IMULDOSA 130mg perfusive solution concentrate medication leaflet

IMULDOSA 130 mg concentrate for solution for infusion

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

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

Each dose contains less than 1 mmol sodium (23 mg).

Polysorbate content

Each unit volume contains 11.1 mg polysorbate 80, which is equivalent to 10.4 mg per 130 mg dose.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

The solution is colourless to slightly yellow and clear to slightly opalescent.

Crohn’s Disease

IMULDOSA is indicated for the treatment of adult patients with moderately to severely active Crohn’s diseasewho have had an inadequate response with, lost response to, or were intolerant to either conventional therapy ora TNFα antagonist or have medical contraindications to such therapies.

IMULDOSA concentrate for solution for infusion is intended for use under the guidance and supervision ofphysicians experienced in the diagnosis and treatment of Crohn's disease.

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

Crohn’s Disease

IMULDOSA treatment is to be initiated with a single intravenous dose based on body weight. The infusionsolution is to be composed of the number of vials of IMULDOSA 130 mg as specified in Table 1 (see section6.6 for preparation).

Table 1 Initial intravenous dosing of IMULDOSA

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

The first subcutaneous dose should be given at week 8 following the intravenous dose. For the posology of thesubsequent subcutaneous dosing regimen, see section 4.2 of the IMULDOSA solution for injection (vial) andsolution for injection in pre-filled syringe SmPC.

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

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

The safety and efficacy of ustekinumab for the treatment of Crohn’s disease in children less than 18 years havenot yet been established. No data are available.

IMULDOSA 130 mg is for intravenous use only. It should be administered over at least one hour. Forinstructions on dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important, active infection (e.g. active tuberculosis; see section 4.4).

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

Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. In clinicalstudies and a post-marketing observational study in patients with psoriasis, serious bacterial, fungal, and viralinfections have been observed in patients receiving ustekinumab (see section 4.8).

Opportunistic infections including reactivation of tuberculosis, other opportunistic bacterial infections (includingatypical mycobacterial infection, listeria meningitis, pneumonia legionella, and nocardiosis), opportunistic fungalinfections, opportunistic viral infections (including encephalitis caused by herpes simplex 2), and parasiticinfections (including ocular toxoplasmosis) have been reported in patients treated with ustekinumab.

Caution should be exercised when considering the use of IMULDOSA in patients with a chronic infection or ahistory of recurrent infection (see section 4.3).

Prior to initiating treatment with IMULDOSA, patients should be evaluated for tuberculosis infection.

IMULDOSA must not be given to patients with active tuberculosis (see section 4.3). Treatment of latenttuberculosis infection should be initiated prior to administering IMULDOSA. Anti-tuberculosis therapy shouldalso be considered prior to initiation of IMULDOSA in patients with a history of latent or active tuberculosis inwhom an adequate course of treatment cannot be confirmed. Patients receiving IMULDOSA should bemonitored 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 apatient develops a serious infection, the patient should be closely monitored and IMULDOSA should not beadministered until the infection resolves.

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Some patients whoreceived ustekinumab in clinical studies and in a post-marketing observational study in patients with psoriasisdeveloped cutaneous and non-cutaneous malignancies (see section 4.8). The risk of malignancy may be higher inpsoriasis 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 inpatients who develop malignancy while receiving ustekinumab. Thus, caution should be exercised whenconsidering the use of IMULDOSA in these patients.

All patients, in particular those greater than 60 years of age, patients with a medical history of prolongedimmunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the appearanceof skin cancer (see section 4.8).

Systemic and respiratory hypersensitivity reactions

Systemic

Serious hypersensitivity reactions have been reported in the post-marketing setting, in some cases several daysafter treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or other serious hypersensitivityreaction occurs, appropriate therapy should be instituted and administration of IMULDOSA should bediscontinued (see section 4.8).

Infusion-related reactions were observed in clinical trials (see section 4.8). Serious infusion-related reactionsincluding anaphylactic reactions to the infusion have been reported in the post-marketing setting. If a serious orlife-threatening reaction is observed, appropriate therapy should be instituted and ustekinumab should bediscontinued.

Respiratory

Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia have beenreported during post-approval use of ustekinumab. Clinical presentations included cough, dyspnoea, andinterstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure andprolonged hospitalisation. Improvement has been reported after discontinuation of ustekinumab and also, in somecases, administration of corticosteroids. If infection has been excluded and diagnosis is confirmed, discontinueustekinumab and institute appropriate treatment (see section 4.8).

