This information is intended for use by health professionals

1. Name of the medicinal product

STELARA 45 mg solution for injection

STELARA 90 mg solution for injection

STELARA 45 mg solution for injection in pre-filled syringe

STELARA 90 mg solution for injection in pre-filled syringe

2. Qualitative and quantitative composition

STELARA 45 mg solution for injection

Each vial contains 45 mg ustekinumab in 0.5 mL.

STELARA 90 mg solution for injection

Each vial contains 90 mg ustekinumab in 1 mL.

STELARA 45 mg solution for injection in pre-filled syringe

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

STELARA 90 mg solution for injection in pre-filled syringe

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

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

STELARA 45 mg solution for injection

Solution for injection.

STELARA 90 mg solution for injection

Solution for injection.

STELARA 45 mg solution for injection in pre-filled syringe

Solution for injection.

STELARA 90 mg solution for injection in pre-filled syringe

Solution for injection.

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

4. Clinical particulars
4.1 Therapeutic indications

Plaque psoriasis

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

Paediatric plaque psoriasis

STELARA is indicated for the treatment of moderate to severe plaque psoriasis in adolescent patients from the age of 12 years and older, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies (see section 5.1).

Psoriatic arthritis (PsA)

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

Crohn's Disease

STELARA is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNFα antagonist or have medical contraindications to such therapies.

4.2 Posology and method of administration

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

Posology

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 up to 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 mg was 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 may be used in patients with a body weight > 100 kg.

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

Elderly (≥ 65 years)

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

Renal and hepatic impairment

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

Paediatric population

The safety and efficacy of STELARA in children with psoriasis less than 12 years of age or in children with psoriatic arthritis less than 18 years of age have not yet been established.

Paediatric plaque psoriasis (12 years and older)

The recommended dose of STELARA based on body weight is shown below (Tables 1 and 2). STELARA should be administered at Weeks 0 and 4, then every 12 weeks thereafter.

Table 1 Recommended dose of STELARA for paediatric psoriasis

Body weight at the time of dosing

Recommended Dose

< 60 kg

0.75 mg/kga

≥ 60-≤ 100 kg

45 mg

> 100 kg

90 mg

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

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

Body weight at time of dosing (kg)

Dose (mg)

Volume of injection (mL)

30

22.5

0.25

31

23.3

0.26

32

24.0

0.27

33

24.8

0.27

34

25.5

0.28

35

26.3

0.29

36

27.0

0.30

37

27.8

0.31

38

28.5

0.32

39

29.3

0.32

40

30.0

0.33

41

30.8

0.34

42

31.5

0.35

43

32.3

0.36

44

33.0

0.37

45

33.8

0.37

46

34.5

0.38

47

35.3

0.39

48

36.0

0.40

49

36.8

0.41

50

37.5

0.42

51

38.3

0.42

52

39.0

0.43

53

39.8

0.44

54

40.5

0.45

55

41.3

0.46

56

42.0

0.46

57

42.8

0.47

58

43.5

0.48

59

44.3

0.49

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

Crohn's Disease

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

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

Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may receive 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 dosing frequency to every 8 weeks (see section 5.1).

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 of therapeutic benefit by week 16 or 16 weeks after switching to the 8-weekly dose.

Immunomodulators and/or corticosteroids may be continued during treatment with STELARA. In patients who have responded to treatment with STELARA, corticosteroids may be reduced or discontinued in accordance with standard of care.

If therapy is interrupted, resumption of treatment with subcutaneous dosing every 8 weeks is safe and effective.

Elderly (≥ 65 years)

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

Renal and hepatic impairment

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

Paediatric population

The safety and efficacy of STELARA in treatment of Crohn's disease in children less than 18 years have not yet been established. No data are available.

Method of administration

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

After proper training in subcutaneous injection technique, patients or their caregivers may inject STELARA if a physician determines that it is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients or their caregivers should be instructed to inject the prescribed 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.

4.3 Contraindications

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).

