ustekinumab: prescribing information – dosing, contraindications, interactions, side effects

Adult 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.
Paediatric Crohn's disease
STELARA is indicated for the treatment of moderately to severely active Crohn’s disease in paediatric patients from the age of 2 years and older, who have had an inadequate response to, or were intolerant to either conventional or biologic therapy.
Adult ulcerative colitis
STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic.
Paediatric ulcerative colitis
STELARA is indicated for the treatment of moderately to severely active ulcerative colitis in paediatric patients from the age of 2 years and older, who have had an inadequate response to, or were intolerant to either conventional therapy or a biologic.

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 children and adolescent patients from the age of 6 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).
Adult 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.
Paediatric Crohn's disease
STELARA is indicated for the treatment of moderately to severely active Crohn’s disease in paediatric patients from the age of 2 years and older, who have had an inadequate response to, or were intolerant to either conventional or biologic therapy.
Adult ulcerative colitis
STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic.
Paediatric ulcerative colitis
STELARA is indicated for the treatment of moderately to severely active ulcerative colitis in paediatric patients from the age of 2 years and older, who have had an inadequate response to, or were intolerant to either conventional therapy or a biologic.

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).
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.
Ulcerative colitis
STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic.

STELARA concentrate for solution for infusion is intended for use under the guidance and supervision of 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 induction dose.

Posology
Crohn’s disease and ulcerative colitis
STELARA treatment is to be initiated with a single intravenous dose based on body weight. The infusion 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 dose of STELARA
Body weight of patient at the time of dosing
Recommended dosea
Number of 130 mg Vials
≤55 kg
260 mg
> 55 kg to ≤85 kg
390 mg
> 85 kg
520 mg a
Approximately 6 mg/kg
The first subcutaneous dose should be given at week 8 following the intravenous dose. For the posology of the subsequent subcutaneous dosing regimen, 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.
Elderly
No dose adjustment is needed for elderly patients (≥65 years) (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
Paediatric Crohn's disease and ulcerative colitis (2 years and older)
Patients weighing less than 40 kg (BSA-based dosing)
Treatment is to be initiated with a single intravenous (IV) dose based on the patient’s body surface area (BSA), see Table 2. The infusion solution is to be composed of infusion solution volume from the total number of vials of STELARA 130 mg as specified in Table 2.
Table 2:
Initial intravenous dose of STELARA
BSA Range (m²) of patient at time of dosing
Body weight < 40 kg
Recommended
Dose
(mg)
Volume of
Infusion solution
(mL)
Number of 130 mg
Vials

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 5).
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
No dose adjustment is needed for elderly patients (≥65 years) (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 6 years of age or in children

with psoriatic arthritis less than 18 years of age have not yet been established.
Paediatric plaque psoriasis (6 years and older)
The recommended dose of 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/kg
≥60-≤100 kg
45 mg
> 100 kg
90 mg
To calculate the volume of injection (mL) for patients < 60 kg, use the following formula: body weight (kg) 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)

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 2).
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
No dose adjustment is needed for elderly patients (≥65 years) (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 6 years of age or in children with psoriatic arthritis less than 18 years of age have not yet been established. The pre-filled pen has not been studied in the paediatric population and is not recommended for use in paediatric patients.
See section 4.2 of the pre-filled syringe SmPC for posology and method of administration in paediatric patients 6 years and older with psoriasis.
Crohn’s disease and ulcerative colitis
In the treatment regimen, the first dose of STELARA is administered intravenously. For the 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 and section 5.2).
Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment (see section 5.1).

Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit 16 weeks after the IV induction dose or 16 weeks after switching to every 8 weeks maintenance 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.
In Crohn’s disease or ulcerative colitis, if therapy is interrupted, resumption of treatment with subcutaneous dosing every 8 weeks is safe and effective.
Elderly
No dose adjustment is needed for elderly patients (≥65 years) (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 for the treatment of Crohn’s disease in paediatric patients less than 2 years or ulcerative colitis in children less than 2 years have not yet been established. No data are available. The pre-filled pen has not been studied in the paediatric population and is not recommended for use in paediatric patients. See section 4.2 of the Concentrate for solution for infusion and pre-filled syringe SmPC for posology and method of administration in paediatric patients 2 years and older with Crohn’s disease or ulcerative colitis.
Method of administration
STELARA 45 mg and 90 mg pre-filled pens 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.

