STELARA 130mg perfusive solution concentrate medication leaflet

STELARA 130 mg concentrate for solution for infusion

Each vial contains 130 mg ustekinumab in 26 mL (5 mg/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.

Concentrate for solution for infusion.

The solution is clear, colourless to light yellow.

Adult 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.

Paediatric Crohn's Disease

STELARA is indicated for the treatment of moderately to severely active Crohn’s disease in paediatricpatients weighing at least 40 kg, who have had an inadequate response to, or were intolerant to eitherconventional or biologic therapy.

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 concentrate for solution for infusion is intended for use under the guidance and supervisionof physicians experienced in the diagnosis and treatment of Crohn's disease or ulcerative colitis.

STELARA concentrate for solution for infusion should only be used for the intravenous inductiondose.

Crohn’s Disease and Ulcerative Colitis

STELARA treatment is to be initiated with a single intravenous dose based on body weight. Theinfusion solution is to be composed of the number of vials of STELARA 130 mg as specified in

Table 1 (see section 6.6 for preparation).

Table 1 Initial intravenous dosing of STELARA

Body weight of patient at the time of Recommended dosea Number of 130 mgdosing STELARA Vials≤ 55 kg 260 mg 2> 55 kg to ≤ 85 kg 390 mg 3> 85 kg 520 mg 4a Approximately 6 mg/kg

The first subcutaneous dose should be given at week 8 following the intravenous dose. For theposology of the subsequent subcutaneous dosing regimen, see section 4.2 of the STELARA solutionfor injection (vial) and solution for injection in pre-filled syringe SmPC or pre-filled pen SmPC.

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.

Paediatric Crohn's disease (patients weighing at least 40 kg)

STELARA treatment is to be initiated with a single intravenous dose based on body weight. Theinfusion solution is to be composed of the number of vials of STELARA 130 mg as specified in

Table 2 (see section 6.6 for preparation).

Table 2 Initial intravenous dosing of STELARA

Body weight of patient at the time of Recommended dosea Number of 130 mgdosing STELARA Vials≥ 40 kg to ≤ 55 kg 260 mg 2> 55 kg to ≤ 85 kg 390 mg 3> 85 kg 520 mg 4a Approximately 6 mg/kg

The first subcutaneous dose should be given at week 8 following the intravenous dose. For theposology of the subsequent subcutaneous dosing regimen, see section 4.2 of the STELARA solutionfor injection (vial) and solution for injection in prefilled syringe SmPC.

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.

STELARA 130 mg is for intravenous use only. It should be administered over at least one hour.

For instructions on dilution of the medicinal product before administration, 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).

Infusion-related reactions were observed in clinical trials (see section 4.8). Serious infusion-relatedreactions including anaphylactic reactions to the infusion have been reported in the post-marketingsetting. If a serious or life-threatening reaction is observed, appropriate therapy should be institutedand ustekinumab should be discontinued.

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.

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.

STELARA contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

STELARA is however, diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This shouldbe taken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate 80

STELARA contains 10.8 mg of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.40mg/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 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, 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 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 excludingnon-melanoma skin cancers were 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 incidenceof malignancies 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 thannon-melanoma skin cancer, were prostate, melanoma, colorectal, and breast cancers. The incidence ofnon-melanoma skin cancer was 0.46 per 100 patient-years of follow-up for ustekinumab-treatedpatients (69 patients in 15,165 patient-years of follow-up). The ratio of patients with basal versussquamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (seesection 4.4).

Hypersensitivity and infusion reactions

In Crohn’s disease and ulcerative colitis intravenous induction studies, no events of anaphylaxis orother serious infusion reactions were reported following the single intravenous dose. In these studies,2.2% of 785 placebo-treated patients and 1.9% of 790 patients treated with the recommended dose ofustekinumab reported adverse events occurring during or within an hour of the infusion. Seriousinfusion-related reactions including anaphylactic reactions to the infusion have been reported in thepost-marketing setting (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.