4.4 Special warnings and precautions for use

Traceability

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

Infections

Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. In clinical studies, serious bacterial, fungal, and viral infections have been observed in patients receiving STELARA (see section 4.8).

Caution should be exercised when considering the use of STELARA in patients with a chronic infection 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 latent tuberculosis infection should be initiated prior to administering STELARA. Anti-tuberculosis therapy should also be considered prior to initiation of STELARA in patients with a history of latent or active tuberculosis 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 and after treatment.

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

Malignancies

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Some patients who received STELARA in clinical studies developed cutaneous and non-cutaneous malignancies (see section 4.8).

No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving STELARA. Thus, caution should be exercised 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 of prolonged immunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the appearance of non-melanoma skin cancer (see section 4.8).

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in the postmarketing setting, in some cases several days after treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or other serious hypersensitivity reaction occurs, appropriate therapy should be instituted and administration of STELARA should be discontinued (see section 4.8).

Latex sensitivity

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

Vaccinations

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 conducted in patients who had recently received live viral or live bacterial vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving STELARA. Before live viral or live bacterial vaccination, treatment with STELARA should be withheld for at least 15 weeks after the last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the Summary of Product Characteristics for the specific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post-vaccination.

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

Long term treatment with STELARA does not suppress the humoral immune response to pneumococcal 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's disease studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of STELARA. Caution should be exercised when considering concomitant use of other immunosuppressants and STELARA or when transitioning from other immunosuppressive biologics (see section 4.5).

Immunotherapy

STELARA has not been evaluated in patients who have undergone allergy immunotherapy. It is not known 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 symptoms that may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course of their disease. As part of the monitoring of the patient's psoriasis, physicians should be alert for symptoms of erythrodermic psoriasis or exfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. STELARA should be discontinued if a drug reaction is suspected.

Special populations

Elderly (≥ 65 years)

No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients, however the number of patients aged 65 and older is not sufficient to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.

4.5 Interaction with other medicinal products and other forms of interaction

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

No interaction studies have been performed in humans. In the population pharmacokinetic analyses of the phase III studies, the effect of the most frequently used concomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored. There were no indications of an interaction with these concomitantly administered medicinal products. 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. The pharmacokinetics of ustekinumab was not impacted by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or Crohn's disease.

The results of an in vitro study do not suggest 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's disease studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of STELARA. (see section 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are no adequate data from the use of ustekinumab in pregnant women. 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). As a precautionary measure, it is preferable to avoid the use of STELARA in pregnancy.

Breast-feeding

It is unknown whether ustekinumab is excreted in human breast milk. Animal studies have shown excretion of ustekinumab at low levels in breast milk. It is not known if ustekinumab is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinue therapy with STELARA must be made taking into account the benefit of breast-feeding to the child and the benefit of STELARA therapy to the woman.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions (> 5%) in controlled periods of the adult psoriasis, psoriatic arthritis and Crohn's disease clinical studies with ustekinumab were nasopharyngitis and headache. Most were considered to be mild and did not necessitate discontinuation of study treatment. The most serious adverse reaction that has been reported for STELARA is serious hypersensitivity reactions including anaphylaxis (see section 4.4). The overall safety profile was similar for patients with psoriasis, psoriatic arthritis and Crohn's disease. No new safety concerns were identified with up to 2 years of treatment in patients with Crohn's Disease.

Tabulated list of adverse reactions

The safety data described below reflect exposure in adults to ustekinumab in 12 phase 2 and phase 3 studies in 5,884 patients (4,135 with psoriasis and/or psoriatic arthritis and 1,749 with Crohn's disease). This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies for at least 6 months or 1 year (4,105 and 2,846 patients respectively with psoriasis, psoriatic arthritis or Crohn's disease) and exposure for at least 4 or 5 years (1,482 and 838 patients with psoriasis respectively).