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).

Summary of the safety profile
The most common adverse reactions in the controlled periods of the adult clinical studies were nasopharyngitis (occurring in 6.9% of ustekinumab-treated patients and 5.4% of patients on placebo) and headache (occurring in 7.0% of ustekinumab-treated patients and 5.2% of patients on placebo).
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, Crohn’s disease and ulcerative colitis.
Tabulated list of adverse reactions
The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3 studies in 6,710 patients (4,135 with psoriasis and/or psoriatic arthritis, 1,749 with Crohn’s disease and 826 patients with ulcerative colitis). This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies in patients with psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis for at least 6 months (4,577 patients) or at least 1 year (3,648 patients). 2,194 patients with psoriasis, Crohn’s disease or ulcerative colitis were exposed for at least 4 years while 1,148 patients with psoriasis or Crohn’s disease were exposed for at least 5 years.
Table 4 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative 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 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 4:
List of adverse reactions
System Organ Class
Frequency: Adverse reaction
Infections and infestations
Common: Upper respiratory tract infection, nasopharyngitis, sinusitis
Uncommon: Cellulitis, dental infections, herpes zoster, lower 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 Rare: Allergic alveolitis, eosinophilic pneumonia Very rare: Organising pneumonia* Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue disorders
Common: Pruritus
Uncommon: Pustular psoriasis, skin exfoliation, acne
Rare: Exfoliative dermatitis, hypersensitivity vasculitis
Very rare: Bullous pemphigoid, cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders
Common: Back pain, myalgia, arthralgia
Very rare: Lupus-like syndrome
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 * See section 4.4, Systemic and respiratory hypersensitivity reactions.
Description of selected adverse reactions
Infections
In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo. In the placebo-controlled period of these clinical studies, the rate of infection was 1.36 per patient-year of follow-up in ustekinumab-treated patients, and 1.34 in placebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 in placebo-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 and ulcerative colitis clinical studies, representing 15,227 patient-years of ustekinumab exposure in 6,710 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 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 (289 serious infections in 15,227 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 did not develop tuberculosis.
Malignancies
In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treated patients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 for placebo-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 and ulcerative colitis clinical studies, representing 15,205 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for Crohn’s disease studies and 2.3 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancers were reported in 76 patients in 15,205 patient-years of follow-up (incidence of 0.50 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 = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal, and breast cancers. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up for ustekinumab-treated

patients (69 patients in 15,165 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (see section 4.4).
Hypersensitivity and infusion reactions
In adult Crohn’s disease and ulcerative colitis intravenous induction studies, no events of anaphylaxis or other 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 of ustekinumab reported adverse events occurring during or within an hour of the infusion. In the paediatric Crohn’s disease study, there was one serious and one non-serious infusion reaction. In the paediatric ulcerative colitis study, there was one serious and two non-serious infusion reactions.
Serious infusion-related reactions including anaphylactic reactions to the infusion have been reported in the post-marketing setting (see section 4.4). In the post-marketing setting, some cases of serious hypersensitivity reactions have been reported in patients with a history of alpha-gal syndrome, allergy to mammalian meat or meat products, or anti-alpha-gal IgE. In most of these cases the reactions occurred at the time of initial administration.
Paediatric population
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 moderate to severe plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for up to 60 weeks and the second study was in 44 patients from 6 to 11 years of age treated for up to 56 weeks. In general, the adverse events reported in these two studies with safety data up to 1 year were similar to those seen in previous studies in adults with plaque psoriasis.
Paediatric patients 2 years and older with Crohn’s disease
The safety of ustekinumab has been studied in one phase 1 and one phase 3 study of paediatric patients with moderately to severely active Crohn’s disease. 34 patients in the phase 1 study were followed up to 240 weeks and 101 patients in the phase 3 study were followed up to 68 weeks, respectively. In general, the safety profile was similar to that seen in previous studies in adults with Crohn’s disease.
Paediatric patients 2 years and older with ulcerative colitis
The safety of ustekinumab has been studied in one phase 3 study of paediatric patients with moderately to severely active ulcerative colitis. In this study, 112 patients were followed up to 68 weeks. In general, the safety profile was similar to that seen in previous studies in adults with ulcerative colitis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The most common adverse reactions in the controlled periods of the adult clinical studies were nasopharyngitis (occurring in 6.9% of ustekinumab-treated patients and 5.4% of patients on placebo) and headache (occurring in 7.0% of ustekinumab-treated patients and 5.2% of patients on placebo).
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, Crohn’s disease and ulcerative colitis.