Paediatric patients weighing at least 40 kg with Crohn’s disease

The safety of ustekinumab has been studied in one phase 1 and one phase 3 study of paediatric patientswith moderately to severely active Crohn’s disease up to week 240 and week 52, respectively. Ingeneral, the safety profile in this cohort (n = 71) was similar to that seen in previous studies in adultswith Crohn’s disease.

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.

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’sdisease (Crohn’s Disease Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical developmentprogram consisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a44 week subcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeksof therapy.

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 Table 1,section 4.2), 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 4). 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 4: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1* UNITI-2**

Placebo Recommended Placebo Recommended

N = 247 dose of N = 209 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 of the STELARA Solution for injection (vial) and Solution for injection in pre-filledsyringe SmPC or pre-filled pen SmPC).

Significantly higher proportions of patients maintained clinical remission and response in theustekinumab treated groups compared to the placebo group at week 44 (see Table 5).

Table 5: 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 every12 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/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 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 6). 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 6: 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 9% (15/158) 19% (29/156)ca biologic

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 35% (56/158) 67% (104/156)ba biologic

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 21% (33/158) 33% (52/156)ca biologic

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 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 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 7).

Table 7: 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)therapy, but not a biologic d

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 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 colits (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 increased clearance of ustekinumab inpatients with Crohn’s disease or ulcerative colitis. No reduced efficacy was observed. There is noapparent correlation between the presence of anti-ustekinumab antibodies and the occurrence ofinjection 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 (see section 4.2 for information on paediatric use).

The safety and efficacy of ustekinumab was evaluated in 48 paediatric patients weighing at least40 kg, in an interim analysis of a multicentre phase 3 study (UNITI-Jr) for paediatric patients withmoderately to severely active Crohn's disease (defined by a Paediatric Crohn’s Disease Activity Index[PCDAI] score >30) through 52 weeks of treatment (8 weeks of induction and 44 weeks ofmaintenance treatment). Patients included in the study either had not adequately responded to or hadnot tolerated prior biologic therapy or conventional therapy for Crohn’s disease. The study included anopen-label induction treatment with a single ustekinumab intravenous dose, of approximately 6 mg/kg(see section 4.2), followed by a randomised double-blind subcutaneous maintenance regimen of 90 mgustekinumab administered either every 8 weeks or every 12 weeks.

The primary endpoint of the study was clinical remission at induction week 8 (defined as PCDAI score≤ 10). The proportion of patients who achieved clinical remission was 52.1% (25/48) and iscomparable to that observed in the adult ustekinumab phase 3 studies.

Clinical response was observed as early as week 3. The proportion of patients in clinical response atweek 8 (defined as a reduction from baseline in the PCDAI score of >12.5 points with a total PCDAIscore not more than 30) was 93.8% (45/48).

Table 8 presents the analyses for the secondary endpoints through maintenance week 44.

Table 8: Summary of Secondary endpoints through Maintenance week 4490 mg 90 mg Total number ofustekinumab ustekinumab patientsevery 8 weeks every 12 weeks N = 48

N = 23 N = 25

Clinical Remission * 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)

Corticosteroid-free Clinical 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)

Remission §

Clinical remission for patients who 64.3% (9/14) 54.5% (6/11) 60.0% (15/25)were in clinical remission atinduction week 8 *

Clinical Response † 52.2% (12/23) 60.0% (15/25) 56.3% (27/48)

Endoscopic response £ 22.7% (5/22) 28.0% (7/25) 25.5% (12/47)

* Clinical remission is defined as PCDAI score ≤10 points.§ Corticosteroid-free remission is defined as PCDAI score of ≤10 points and not receiving corticosteroids for at least90 days prior to Week M-44.† Clinical response is defined as a reduction from baseline in the PCDAI score of ≥12.5 points with a total PCDAI scorenot more than 30.£ Endoscopic response is defined as a reduction in the SES-CD score of ≥50% or SES-CD score ≤2, in patients with abaseline SES-CD score of ≥3.