Table 3 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis and Crohn's disease 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 following convention: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3 List of adverse reactions

System Organ Class

Frequency: Adverse reaction

Infections and infestations

Common: Upper respiratory tract infection, nasopharyngitis

Uncommon: Cellulitis, dental infections, herpes zoster, lower respiratory 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 mediastinal disorders

Common: Oropharyngeal pain

Uncommon: Nasal congestion

Gastrointestinal disorders

Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue disorders

Common: Pruritus

Uncommon: Pustular psoriasis, skin exfoliation, acne

Rare: Exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Common: Back pain, myalgia, arthralgia

General disorders and administration site conditions

Common: Fatigue, injection site erythema, injection site pain

Uncommon: Injection site reactions (including haemorrhage, haematoma, induration, swelling and pruritus), asthenia

Description of selected adverse reactions

Infections

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis and Crohn's disease, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo. In the placebo-controlled period of clinical studies of patients with psoriasis, patients with psoriatic arthritis and patients with Crohn's disease, the rate of infection was 1.38 per patient-year of follow-up in ustekinumab-treated patients, and 1.35 in placebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (27 serious infections in 829 patient-years of follow-up) and 0.03 in placebo-treated patients (11 serious infections in 385 patient-years of follow-up) (see section 4.4).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical studies, representing 10,953 patient-years of exposure in 5,884 patients, the median follow up was 0.99 years; 3.2 years for psoriasis studies, 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's disease studies. The rate of infection was 0.91 per patient-year of follow-up in ustekinumab-treated patients, and the rate of serious infections was 0.02 per patient-year of follow-up in ustekinumab-treated patients (178 serious infections in 10,953 patient-years of follow-up) and serious infections reported included anal abscess, cellulitis, pneumonia, diverticulitis, gastroenteritis and viral infections.

In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis.

Malignancies

In the placebo-controlled period of the psoriasis, psoriatic arthritis and Crohn's disease clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.12 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 829 patient-years of follow-up) compared with 0.26 for placebo-treated patients (1 patient in 385 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.48 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 829 patient-years of follow-up) compared to 0.52 for placebo-treated patients (2 patients in 385 patient-years of follow-up).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical studies, representing 10,935 patient-years of exposure in 5,884 patients, the median follow-up was 1.0 years; 3.2 years for psoriasis studies, 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's disease studies. Malignancies excluding non-melanoma skin cancers were reported in 58 patients in 10,935 patient-years of follow-up (incidence of 0.53 per 100 patient-years of follow-up for ustekinumab-treated patients). The incidence of malignancies reported in ustekinumab-treated patients was comparable to the incidence expected in the general population (standardised incidence ratio = 0.87 [95% confidence interval: 0.66, 1.14], adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal and breast cancers. The incidence of non-melanoma skin cancer was 0.49 per 100 patient-years of follow-up for ustekinumab-treated patients (53 patients in 10,919 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (4:1) is comparable with the ratio expected in the general population (see section 4.4).

Hypersensitivity reactions

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

Paediatric population

Undesirable effects in paediatric patients 12 years and older with plaque psoriasis

The safety of ustekinumab has been studied in a phase 3 study of 110 patients from 12 to 17 years of age for up to 60 weeks. In this study, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

4.9 Overdose

Single doses up to 6 mg/kg have been administered intravenously in clinical studies without dose-limiting toxicity. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the bioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute to complement- 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 macrophages and 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 has been associated with immune mediated diseases, such as psoriasis, psoriatic arthritis and Crohn's disease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, psoriatic arthritis and Crohn's disease 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 inflammatory markers including C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, which were then maintained throughout the maintenance phase.

Immunisation

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 pneumococcal polysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similar proportions of adult patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers were similar among STELARA-treated and control patients.

Clinical efficacy

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 who were candidates for phototherapy or systemic therapy. In addition, a randomised, blinded assessor, active-controlled study compared ustekinumab and etanercept in patients with moderate to severe plaque psoriasis who had had an inadequate response to, intolerance to, or contraindication to ciclosporin, MTX, or PUVA.

Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of these patients were either non-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 and followed by the same dose every 12 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16 followed by dosing every 12 weeks. Patients originally 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-randomised to receive ustekinumab every 12 weeks or to placebo (i.e., withdrawal of therapy). Patients who were re-randomised to placebo at week 40 reinitiated ustekinumab at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at week 40. All patients were followed 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 either non-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at 16 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. All patients were followed for up to 52 weeks following first administration of study treatment.

Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis who inadequately responded to, were intolerant to, or had a contraindication to other systemic therapy and compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept. During the 12-week active-controlled portion of the study, patients were randomised to receive etanercept (50 mg twice a week), ustekinumab 45 mg at Weeks 0 and 4, or ustekinumab 90 mg at 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. Approximately one 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 response from baseline at week 12 (see Tables 4 and 5).

Table 4 Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2 (PHOENIX 2)

Week 12

2 doses (week 0 and week 4)

Week 28

3 doses (week 0, week 4 and week 16)

PBO

45 mg

90 mg

45 mg

90 mg

Psoriasis Study 1

Number of patients randomised

255

255

256

250

243

PASI 50 response N (%)

26 (10%)

213 (84%)a

220 (86%)a

228 (91%)

234 (96%)

PASI 75 response N (%)

8 (3%)

171 (67%)a

170 (66%)a

178 (71%)

191 (79%)

PASI 90 response N (%)

5 (2%)

106 (42%)a

94 (37%)a

123 (49%)

135 (56%)

PGAb of cleared or minimal N (%)

10 (4%)

151 (59%)a

156 (61%)a

146 (58%)

160 (66%)

Number of patients ≤ 100 kg

166

168

164

164

153

PASI 75 response N (%)

6 (4%)

124 (74%)

107 (65%)

130 (79%)

124 (81%)

Number of patients > 100 kg

89

87

92

86

90

PASI 75 response N (%)

2 (2%)

47 (54%)

63 (68%)

48 (56%)

67 (74%)

Psoriasis Study 2

Number of patients randomised

410

409

411

397

400

PASI 50 response N (%)

41 (10%)

342 (84%)a

367 (89%)a

369 (93%)

380 (95%)

PASI 75 response N (%)

15 (4%)

273 (67%)a

311 (76%)a

276 (70%)

314 (79%)

PASI 90 response N (%)

3 (1%)

173 (42%)a

209 (51%)a

178 (45%)

217 (54%)

PGAb of cleared or minimal N (%)

18 (4%)

277 (68%)a

300 (73%)a

241 (61%)

279 (70%)

Number of patients ≤ 100 kg

290

297

289

287

280

PASI 75 response N (%)

12 (4%)

218 (73%)

225 (78%)

217 (76%)

226 (81%)

Number of patients > 100 kg

120

112

121

110

119

PASI 75 response N (%)

3 (3%)

55 (49%)

86 (71%)

59 (54%)

88 (74%)

a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with placebo (PBO).

b PGA = Physician Global Assessment

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

Psoriasis Study 3

Etanercept

24 doses

(50 mg twice a week)

Ustekinumab

2 doses (week 0 and week 4)

45 mg

90 mg

Number of patients randomised

347

209

347

PASI 50 response N (%)

286 (82%)

181 (87%)

320 (92%)a

PASI 75 response N (%)

197 (57%)

141 (67%)b

256 (74%)a

PASI 90 response N (%)

80 (23%)

76 (36%)a

155 (45%)a

PGA of cleared or minimal N (%)

170 (49%)

136 (65%)a

245 (71%)a

Number of patients ≤ 100 kg

251

151

244

PASI 75 response N (%)

154 (61%)

109 (72%)

189 (77%)

Number of patients > 100 kg

96

58

103

PASI 75 response N (%)

43 (45%)

32 (55%)

67 (65%)

a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with etanercept.

b p = 0.012 for ustekinumab 45 mg in comparison with etanercept.

In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatment compared with treatment withdrawal (p < 0.001). Similar results were seen with each dose of ustekinumab. 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 75 responders. 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 regimen after loss of ≥ 50% of PASI improvement 85% regained PASI 75 response within 12 weeks after re-initiating therapy.