Tabulated list of adverse reactions
The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3 studies in 6,710 patients (4,135 with psoriasis and/or psoriatic arthritis, 1,749 with Crohn’s disease and 826 patients with ulcerative colitis). This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies in patients with psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis for at least 6 months (4,577 patients) or at least 1 year (3,648 patients). 2,194 patients with psoriasis, Crohn’s disease or ulcerative colitis were exposed for at least 4 years while 1,148 patients with psoriasis or Crohn’s disease were exposed for at least 5 years.
Table 4 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative 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 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 4:
List of adverse reactions
System Organ Class
Frequency: Adverse reaction
Infections and infestations
Common: Upper respiratory tract infection, nasopharyngitis, sinusitis
Uncommon: Cellulitis, dental infections, herpes zoster, lower 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 Rare: Allergic alveolitis, eosinophilic pneumonia Very rare: Organising pneumonia* Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting Skin and subcutaneous tissue disorders Common: Pruritus Uncommon: Pustular psoriasis, skin exfoliation, acne Rare: Exfoliative dermatitis, hypersensitivity vasculitis Very rare: Bullous pemphigoid, cutaneous lupus erythematosus Musculoskeletal and connective tissue disorders Common: Back pain, myalgia, arthralgia Very rare: Lupus-like syndrome 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 * See section 4.4, Systemic and respiratory hypersensitivity reactions.

Description of selected adverse reactions
Infections
In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo. In the placebo-controlled period of these clinical studies, the rate of infection was 1.36 per patient-year of follow-up in ustekinumab-treated patients, and 1.34 in placebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 in placebo-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 and ulcerative colitis clinical studies, representing 15,227 patient-years of ustekinumab exposure in 6,710 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 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 (289 serious infections in 15,227 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 did not develop tuberculosis.
Malignancies
In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treated patients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 for placebo-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 and ulcerative colitis clinical studies, representing 15,205 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for Crohn’s disease studies and 2.3 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancers were reported in 76 patients in 15,205 patient-years of follow-up (incidence of 0.50 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 = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal, and breast cancers. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up for ustekinumab-treated patients (69 patients in 15,165 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (3:1) 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). In the post-marketing setting, some cases of serious hypersensitivity reactions have been reported in patients with a history of alpha-gal syndrome, allergy to mammalian meat or meat products, or anti-alpha-gal IgE. In most of these cases the reactions occurred at the time of initial administration.