Cardiovascular events including myocardial infarction and cerebrovascular accident have been observed inpatients with psoriasis exposed to ustekinumab in a post-marketing observational study. Risk factors forcardiovascular disease should be regularly assessed during treatment with ustekinumab.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin (BCG))should not be given concurrently with IMULDOSA. Specific studies have not been conducted in patients whohad recently received live viral or live bacterial vaccines. No data are available on the secondary transmission ofinfection by live vaccines in patients receiving ustekinumab. Before live viral or live bacterial vaccination,treatment with IMULDOSA should be withheld for at least 15 weeks after the last dose and can be resumed atleast 2 weeks after vaccination. Prescribers should consult the Summary of Product Characteristics for thespecific 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 notrecommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (seesections 4.5 and 4.6). If there is a clear clinical benefit for the individual infant, administration of a live vaccinemight be considered at an earlier timepoint, if infant ustekinumab serum levels are undetectable.

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

Long term treatment with ustekinumab does not suppress the humoral immune response to pneumococcalpolysaccharide or tetanus vaccines (see section 5.1).

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants, includingbiologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did notappear to influence the safety or efficacy of ustekinumab. In Crohn’s disease studies, concomitant use ofimmunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. Cautionshould be exercised when considering concomitant use of other immunosuppressants and IMULDOSA or whentransitioning from other immunosuppressive biologics (see section 4.5).

Immunotherapy

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

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see section4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may be clinicallyindistinguishable from exfoliative dermatitis, as part of the natural course of their disease. As part of themonitoring of the patient’s psoriasis, physicians should be alert for symptoms of erythrodermic psoriasis orexfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. IMULDOSA should bediscontinued if a drug reaction is suspected.

Lupus-related conditions

Cases of lupus-related conditions have been reported in patients treated with ustekinumab, including cutaneouslupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposed areas of the skin or ifaccompanied 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.

No overall differences in efficacy or safety in patients age 65 and older who received ustekinumab wereobserved compared to younger patients in clinical studies in approved indications, however the number ofpatients 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 intreating the elderly.

IMULDOSA contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’. IMULDOSA ishowever, diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken intoconsideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate content

IMULDOSA contains 11.1 mg polysorbate 80 in each unit volume, which is equivalent to 10.4 mg per 130 mgdose.

Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.

Live vaccines should not be given concurrently with IMULDOSA.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is notrecommended for twelve months following birth or until ustekinumab infant serum levels are undetectable (seesections 4.4 and 4.6). If there is a clear clinical benefit for the individual infant, administration of a live vaccinemight 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 usedconcomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid,metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored. There were noindications of an interaction with these concomitantly administered medicinal products. The basis for thisanalysis was that at least 100 patients (> 5% of the studied population) were treated concomitantly with thesemedicinal products for at least 90% of the study period. The pharmacokinetics of ustekinumab was not impactedby concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids in patients withpsoriatic arthritis, Crohn’s disease or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or

The results of an in vitro study and a phase 1 study in subjects with active Crohn’s disease do not suggest the needfor 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, includingbiologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did notappear to influence the safety or efficacy of ustekinumab. In Crohn’s disease studies, concomitant use ofimmunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab (seesection 4.4).

Women of childbearing potential should use effective methods of contraception during treatment and for at least15 weeks after treatment.

Data from a moderate number of prospectively collected pregnancies following exposure to ustekinumab withknown outcomes, including more than 450 pregnancies exposed during the first trimester, do not indicate anincreased risk of major congenital malformations in the newborn.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetaldevelopment, 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 useof IMULDOSA in pregnancy.

Ustekinumab crosses the placenta and has been detected in the serum of infants born to female patients treatedwith ustekinumab during pregnancy. The clinical impact of this is unknown, however, the risk of infection ininfants 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 birthor until ustekinumab infant serum levels are undetectable (see sections 4.4 and 4.5). If there is a clear clinicalbenefit for the individual infant, administration of a live vaccine might be considered at an earlier timepoint, ifinfant ustekinumab serum levels are undetectable.

Limited data from published literature suggests that ustekinumab is excreted in human breast milk in very smallamounts. It is not known if ustekinumab is absorbed systemically after ingestion. Because of the potential foradverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feedingduring treatment and up to 15 weeks after treatment or to discontinue therapy with IMULDOSA must be madetaking into account the benefit of breast-feeding to the child and the benefit of IMULDOSA therapy to thewoman.

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

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

The most common adverse reactions (> 5%) in controlled periods of the adult psoriasis, psoriatic arthritis,

Crohn’s disease clinical studies with ustekinumab were nasopharyngitis and headache. Most were considered tobe mild and did not necessitate discontinuation of study treatment. The most serious adverse reaction that hasbeen reported for ustekinumab is serious hypersensitivity reactions including anaphylaxis (see section 4.4). Theoverall safety profile was similar for patients with psoriasis, psoriatic arthritis, Crohn’s disease.