In Psoriasis Study 1, at week 2 and week 12, significantly greater improvements from baseline were demonstrated in the DLQI in each ustekinumab treatment group compared with placebo. The improvement 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 component summary scores of the SF-36 and in the Itch Visual Analogue Scale (VAS) were also significant in each ustekinumab treatment group compared with placebo. In Psoriasis Study 2, the Hospital Anxiety and Depression Scale (HADS) and Work Limitations Questionnaire (WLQ) were also significantly improved 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-related quality of life, and reduce the rate of progression of peripheral joint damage in adult patients with active 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) despite non-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%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients in both studies had enthesitis and dactylitis at baseline, respectively. Patients were randomised to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX (≤ 25 mg/week).

In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In Study 1 previous treatment with anti-tumour necrosis factor (TNF)α agent was not allowed. In Study 2, the majority of patients (58%, n = 180) had been previously treated with one or more anti-TNFα agent(s), of whom over 70% had discontinued 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 activity compared 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 are shown in Table 6 below.

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

Psoriatic arthritis Study 1

Psoriatic arthritis Study 2

PBO

45 mg

90 mg

PBO

45 mg

90 mg

Number of patients randomised

206

205

204

104

103

105

ACR 20 response, N (%)

47 (23%)

87 (42%)a

101 (50%)a

21 (20%)

45 (44%)a

46 (44%)a

ACR 50 response, N (%)

18 (9%)

51 (25%)a

57 (28%)a

7 (7%)

18 (17%)b

24 (23%)a

ACR 70 response, N (%)

5 (2%)

25 (12%)a

29 (14%)a

3 (3%)

7 (7%)c

9 (9%)c

Number of patients with ≥ 3% BSAd

146

145

149

80

80

81

PASI 75 response, N (%)

16 (11%)

83 (57%)a

93 (62%)a

4 (5%)

41 (51%)a

45 (56%)a

PASI 90 response, N (%)

4 (3%)

60 (41%)a

65 (44%)a

3 (4%)

24 (30%)a

36 (44%)a

Combined PASI 75 and ACR 20 response, N (%)

8 (5%)

40 (28%)a

62 (42%)a

2 (3%)

24 (30%)a

31 (38%)a

Number of patients ≤ 100 kg

154

153

154

74

74

73

ACR 20 response, N (%)

39 (25%)

67 (44%)

78 (51%)

17 (23%)

32 (43%)

34 (47%)

Number of patients with ≥ 3% BSAd

105

105

111

54

58

57

PASI 75 response, N (%)

14 (13%)

64 (61%)

73 (66%)

4 (7%)

31 (53%)

32 (56%)

Number of patients > 100 kg

52

52

50

30

29

31

ACR 20 response, N (%)

8 (15%)

20 (38%)

23 (46%)

4 (13%)

13 (45%)

12 (39%)

Number of patients with ≥ 3% BSAd

41

40

38

26

22

24

PASI 75 response, N (%)

2 (5%)

19 (48%)

20 (53%)

0

10 (45%)

13 (54%)

a p < 0.001

b p < 0.05

c p = NS

d 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 1 and 2) and week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at week 100 were achieved by 57% and 64%, for 45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at week 52 were achieved by 47% and 48%, for 45 mg and 90 mg, respectively.

The proportion of patients achieving a modified PsA response criteria (PsARC) response was also significantly greater in the ustekinumab groups compared to placebo at week 24. PsARC responses were maintained through weeks 52 and 100. A higher proportion of patients treated with ustekinumab who had spondylitis with peripheral arthritis as their primary presentation, demonstrated 50 and 70 percent improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores compared with placebo at week 24.

