endoscopy subscore ≥ 2). The clinical development program consisted of oneintravenous induction study (referred to as UNIFI-I) with treatment of up to 16 weeks followed by a44 week subcutaneous randomised withdrawal maintenance study (referred to as UNIFI-M)representing at least 52 weeks of therapy.

Efficacy results presented for UNIFI-I and UNIFI-M were based on central review of endoscopies.

UNIFI-I included 961 patients. The primary endpoint for the induction study was the proportion ofsubjects in clinical remission at week 8. Patients were randomised to receive a single intravenousadministration of either the recommended tiered dose of approximately 6 mg/kg (see Table 1,section 4.2), a fixed dose of 130 mg ustekinumab, or placebo at week 0.

Concomitant doses of oral corticosteroids, immunomodulators, and aminosalicylates were permittedand 90% of patients continued to receive at least one of these medications. Enrolled patients had tohave failed conventional therapy (corticosteroids or immunomodulators) or at least one biologic (a

TNFα antagonist and/or vedolizumab). 49% of patients had failed conventional therapy, but not abiologic (of which 94% where biological-naïve). 51% of patients had failed or were intolerant to abiologic. Approximately 50% of the patients had failed at least 1 prior anti-TNF therapy (of which48% were primary non-responders) and 17% had failed at least 1 anti-TNFα therapy and vedolizumab.

In UNIFI-I a significantly greater proportion of patients were in clinical remission in the ustekinumabtreated group compared to placebo at week 8 (Table 7). As early as Week 2, the earliest scheduledstudy visit, and at each visit thereafter, a higher proportion of ustekinumab patients had no rectalbleeding or achieved normal stool frequency as compared with placebo patients. Significantdifferences in partial Mayo score and symptomatic remission were observed between ustekinumab andplacebo as early as Week 2.

Efficacy was higher in the tiered dose group (6 mg/kg) compared to the 130 mg dose group in selectendpoints, and tiered dosing is therefore the recommended intravenous induction dose.

Table 7: Summary of Key Efficacy Outcomes in UNIFI-I (Week 8)

Placebo Recommended dose

N = 319 of ustekinumab£

N = 322

Clinical Remission* 5% 16%a

In patients who failed conventional therapy, but not a 9% (15/158) 19% (29/156)cbiologic

In patients who failed biological therapy¥ 1% (2/161) 13% (21/166)b

In patients who failed both a TNF and vedolizumab 0% (0/47) 10% (6/58%)c

Clinical Response§ 31% 62%a

In patients who failed conventional therapy, but not a 35% (56/158) 67% (104/156)bbiologic

In patients who failed biological therapy¥ 27% (44/161) 57% (95/166)b

In patients who failed both a TNF and vedolizumab 28% (13/47) 52% (30/58)c

Mucosal Healing† 14% 27%a

In patients who failed conventional therapy, but not a 21% (33/158) 33% (52/156)cbiologic

In patients who failed biological therapy 7% (11/161) 21% (35/166)b

Symptomatic Remission‡ 23% 45%b

Combined Symptomatic Remission and Mucosal 8% 21%b

Healing⸸£ Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 1.

* Clinical remission is defined as Mayo score ≤2 points, with no individual subscore > 1.§ Clinical response is defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, with either a decreasefrom baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1.¥ A TNFα antagonist and/or vedolizumab.† Mucosal healing is defined as a Mayo endoscopic subscore of 0 or 1.‡ Symptomatic remission is defined as a Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0.⸸ Combined symptomatic remission and mucosal healing is defined as a stool frequency subscore of 0 or 1, a rectalbleeding subscore of 0, and an endoscopy subscore of 0 or 1.a p < 0.001b Nominally significant (p < 0.001)c Nominally significant (p < 0.05)

UNIFI-M, evaluated 523 patients who achieved clinical response with single IV administration ofustekinumab in UNIFI-I. Patients were randomised to receive a subcutaneous maintenance regimen ofeither 90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12 weeks or placebo for 44 weeks(for recommended maintenance posology, see section 4.2 of the STELARA Solution for injection(vial) and Solution for injection in pre-filled syringe SmPC or pre-filled pen SmPC).

Significantly greater proportions of patients were in clinical remission in both ustekinumab treatedgroups compared to the placebo group at week 44 (see Table 8).