Dosing frequency adjustment

Patients who entered the maintenance regimen and experienced loss of response (LOR) based on

PCDAI score were eligible for dose adjustment. Patients were either switched from treatment every 12weeks to every 8 weeks or stayed on treatment every 8 weeks (sham adjustment). 2 patients were doseadjusted to the shorter dosing interval. In these patients, clinical remission was achieved in 100% (2/2)of patients 8 weeks after dose adjustment.

The safety profile of the induction dose regimen and both maintenance dose regimens in the paediatricpopulation weighing at least 40 kg is comparable with that established in the adult Crohn’s diseasepopulation (see Section 4.8).

Serum and faecal inflammatory biomarkers

The mean change from baseline at maintenance week 44 in C-Reactive protein (CRP) and faecalcalprotectin concentrations were -11.17 mg/L (24.159) and -538.2 mg/kg (1271.33), respectively.

The total IMPACT-III scores and all subdomains (bowel symptoms, fatigue-related systemicsymptoms, and well-being) demonstrated clinically meaningful improvements after 52 weeks.

Following the recommended intravenous induction dose, median peak serum ustekinumabconcentration, observed 1 hour after the infusion, was 126.1 μg/mL in patients with Crohn’s diseaseand 127.0 µg/mL in patients with ulcerative colitis.

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 ulcerative colitis, Crohn’s disease, psoriasis and/or psoriaticarthritis, ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies.

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.

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

No specific studies have been conducted with intravenous ustekinumab in elderly or paediatricpatients weighing less than 40 kg.

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.

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).

Serum ustekinumab concentrations in paediatric Crohn’s disease patients weighing at least 40 kg,treated with the recommended weight-based dose were generally comparable to those in the adult

Crohn’s disease population treated with the adult weight-based dose.

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.

EDTA disodium salt dihydrate (E385)

L-histidine

L-histidine monohydrochloride monohydrate

L-methionine

Polysorbate 80 (E433)

Sucrose

Water for injection

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. STELARA should only be diluted with sodium chloride 9 mg/mL (0.9%) solution.

STELARA should not be administered concomitantly in the same intravenous line with othermedicinal products.

3 years.

Do not freeze.

Chemical and physical in-use stability has been demonstrated for 8 hours at 15-25°C.

From a microbiological point of view, unless the method of dilution precludes the risk of microbialcontamination, the product should be used immediately. If not used immediately, in-use storage timesand conditions are the responsibility of user.

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

Keep the vial in the outer carton in order to protect from light.

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

26 mL solution in a type I glass 30 mL vial closed with a coated butyl rubber stopper. STELARA isavailable in a 1 vial pack.

The solution in the STELARA vial should not be shaken. The solution should be visually inspected forparticulate matter or discolouration prior to administration. The solution is clear, colourless to lightyellow. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreignparticulate matter is present.

STELARA concentrate for solution for infusion must be diluted and prepared by a healthcareprofessional using aseptic technique.

1. Calculate the dose and the number of STELARA vials needed based on patient weight (seesection 4.2, Table 1). Each 26 mL vial of STELARA contains 130 mg of ustekinumab. Only usecomplete vials of STELARA.

2. Withdraw and discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the250 mL infusion bag equal to the volume of STELARA to be added. (discard 26 mL sodiumchloride for each vial of STELARA needed, for 2 vials-discard 52 mL, for 3 vials- discard78 mL, for 4 vials- discard 104 mL)3. Withdraw 26 mL of STELARA from each vial needed and add it to the 250 mL infusion bag.

The final volume in the infusion bag should be 250 mL. Gently mix.

4. Visually inspect the diluted solution before administration. Do not use if visibly opaqueparticles, discolouration or foreign particles are observed.

5. Administer the diluted solution over a period of at least one hour. Once diluted, the infusionshould be completed within eight hours of the dilution in the infusion bag.

6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (poresize 0.2 micrometer).

7. Each vial is for single use only and any unused medicinal product should be disposed of inaccordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/08/494/005

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