Responses observed in the ustekinumab treated groups were similar in patients receiving and not receiving concomitant MTX, and were maintained through weeks 52 and 100. Patients previously treated with anti-TNFα agents who received ustekinumab achieved a greater response at week 24 than patients 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 in enthesitis and dactylitis score was observed in the ustekinumab groups compared with placebo at week 24. In PsA Study 2 significant improvement in enthesitis score and numerical improvement (not statistically significant) in dactylitis score was observed in the ustekinumab 90 mg group compared with placebo at week 24. Improvements in enthesitis score and dactylitis score were maintained through 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 to baseline. A pre-specified integrated analysis combining data from 927 subjects in both PsA Study 1 and 2 was performed. Ustekinumab demonstrated a statistically significant decrease in the rate of progression of structural damage compared to placebo, as measured by change from baseline to week 24 in the total modified vdH-S score (mean ± SD score was 0.97 ± 3.85 in the placebo group compared 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 considered demonstrated irrespective of concomitant MTX use, and was maintained through Weeks 52 (integrated analysis) and 100 (PsA Study 1).

Physical function and health-related quality of life

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 of patients achieving a clinically meaningful ≥ 0.3 improvement in HAQ-DI score from baseline was also significantly 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 with placebo at week 24, which was maintained through weeks 52 and 100. In PsA Study 2 there was a significant 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 patients achieving a clinically significant improvement in fatigue (4 points in FACIT-F) was also significantly greater in the ustekinumab groups compared with placebo. Improvements in FACIT scores were maintained through week 52.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with ustekinumab in one or more subsets of the paediatric population aged 6 to 11 years in moderate to severe plaque psoriasis and juvenile idiopathic arthritis (see section 4.2 for information on paediatric use).

Paediatric plaque psoriasis

Ustekinumab has been shown to improve signs and symptoms, and health related quality of life in paediatric patients 12 years and older with plaque psoriasis.

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

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

The primary endpoint was the proportion of patients who achieve a PGA score of cleared (0) or minimal (1) at week 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in Children's Dermatology Life Quality Index (CDLQI), change from baseline in the total scale score of PedsQL (Paediatric Quality of Life Inventory) at week 12. At week 12, subjects treated with ustekinumab showed significantly greater improvement in their psoriasis and health related quality of life compared with placebo (Table 7).

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

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

Paediatric psoriasis study (CADMUS)

Week 12

Week 52

Placebo

Recommended dose of Ustekinumab

Recommended dose of Ustekinumab

N (%)

N (%)

N (%)

Patients randomised

37

36

35

PGA

PGA of cleared (0) or minimal (1)

2 (5.4%)

25 (69.4%)a

20 (57.1%)

PGA of Cleared (0)

1 (2.7%)

17 (47.2%)a

13 (37.1%)

PASI

PASI 75 responders

4 (10.8%)

29 (80.6%)a

28 (80.0%)

PASI 90 responders

2 (5.4%)

22 (61.1%)a

23 (65.7%)

PASI 100 responders

1 (2.7%)

14 (38.9%)a

13 (37.1%)

CDLQI

CDLQI of 0 or 1b

6 (16.2%)

18 (50.0%)c

20 (57.1%)

PedsQL

Change from baseline

Mean (SD)d

3.35 (10.04)

8.03 (10.44)e

7.26 (10.92)

a p < 0.001

b CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality of life in the paediatric population. CDLQI of 0 or 1 indicates no effect on child's quality of life.

c p = 0.002

d PedsQL: The PedsQL Total Scale Score is a general health-related quality of life measure developed for use in children and adolescent populations. For the placebo group at week 12, N = 36

e p = 0.028

During the placebo controlled period through week 12, the efficacy of both the recommended and half of the recommended dose groups were generally comparable at the primary endpoint (69.4% and 67.6% respectively) although there was evidence of a dose response for higher level efficacy criteria (e.g. PGA of cleared (0), PASI 90). Beyond week 12, efficacy was generally higher and better sustained in the recommended dose group compared with half of the recommended dosage group in which a modest loss of efficacy was more frequently observed toward the end of each 12 week dosing interval. The safety profiles of the recommended dose and half of the recommended dose were comparable.

