4.1. Therapeutic indications

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 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.

Otulfi concentrate for solution for infusion should only be used for the intravenous induction dose.

Posology

Adults

Crohn's Disease and Ulcerative Colitis

Otulfi 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 Otulfi 130 mg as specified in Table 1 (see section 6.6 for preparation).

Table 1 Initial intravenous dosing of Otulfi

Body weight of patient at the time of dosing

Recommended dosea

Number of 130 mg Otulfi Vials

≤ 55 kg

260 mg

2

> 55 kg to ≤ 85 kg

390 mg

3

> 85 kg

520 mg

4

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 Otulfi solution for injection in pre-filled syringe SmPC.

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)

OTULFI 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 OTULFI 130 mg as specified in Table 2 (see section 6.6 for preparation).

Table 2 Initial intravenous dosing of OTULFI

Body weight of patient at the time of dosing

Recommended dosea

Number of 130 mg OTULFI Vials

≥ 40 kg to ≤ 55 kg

260 mg

2

> 55 kg to ≤ 85 kg

390 mg

3

> 85 kg

520 mg

4

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 OTULFI solution for injection (vial) and solution for injection in prefilled syringe SmPC.

The safety and efficacy of ustekinumab for the treatment of Crohn's disease in 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 130 mg is for intravenous use only. It should be administered over at least one hour. For instructions on dilution of the medicinal product before administration, see section 6.6.

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).

Infusion-related reactions

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.

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 Otulfi 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 Otulfi 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.

Sodium content

Otulfi contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'. Otulfi 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).

Otulfi contains Polysorbate 80

This medicinal product contains 10.4 mg of polysorbate 80 (E433) in each vial of 26 mL which is equivalent to 0.4 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) 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 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 and infusion reactions

In 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. Serious infusion-related reactions including anaphylactic reactions to the infusion have been reported in the post-marketing setting (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.