4.1. Therapeutic indications

Plaque psoriasis

Otulfi 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

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

Psoriatic arthritis (PsA)

Otulfi, 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

Otulfi 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

OTULFI is indicated for the treatment of moderately to severely active Crohn's disease in paediatric patients weighing at least 40 kg, who have had an inadequate response to, or were intolerant to either conventional or biologic therapy.

Ulcerative colitis

Otulfi 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 (see section 5.1).

4.2. Posology and method of administration

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

Posology

Plaque psoriasis

The recommended posology of Otulfi 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 Otulfi 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

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

Paediatric population

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

Table 1 Recommended dose of Otulfi 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 Otulfi for paediatric psoriasis patients < 60 kg

Body weight at time of dosing (kg)

Dose (mg)

Volume of injection (mL)

15

11.3

0.12

16

12.0

0.13

17

12.8

0.14

18

13.5

0.15

19

14.3

0.16

20

15.0

0.17

21

15.8

0.17

22

16.5

0.18

23

17.3

0.19

24

18.0

0.20

25

18.8

0.21

26

19.5

0.22

27

20.3

0.22

28

21.0

0.23

29

21.8

0.24

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.

Adults

Crohn's Disease and Ulcerative Colitis

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

The first subcutaneous administration of 90 mg Otulfi 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, 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 the 8-weekly maintenance dose.

Immunomodulators and/or corticosteroids may be continued during treatment with Otulfi. In patients who have responded to treatment with Otulfi, 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 (≥ 65 years)

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

Renal and hepatic impairment

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

Paediatric population

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

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

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

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, 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 dose adjustment.

Immunomodulators, 5-aminosalicylate (5-ASA) compounds, antibiotics, and/or corticosteroids may be continued during treatment with OTULFI. In patients who have responded to treatment with OTULFI, these medications maybe reduced or discontinued in accordance with standard of care.

The safety and efficacy of ustekinumab in treatment of Crohn's disease for paediatric patients weighing less than 40 kg or ulcerative colitis in children less than 18 years have not yet been established. No data are available.

Method of administration

Otulfi 45 mg vials 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 Otulfi 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 Otulfi 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 and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viral infections have been observed in patients receiving ustekinumab (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 Otulfi in patients with a chronic infection or a history of recurrent infection (see section 4.3).

Prior to initiating treatment with Otulfi, patients should be evaluated for tuberculosis infection. Otulfi must not be given to patients with active tuberculosis (see section 4.3). Treatment of latent tuberculosis infection should be initiated prior to administering Otulfi. Anti-tuberculosis therapy should also be considered prior to initiation of Otulfi in patients with a history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving Otulfi 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 Otulfi 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 ustekinumab 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 ustekinumab. Thus, caution should be exercised when considering the use of Otulfi 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

Systemic

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 Otulfi should be discontinued (see section 4.8).

Respiratory

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 ustekinumab in a post-marketing observational study. Risk factors for cardiovascular disease should be regularly assessed during treatment with Otulfi.

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 Otulfi. 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 ustekinumab. Before live viral or live bacterial vaccination, treatment with Otulfi 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 Otulfi may receive concurrent inactivated or non-live vaccinations.

Long term treatment with ustekinumab 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 ustekinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab.

In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. Caution should be exercised when considering concomitant use of other immunosuppressants and Otulfi or when transitioning from other immunosuppressive biologics (see section 4.5).

Immunotherapy

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

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see section 4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with 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. Otulfi 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 (≥ 65 years)

No overall differences in efficacy or safety in patients aged 65 and older who received ustekinumab 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.

Otulfi contains polysorbate 80

This medicinal product contains 0.02 mg of polysorbate 80 (E433) in each vial of 0.5 mL which is equivalent to 0.04 mg/ml.

Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Live vaccines should not be given concurrently with Otulfi.

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 ustekinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. (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

Data from a moderate number of prospectively collected pregnancies following exposure to ustekinumab 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 Otulfi 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 Otulfi must be made taking into account the benefit of breast-feeding to the child and the benefit of Otulfi 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

Otulfi 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, Crohn's disease and ulcerative colitis 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 ustekinumab 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 ustekinumab 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 for at least 4 years while 1,148 patients with psoriasis or Crohn's disease were exposed for at least 5 years.

Table 3 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 3 List of adverse reactions

System Organ Class

Frequency: Adverse reaction

Infections and infestations

Common: Upper respiratory tract infection, nasopharyngitis, sinusitis

Uncommon: Cellulitis, dental infections, herpes zoster, lower 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).

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 weighing at least 40 kg with Crohn's disease

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

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

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.