Table 8: Summary of Key Efficacy Measures in UNIFI-M (week 44; 52 weeks from initiation of theinduction dose)

Placebo* 90 mg 90 mg

N = 175 ustekinumab ustekinumabevery 8 Weeks every

N = 176 12 Weeks

N = 172

Clinical Remission** 24% 44% a 38% b

In patients who failed conventional 31% (27/87) 48% (41/85)d 49% (50/102) dtherapy, but not a biologic

In patients who failed biological therapy¥ 17% (15/88) 40% (36/91) c 23% (16/70) d

In patients who failed both a TNF and 15% (4/27) 33% (7/21)e 23% (5/22)evedolizumab

Maintenance of Clinical Response through 45% 71% a 68% aweek 44§

In patients who failed conventional 51% (44/87) 78% (66/85) c 77% (78/102) ctherapy, but not a biologic

In patients who failed biological therapy¥ 39% (34/88) 65% (59/91) c 56% (39/70) d

In patients who failed both a TNF and 41% (11/27) 67% (14/21)e 50% (11/22)evedolizumab

Mucosal Healing† 29% 51% a 44% b

Maintenance of Clinical Remission through 38% (17/45) 58% (22/38) 65% (26/40) cweek 44£

Corticosteroid Free Clinical Remission€ 23% 42% a 38% b

Durable Remissionǁ 35% 57% c 48% d

Symptomatic Remission‡ 45% 68% c 62% d

Combined Symptomatic Remission and 28% 48% c 41% d

Mucosal Healing⸸

* Following response to IV ustekinumab.

** Clinical remission is defined as Mayo score ≤2 points, with no individual subscore > 1.§ Clinical response is defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, with either adecrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1.¥ A TNFα antagonist and/or vedolizumab.† Mucosal healing is defined as a Mayo endoscopic sub-score of 0 or 1.£ Maintenance of clinical remission through Week 44 is defined as patients in clinical remission through Week 44among patients in clinical remission at maintenance baseline.€ Corticosteroid-free clinical remission is defined as patients in clinical remission and not receiving corticosteroids at

Week 44.ǁ Durable Remission is defined as partial Mayo remission at ≥80% of all visits prior to Week 44 and in partial Mayoremission at last visit (Week 44).‡ Symptomatic remission is defined as a Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0.⸸ Combined symptomatic remission and mucosal healing is defined as a stool frequency subscore of 0 or 1, a rectalbleeding subscore of 0, and an endoscopy subscore of 0 or 1.a p < 0.001b p < 0.05c Nominally significant (p < 0.001)d Nominally significant (p < 0.05)e Not statistically significant

The beneficial effect of ustekinumab on clinical response, mucosal healing and clinical remission wasobserved in induction and in maintenance both in patients who failed conventional therapy but not abiologic therapy, as well as in those who had failed at least one prior TNFα antagonist therapyincluding in patients with a primary non-response to TNFα antagonist therapy. A beneficial effect wasalso observed in induction in patients who failed at least one prior TNFα antagonist therapy andvedolizumab, however the number of patients in this subgroup was too small to draw definitiveconclusions about the beneficial effect in this group during maintenance.

Week 16 Responders to Ustekinumab Induction

Ustekinumab treated patients who were not in response at week 8 of UNIFI-I received anadministration of 90 mg SC ustekinumab at week 8 (36% of patients). Of those patients, 9% ofpatients who were initially randomised to the recommended induction dose achieved clinical remissionand 58% achieved clinical response at Week 16.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNFI-I study butwere in response at week 16 (157 patients) entered into the non-randomised portion of UNIFI-M andcontinued to receive maintenance dosing every 8 weeks; among these patients, a majority (62%)maintained response and 30% achieved remission at week 44.

Study Extension

In UNIFI, patients who completed the study through week 44 were eligible to continue treatment in astudy extension. Among the 400 patients who entered on and were treated with ustekinumab every 12or 8 weeks in the study extension, symptomatic remission was generally maintained through week 200for patients who failed conventional therapy (but not a biologic therapy) and those who failed biologictherapy, including those who failed both anti-TNF and vedolizumab. Among patients who received4 years of ustekinumab treatment and were assessed using the full Mayo score at maintenanceweek 200, 74.2% (69/93) and 68.3% (41/60) maintained mucosal healing and clinical remission,respectively.

The safety analysis including 457 patients (1289.9 person-years) followed up to 220 weeks showed asafety profile between week 44 and 220 that was comparable with that observed up to week 44.