Crohn's Disease

The safety and efficacy of ustekinumab was assessed in three randomized, double-blind, placebo-controlled, multicenter 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 program consisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 week subcutaneous randomized withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.

The induction studies included 1409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary endpoint for both induction studies was the proportion of subjects in clinical response (defined as a reduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analyzed through 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 one of these medications. In both studies, patients were randomised to receive a single intravenous administration 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% of the 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 to anti-TNFα therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids or immunomodulators, and were either anti-TNF-α naïve (68.6%) or had previously received but not failed anti-TNFα therapy (31.4%).

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

Table 8: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1*

UNITI-2**

Placebo

N = 247

Recommended dose of ustekinumab

N = 249

Placebo

N = 209

Recommended dose of ustekinumab

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%)a

70 Point Response, week 3

67 (27.1%)

101 (40.6%)b

66 (31.6%)

106 (50.7%)a

70 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 least 100 points or being in clinical remission

70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failures

a p < 0.001

b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical response at week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomized to receive a subcutaneous maintenance regimen of either 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).

Significantly higher proportions of patients maintained clinical remission and response in the ustekinumab treated groups compared to the placebo group at week 44 (see Table 9).

Table 9: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from initiation of the induction dose)

Placebo*

N = 131

90 mg ustekinumab every 8 weeks

N = 128

90 mg ustekinumab every 12 weeks

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 therapy

46% (36/79)

67% (52/78)a

56% (44/78)

who entered from study CRD3002

44% (31/70)

63% (45/72)c

57% (41/72)

who are Anti-TNFα naïve

49% (25/51)

65% (34/52)c

57% (30/53)

who entered from study CRD3001§

26% (16/61)

41% (23/56)

39% (22/57)

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

* The placebo group consisted of patients who were in response to ustekinumab and were randomized to receive placebo at 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 < 0.01

b p < 0.05

c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every 12 weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response was 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-randomized portion of the maintenance study (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 receive maintenance dosing every 8 weeks; among these patients with continued maintenance dosing, a majority maintained response (68.1%) and achieved remission (50.2%) at week 44, at proportions that were similar to the patients who initially responded to ustekinumab induction.

Of 131 patients who responded to ustekinumab induction, and were randomized to the placebo group at the start of the maintenance study, 51 subsequently lost response and received 90 mg ustekinumab subcutaneously every 8 weeks. The majority of patients who lost response and resumed ustekinumab did so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinical response and 39.2% percent achieved clinical remission 16 weeks after receiving the first subcutaneous dose of ustekinumab.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension, clinical remission and response were generally maintained through week 92 for both patients who failed TNF-therapies and those who failed conventional therapies.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopic disease 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 the ustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of ustekinumab-treated patients achieved a fistula response over 44 weeks (defined as ≥ 50% reduction from 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

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 significantly greater 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 in ustekinumab-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 through week 92.

Immunogenicity

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

Paediatric population

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

5.2 Pharmacokinetic properties

Absorption

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

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

Distribution

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

Biotransformation

The exact metabolic pathway for ustekinumab is unknown.

Elimination

Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab was approximately 3 weeks in patients with psoriasis, psoriatic arthritis or Crohn's disease, ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokinetic 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 not impacted by gender. Population pharmacokinetic analysis showed that there was a trend towards a higher 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 approximately dose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately 24 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 multiple subcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations of ustekinumab were achieved by week 28 after initial subcutaneous doses at Weeks 0 and 4 followed by doses every 12 weeks. The median steady-state trough concentration ranged from 0.21 μg/mL to 0.26 μg/mL (45 mg) and from 0.47 μg/mL to 0.49 μg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.