Paediatric population
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 moderate to severe plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for up to 60 weeks and the second study was in 44 patients from 6 to 11 years of age treated for up to 56 weeks. In general, the adverse events reported in these two studies with safety data up to 1 year were similar to those seen in previous studies in adults with plaque psoriasis.
Paediatric patients 2 years and older with Crohn’s disease
The safety of ustekinumab has been studied in one phase 1 and one phase 3 study of paediatric patients with moderately to severely active Crohn’s disease. 34 patients in the phase 1 study were followed up to 240 weeks and 101 patients in the phase 3 study were followed up to 68 weeks, respectively. In general, the safety profile was similar to that seen in previous studies in adults with Crohn’s disease.
Paediatric patients 2 years and older with ulcerative colitis
The safety of ustekinumab has been studied in one phase 3 study of paediatric patients with moderately to severely active ulcerative colitis. In this study, 112 patients were followed up to 68 weeks. In general, the safety profile was similar to that seen in previous studies in adults with ulcerative colitis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The most common adverse reactions in the controlled periods of the adult clinical studies were nasopharyngitis (occurring in 6.9% of ustekinumab-treated patients and 5.4% of patients on placebo) and headache (occurring in 7.0% of ustekinumab-treated patients and 5.2% of patients on placebo).
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, Crohn’s disease and ulcerative colitis.
Tabulated list of adverse reactions
The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3 studies in 6,710 patients (4,135 with psoriasis and/or psoriatic arthritis, 1,749 with Crohn’s disease and 826 patients with ulcerative colitis). This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies in patients with psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis for at least 6 months (4,577 patients) or at least 1 year (3,648 patients). 2,194 patients with psoriasis, Crohn’s disease or ulcerative colitis were exposed for at least 4 years while 1,148 patients with psoriasis or Crohn’s disease were exposed for at least 5 years.
Table 1 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative 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 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 1:
List of adverse reactions
System Organ Class
Frequency: Adverse reaction
Infections and infestations
Common: Upper respiratory tract infection, nasopharyngitis, sinusitis
Uncommon: Cellulitis, dental infections, herpes zoster, 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 Rare: Allergic alveolitis, eosinophilic pneumonia Very rare: Organising pneumonia* Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting Skin and subcutaneous tissue disorders Common: Pruritus Uncommon: Pustular psoriasis, skin exfoliation, acne Rare: Exfoliative dermatitis, hypersensitivity vasculitis Very rare: Bullous pemphigoid, cutaneous lupus erythematosus Musculoskeletal and connective tissue disorders Common: Back pain, myalgia, arthralgia Very rare: Lupus-like syndrome 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 * See section 4.4, Systemic and respiratory hypersensitivity reactions.
Description of selected adverse reactions
Infections
In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo. In the placebo-controlled period of these clinical studies, the rate of infection was 1.36 per patient-year of follow-up in ustekinumab-treated patients, and 1.34 in placebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 in placebo-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 and ulcerative colitis clinical studies, representing 15,227 patient-years of ustekinumab exposure in 6,710 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 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 (289 serious infections in 15,227 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 did not develop tuberculosis.
Malignancies
In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treated patients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 for placebo-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 and ulcerative colitis clinical studies, representing 15,205 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2 years; 1.7 years for psoriatic disease studies, 0.6 year for Crohn’s disease studies and 2.3 years for ulcerative colitis studies. Malignancies excluding nonmelanoma 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 incidence of malignancies reported in ustekinumab-treated patients was comparable to the incidence expected in the general population (standardised incidence ratio = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, gender and race). The most frequently observed malignancies, other than nonmelanoma skin cancer, were prostate, melanoma, colorectal, and breast cancers. The incidence of nonmelanoma skin cancer was 0.46 per 100 patient-years of follow up for ustekinumab-treated patients (69 patients in 15,165 patient years of follow up). The ratio of patients with basal versus squamous cell skin cancers (3:1) 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). In the post-marketing setting, some cases of serious hypersensitivity reactions have been reported in patients with a history of alpha-gal syndrome, allergy to mammalian meat or meat products, or anti-alpha-gal IgE. In most of these cases the reactions occurred at the time of initial administration.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viral infections have been observed in patients receiving STELARA (see section 4.8).
Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections (including atypical mycobacterial infection, listeria meningitis, pneumonia legionella, and nocardiosis), opportunistic fungal infections, opportunistic viral infections (including encephalitis caused by herpes simplex 2), and parasitic infections (including ocular toxoplasmosis) have been reported in patients treated with ustekinumab.
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 and in a post-marketing observational study in patients with psoriasis developed cutaneous and non-cutaneous malignancies (see section 4.8). The risk of malignancy may be higher in psoriasis patients who have been treated with other biologics during the course of their disease.