No new safety concerns were identified in this study extension with up to 4 years of treatment inpatients with ulcerative colitis.

Endoscopic Normalisation

Endoscopic normalisation was defined as a Mayo endoscopic subscore of 0 and was observed as earlyas week 8 of UNIFI-I. At week 44 of UNIFI-M, it was achieved in 24% and 29% of patients treatedwith ustekinumab every 12 or 8 weeks, respectively, as compared to 18% of patients in the placebogroup.

Histologic & Histo-Endoscopic Mucosal Healing

Histologic healing (defined as neutrophil infiltration in < 5% of crypts, no crypt destruction, and noerosions, ulcerations, or granulation tissue) was assessed at week 8 of UNIFI-I and Week 44 of

UNIFI-M. At week 8, after a single intravenous induction dose, significantly greater proportions ofpatients in the recommended dose group achieved histologic healing (36%) compared with patients inthe placebo group (22%). At Week 44 maintenance of this effect was observed with significantly morepatients in histologic healing in the every 12 week (54%) and every 8 week (59%) ustekinumab groupsas compared to placebo (33%).

A combined endpoint of histo-endoscopic mucosal healing defined as subjects having both mucosalhealing and histologic healing was evaluated at week 8 of UNIFI-I and week 44 of UNIFI-M. Patientsreceiving ustekinumab at the recommended dose showed significant improvements on the histo-endoscopic mucosal healing endpoint at week 8 in the ustekinumab group (18%) as compared to theplacebo group (9%). At week 44, maintenance of this effect was observed with significantly morepatients in histo-endoscopic mucosal healing in the every 12 week (39%) and every 8 week (46%)ustekinumab groups as compared to placebo (24%).

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

SF-36 and EuroQoL-5D (EQ-5D) questionnaires.

At week 8 of UNIFI-I, patients receiving ustekinumab showed significantly greater and clinicallymeaningful improvements on IBDQ total score, EQ-5D and EQ-5D VAS, and SF-36 Mental

Component Summary Score and SF-36 Physical Component Summary Score when compared toplacebo. These improvements were maintained in ustekinumab-treated patients in UNIFI-M throughweek 44. Improvement in health-related quality of life as measured by IBDQ and SF-36 was generallymaintained during the extension through week 200.

Patients receiving ustekinumab experienced significantly more improvements in work productivity asassessed by greater reductions in overall work impairment and in activity impairment as assessed bythe WPAI-GH questionnaire than patients receiving placebo.

Hospitalisations and ulcerative colitis (UC) related surgeries

Through week 8 of UNIFI-I, the proportions of subjects with UC disease related hospitalisations weresignificantly lower for subjects in the ustekinumab recommended dose group (1.6%, 5/322) comparedwith subjects in the placebo group (4.4%, 14/319) and no subjects underwent UC disease relatedsurgeries in subjects receiving ustekinumab at the recommended induction dose compared to 0.6%(2/319) subjects in the placebo group.

Through week 44 of UNIFI-M, a significantly lower number of UC-related hospitalisations wasobserved in subjects in the combined ustekinumab group (2.0%, 7/348) as compared with subjects inthe placebo group (5.7%, 10/175). A numerically lower number of subjects in the ustekinumab group(0.6%, 2/348) underwent UC disease related surgeries compared with subjects in the placebo group(1.7%, 3/175) through week 44.

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 or ulcerative colitis where no reducedefficacy was observed. There is no apparent correlation between the presence of anti-ustekinumabantibodies and the 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 and ulcerativecolitis. The pre-filled pen has not been studied in the paediatric population and is not recommendedfor use by paediatric patients.