In patients with Crohn's disease, following an intravenous dose of ~6 mg/kg, starting at week 8, subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. Median steady-state trough concentrations ranged from 1.97 μg/mL to 2.24 μg/mL and from 0.61 μg/mL to 0.76 μg/mL for 90 mg ustekinumab every 8 weeks or every 12 weeks respectively. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumab every 8 weeks were associated with higher clinical remission rates as compared 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 was found to be the most significant covariate affecting the clearance of ustekinumab. The median CL/F in patients 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 as compared to patients with weight ≤ 100 kg. The median trough serum concentrations of ustekinumab in patients with higher weight (> 100 kg) in the 90 mg group were comparable to those in patients with lower weight (≤ 100 kg) in the 45 mg group. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.

Special populations

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-Asian patients with psoriasis.

In patients with Crohn's disease, variability in ustekinumab CL was affected by body weight, serum albumin level, CRP, TNF antagonist failure status, sex, race (Asian versus non-Asian), and antibody to ustekinumab status while body weight was the main covariate affecting the volume of distribution. Concomitant use of immunomodulators did not have a significant impact on ustekinumab disposition. The impact of these statistically significant covariates on the respective PK parameters was within ± 20% when evaluated across a representative range of covariate values or categories in the data which is within the overall variability observed in the PK of ustekinumab.

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

Serum ustekinumab concentrations in paediatric psoriasis patients 12 to 17 years of age, treated with the recommended weight-based dose were generally comparable to those in the adult psoriasis population treated with the adult dose, while serum ustekinumab concentrations in paediatric psoriasis patients treated with half of the recommended weight-based dose were generally lower than those in adults.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies of repeated-dose toxicity and developmental and reproductive toxicity, including safety pharmacology evaluations. In developmental and reproductive toxicity studies in cynomolgus monkeys, neither adverse effects on male fertility indices nor birth defects or developmental toxicity were observed. No adverse effects on female fertility indices were observed using an analogous antibody to IL-12/23 in mice.

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

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

6. Pharmaceutical particulars
6.1 List of excipients

L-histidine

L-histidine monohydrochloride monohydrate

Polysorbate 80

Sucrose

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

STELARA 45 mg solution for injection

2 years

STELARA 90 mg solution for injection

2 years

STELARA 45 mg solution for injection in pre-filled syringe

3 years

STELARA 90 mg solution for injection in pre-filled syringe

3 years

6.4 Special precautions for storage

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

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

6.5 Nature and contents of container

STELARA 45 mg solution for injection

0.5 mL solution in a type I glass 2 mL vial closed with a coated butyl rubber stopper.

STELARA 90 mg solution for injection

1 mL solution in a type I glass 2 mL vial closed with a coated butyl rubber stopper.

STELARA 45 mg solution for injection in pre-filled syringe

0.5 mL solution in a type I glass 1 mL syringe with a fixed stainless steel needle and a needle cover containing dry natural rubber (a derivative of latex). The syringe is fitted with a passive safety guard.

STELARA 90 mg solution for injection in pre-filled syringe

1 mL solution in a type I glass 1 mL syringe with a fixed stainless steel needle and a needle cover containing dry natural rubber (a derivative of latex). The syringe is fitted with a passive safety guard.

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

6.6 Special precautions for disposal and other handling

The solution in the STELARA vial or pre-filled syringe should not be shaken. The solution should be visually inspected for particulate matter or discoloration prior to subcutaneous administration. The solution is clear to slightly opalescent, colourless to light yellow and may contain a few small translucent or white particles of protein. This appearance is not unusual for proteinaceous solutions. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreign particulate matter is present. 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 the vial and the syringe should not be used. STELARA is supplied as a sterile, single-use vial or single-use pre-filled syringe. The syringe, needle and vial must never be re-used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Janssen-Cilag International NV

Turnhoutseweg 30

2340 Beerse

Belgium

8. Marketing authorisation number(s)

STELARA 45 mg solution for injection

EU/1/08/494/001

STELARA 90 mg solution for injection

EU/1/08/494/002

STELARA 45 mg solution for injection in pre-filled syringe

EU/1/08/494/003

STELARA 90 mg solution for injection in pre-filled syringe

EU/1/08/494/004

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 January 2009

Date of latest renewal: 19 September 2013

10. Date of revision of the text

26 July 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/