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 skin cancer (see section 4.8).
Systemic and respiratory 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).
Infusion-related reactions were observed in clinical trials (see section 4.8). Serious infusion-related reactions including anaphylactic reactions to the infusion have been reported in the post-marketing setting. If a serious or life-threatening reaction is observed, appropriate therapy should be instituted and ustekinumab should be discontinued.
Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia have been reported during post-approval use of ustekinumab. Clinical presentations included cough, dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalisation. Improvement has been reported after discontinuation of ustekinumab and also, in some cases, administration of corticosteroids. If infection has been excluded and diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment (see section 4.8).
Cardiovascular events
Cardiovascular events including myocardial infarction and cerebrovascular accident have been observed 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.
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.
Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum 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 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 and ulcerative colitis 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.
Lupus-related conditions
Cases of lupus-related conditions have been reported in patients treated with ustekinumab, including cutaneous lupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposed areas of the skin or if accompanied by arthralgia, the patient should seek medical attention promptly. If the diagnosis of a lupus-related condition is confirmed, ustekinumab should be discontinued and appropriate treatment initiated.
Special populations
Elderly
No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients in clinical studies in approved indications, 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.
Excipients with known effect
Sodium content
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 should be taken into consideration for patients on a controlled sodium diet (see section 6.6).
Polysorbate 80 content
STELARA contains 10.8 mg of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.40 mg/mL. Polysorbates may cause allergic reactions.

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 and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viral infections have been observed in patients receiving STELARA (see section 4.8).
Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections (including atypical mycobacterial infection, listeria meningitis, pneumonia legionella, and nocardiosis), opportunistic fungal infections, opportunistic viral infections (including encephalitis caused by herpes simplex 2), and parasitic infections (including ocular toxoplasmosis) have been reported in patients treated with ustekinumab.
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 and in a post-marketing observational study in patients with psoriasis developed cutaneous and non-cutaneous malignancies (see section 4.8). The risk of malignancy may be higher in psoriasis patients who have been treated with other biologics during the course of their disease.
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 skin cancer (see section 4.8).

Systemic and respiratory 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).
Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia have been reported during post-approval use of ustekinumab. Clinical presentations included cough, dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalisation. Improvement has been reported after discontinuation of ustekinumab and also, in some cases, administration of corticosteroids. If infection has been excluded and diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment (see section 4.8).
Cardiovascular events
Cardiovascular events including myocardial infarction and cerebrovascular accident have been observed in patients with psoriasis exposed to STELARA in a post-marketing observational study.
Risk factors for cardiovascular disease should be regularly assessed during treatment with STELARA.
Latex sensitivity
The needle cover 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.
Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum 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 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 and ulcerative colitis 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.
Lupus-related conditions
Cases of lupus-related conditions have been reported in patients treated with ustekinumab, including cutaneous lupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposed areas of the skin or if accompanied by arthralgia, the patient should seek medical attention promptly. If the diagnosis of a lupus-related condition is confirmed, ustekinumab should be discontinued and appropriate treatment initiated.
Special populations
Elderly
No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients in clinical studies in approved indications, 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.
Excipient with known effect
Polysorbate 80 content
STELARA contains 0.04 mg (90 mg/1.0 mL) or 0.02 mg (45 mg/0.5 mL) of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.04 mg/mL. Polysorbates may cause allergic reactions.

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 and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viral infections have been observed in patients receiving STELARA (see section 4.8).

Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections (including atypical mycobacterial infection, listeria meningitis, pneumonia legionella, and nocardiosis), opportunistic fungal infections, opportunistic viral infections (including encephalitis caused by herpes simplex 2), and parasitic infections (including ocular toxoplasmosis) have been reported in patients treated with ustekinumab.
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 and in a post-marketing observational study in patients with psoriasis developed cutaneous and non-cutaneous malignancies (see section 4.8). The risk of malignancy may be higher in psoriasis patients who have been treated with other biologics during the course of their disease.
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 skin cancer (see section 4.8).
Systemic and respiratory 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).
Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia have been reported during post-approval use of ustekinumab. Clinical presentations included cough, dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalisation. Improvement has been reported after discontinuation of ustekinumab and also, in some cases, administration of corticosteroids. If infection has been excluded and diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment (see section 4.8).
Cardiovascular events
Cardiovascular events including myocardial infarction and cerebrovascular accident have been observed in patients with psoriasis exposed to STELARA in a post-marketing observational study.
Risk factors for cardiovascular disease should be regularly assessed during treatment with STELARA.
Latex sensitivity
The needle cover inside the bottom cap of the pre-filled pen is manufactured from dry natural rubber