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, Crohn’s disease or ulcerativecolitis, ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a populationpharmacokinetic analysis, the apparent clearance (CL/F) and apparent volume of distribution (V/F)were 0.465 l/day and 15.7 l, respectively, in patients with psoriasis. The CL/F of ustekinumab was notimpacted by gender. Population pharmacokinetic analysis showed that there was a trend towards ahigher clearance of 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 and ulcerative colitis, following an intravenous dose of ~6 mg/kg,starting at week 8, subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8or 12 weeks. Steady state ustekinumab concentration was achieved by the start of the secondmaintenance dose. In patients with Crohn’s disease, median steady-state trough concentrations rangedfrom 1.97 μg/mL to 2.24 μg/mL and from 0.61 μg/mL to 0.76 μg/mL for 90 mg ustekinumab every8 weeks or every 12 weeks respectively. In patients with ulcerative colitis, median steady-state troughconcentrations ranged from 2.69 μg/mL to 3.09 μg/mL and from 0.92 μg/mL to 1.19 μg/mL for 90 mgustekinumab every 8 weeks or every 12 weeks. The steady-state trough ustekinumab levels resultingfrom 90 mg ustekinumab every 8 weeks were associated with higher clinical remission rates ascompared to the steady-state trough 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 and ulcerative colitis, based on observed data and population PKanalyses, randomised subjects who lost response to treatment had lower serum ustekinumabconcentrations over time compared with subjects who did not lose response. In Crohn’s disease, doseadjustment from 90 mg every 12 weeks to 90 mg every 8 weeks was associated with an increase intrough serum ustekinumab concentrations and an accompanying increase in efficacy. In ulcerativecolitis, population PK model based simulations demonstrated that adjusting dosing from 90 mg every12 weeks to every 8 weeks would be expected to result in a 3-fold increase in steady-state troughustekinumab concentrations. Additionally on the basis of clinical trial data in patients with ulcerativecolitis, a positive exposure-response relationship was established between trough concentrations, andclinical remission and mucosal healing.

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 and ulcerative colitis.

In patients with Crohn’s disease and ulcerative colitis, variability in ustekinumab clearance wasaffected by body weight, serum albumin level, sex, and antibody to ustekinumab status while bodyweight was the main covariate affecting the volume of distribution. Additionally in Crohn’s disease,clearance was affected by C-reactive protein, TNF antagonist failure status and race (Asian versusnon-Asian). The impact of these covariates was within ± 20% of the typical or reference value of therespective PK parameter, thus dose adjustment is not warranted for these covariates. Concomitant useof immunomodulators did not 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.

The bioavailability of ustekinumab following administration by syringe or pre-filled pen wascomparable.

The pre-filled pen has not been studied in the paediatric population and is not recommended for use bypaediatric patients.

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.

STELARA 45 mg solution for injection in pre-filled pen3 years

STELARA 90 mg solution for injection in pre-filled pen3 years

Individual pre-filled pens may be stored at room temperature up to 30°C for a maximum single periodof up to 30 days in the original carton in order to protect from light. Record the date when the pre-filled pen is first removed from the refrigerator and the discard date in the space provided on the outercarton. The discard date must not exceed the original expiry date printed on the carton. Once a pre-filled pen has been stored at room temperature (up to 30°C), it should not be returned to therefrigerator. Discard the pre-filled pen if not used within 30 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 pre-filled pen in the outer carton in order to protect from light.

If needed, individual pre-filled pens may be stored at room temperature up to 30°C (see section 6.3).

STELARA 45 mg solution for injection in pre-filled pen0.5 mL solution in a type I glass 1 mL syringe with a fixed stainless steel needle assembled in apre-filled pen with a passive needle guard. The needle cover inside the bottom cap of the pre-filled pencontains dry natural rubber (a derivative of latex).

STELARA 90 mg solution for injection in pre-filled pen1 mL solution in a type I glass 1 mL syringe with a fixed stainless steel needle assembled in apre-filled pen with a passive needle guard. The needle cover inside the bottom cap of the pre-filled pencontains dry natural rubber (a derivative of latex).

STELARA is available in a pack of 1 pre-filled pen.

The solution in the STELARA pre-filled pen should not be shaken. The solution should be visuallyinspected for particulate matter or discolouration prior to subcutaneous administration. The solution isclear to slightly opalescent, colourless to light yellow and may contain a few small translucent orwhite particles of protein. This appearance is not unusual for proteinaceous solutions. The medicinalproduct should not be used if the solution is discoloured or cloudy, or if foreign particulate matter ispresent. Before administration, STELARA should be allowed to reach room temperature(approximately half an hour). Detailed instructions for use are provided in the package leaflet.

STELARA does not contain preservatives; therefore any unused medicinal product remaining in thepre-filled pen should not be used. STELARA is supplied as a sterile, single-use pre-filled pen. Thepre-filled pen must never be re-used. Any unused medicinal product or waste material should bedisposed of in accordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

STELARA 45 mg solution for injection in pre-filled pen

EU/1/08/494/006

STELARA 90 mg solution for injection in pre-filled pen

EU/1/08/494/007

Date of first authorisation: 16 January 2009

Date of latest renewal: 19 September 2013

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

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