(a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
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.
Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum 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 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 and ulcerative colitis 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.
Lupus-related conditions
Cases of lupus-related conditions have been reported in patients treated with ustekinumab, including cutaneous lupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposed areas of the skin or if accompanied by arthralgia, the patient should seek medical attention promptly. If the diagnosis of a lupus-related condition is confirmed, ustekinumab should be discontinued and appropriate treatment initiated.
Special populations
Elderly
No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients in clinical studies in approved indications, 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.
Excipient with known effect
Polysorbate 80 content
STELARA contains 0.04 mg (90 mg/1.0 mL) or 0.02 mg (45 mg/0.5 mL) of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.04 mg/mL. Polysorbates may cause allergic reactions.

Live vaccines should not be given concurrently with STELARA.
Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum levels are undetectable.
In the population pharmacokinetic analyses of the phase 3 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 in patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or Crohn’s disease or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.
The results of an in vitro study and a phase 1 study in subjects with active Crohn’s disease 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 and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of STELARA (see section 4.4).

Live vaccines should not be given concurrently with STELARA.
Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum levels are undetectable.
In the population pharmacokinetic analyses of the phase 3 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 in patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or Crohn’s disease or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.
The results of an in vitro study and a phase 1 study in subjects with active Crohn’s disease 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 and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of STELARA. (see section 4.4).

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
Data from a moderate number of prospectively collected pregnancies following exposure to STELARA with known outcomes, including more than 450 pregnancies exposed during the first trimester, 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 to avoid the use of STELARA in pregnancy.
Ustekinumab crosses the placenta and has been detected in the serum of infants born to female patients treated with ustekinumab during pregnancy. The clinical impact of this is unknown, however, the risk of 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 ustekinumab is not recommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (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 ustekinumab serum levels are undetectable.
Breast-feeding
Limited data from published literature suggests that ustekinumab is excreted in human breast milk in very small amounts. 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).

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

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

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, Crohn’s disease and ulcerative colitis.
By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, 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 inflammatory markers including C-Reactive Protein (CRP) and faecal calprotectin during the induction phase, which were then maintained throughout the maintenance phase. CRP was assessed during the study extension and the reductions observed during maintenance were generally sustained through week 252.
In patients with ulcerative colitis, treatment with ustekinumab resulted in a decrease in inflammatory markers including CRP and faecal calprotectin during the induction phase, which was maintained throughout the maintenance phase and study extension through week 200.
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 titres were similar among STELARA-treated and control patients.
Clinical efficacy
Crohn’s disease

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, Crohn’s disease and ulcerative colitis.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, 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 inflammatory markers including C-Reactive Protein (CRP) and faecal calprotectin during the induction phase, which were then maintained throughout the maintenance phase. CRP was assessed during the study extension and the reductions observed during maintenance were generally sustained through week 252.
In patients with ulcerative colitis, treatment with ustekinumab resulted in a decrease in inflammatory markers including CRP and faecal calprotectin during the induction phase, which was maintained throughout the maintenance phase and study extension through week 200.
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 titres were similar among STELARA-treated and control patients.
Clinical efficacy
Plaque psoriasis (Adults)

Following the recommended intravenous induction dose, median peak serum ustekinumab concentration, observed 1 hour after the infusion, was 126.1 μg/mL in patients with Crohn’s disease and 127.0 µg/mL in patients with ulcerative colitis.
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 ulcerative colitis, Crohn’s disease, psoriasis and/or psoriatic arthritis, 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 approximately dose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg.
Special populations
No pharmacokinetic data are available in patients with impaired renal or hepatic function.
No specific studies have been conducted with intravenous ustekinumab in elderly patients.
In patients with Crohn’s disease and ulcerative colitis, variability in ustekinumab clearance was affected by body weight, serum albumin level, sex, and antibody to ustekinumab status while body weight 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 versus non-Asian). The impact of these covariates was within ±20% of the typical or reference value of the respective PK parameter, thus dose adjustment is not warranted for these covariates. Concomitant use of immunomodulators did not have a significant impact on ustekinumab disposition.
Regulation of CYP450 enzymes

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, Crohn’s disease or ulcerative colitis, 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

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, Crohn’s disease or ulcerative colitis, 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