The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3 studies in6,710 patients (4,135 with psoriasis and/or psoriatic arthritis and 1,749 with Crohn’s disease). This includesexposure to ustekinumab in the controlled and non-controlled periods of the clinical studies in patients withpsoriasis, psoriatic arthritis or Crohn’s disease for at least 6 months (4,577 patients) or at least 1 year (3,648patients). 2,194 patients with psoriasis, Crohn’s disease were exposed for at least 4 years while 1,148patients with psoriasis or Crohn’s disease were exposed for at least 5 years.

Table 2 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis and Crohn’s disease clinicalstudies as well as adverse reactions reported from post-marketing experience. The adverse reactions are classifiedby 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), notknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 2 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 respiratorytract infection, viral upper respiratory tract infection, vulvovaginal mycoticinfection

Immune system disorders Uncommon: Hypersensitivity reactions (including rash, urticaria)

Rare: Serious hypersensitivity reactions (including anaphylaxis,angioedema)

Psychiatric disorders Uncommon: Depression

Nervous system disorders Common: Dizziness, headache

Uncommon: Facial palsy

Respiratory, thoracic and Common: Oropharyngeal painmediastinal disorders Uncommon: Nasal congestion

Rare: Allergic alveolitis, eosinophilic pneumonia

Very rare: Organising pneumonia*

Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue Common: Pruritusdisorders Uncommon: Pustular psoriasis, skin exfoliation, acne

Rare: Exfoliative dermatitis, hypersensitivity vasculitis

Very rare: Bullous pemphigoid, cutaneous lupus erythematosus

Musculoskeletal and connective Common: Back pain, myalgia, arthralgiatissue disorders Very rare: Lupus-like syndrome

General disorders and Common: Fatigue, injection site erythema, injection site painadministration site conditions Uncommon: Injection site reactions (including haemorrhage,haematoma, induration, swelling and pruritus), asthenia

* See section 4.4, Systemic and respiratory hypersensitivity reactions.

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis and Crohn’s disease, the rates ofinfection 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 of0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infections in 930 patient-years offollow-up) and 0.03 in placebo-treated patients (15 serious infections in 434 patient-years of follow-up) (seesection 4.4).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn’s disease clinical studies,representing 15,227 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2years; 1.7 years for psoriatic disease studies and 0.6 year for Crohn’s disease studies. The rate of infection was0.85 per patient-year of follow-up in ustekinumab-treated patients, and the rate of serious infections was 0.02 perpatient-year of follow-up in ustekinumab-treated patients (289 serious infections in 15,227 patient-years offollow-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 developtuberculosis.

In the placebo-controlled period of the psoriasis, psoriatic arthritis and Crohn’s disease clinical studies, theincidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up forustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treatedpatients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per100 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 and Crohn’s disease clinical studies,representing 15,205 patient-years of ustekinumab exposure in 6,710 patients, the median follow-up was 1.2years; 1.7 years for psoriatic disease studies and 0.6 year for Crohn’s disease studies. Malignancies excludingnon-melanoma skin cancers were reported in 76 patients in 15,205 patient-years of follow-up (incidence of 0.50per 100 patient- years of follow-up for ustekinumab-treated patients). The incidence of malignancies reported inustekinumab-treated patients was comparable to the incidence expected in the general population (standardisedincidence ratio = 0.94 [95% confidence interval: 0.73, 1.18], adjusted for age, gender and race). The mostfrequently 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 forustekinumab-treated patients (69 patients in 15,165 patient-years of follow-up). The ratio of patients with basalversus squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (seesection 4.4).

Hypersensitivity and infusion reactions

In Crohn’s disease intravenous induction studies, no events of anaphylaxis or other serious infusion reactionswere reported following the single intravenous dose. In these studies, 2.2% of 785 placebo-treated patients and1.9% of 790 patients treated with the recommended dose of ustekinumab reported adverse events occurringduring or within an hour of the infusion. Serious infusion-related reactions including anaphylactic reactions tothe infusion have been reported in the post-marketing setting (see section 4.4).

Paediatric patients 6 years and older with plaque psoriasis

The safety of ustekinumab has been studied in two phase 3 studies of paediatric patients with moderate to severeplaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for up to 60 weeks and thesecond study was in 44 patients from 6 to 11 years of age treated for up to 56 weeks. In general, the adverse eventsreported in these two studies with safety data up to 1 year were similar to those seen in previous studies in adultswith plaque psoriasis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked toreport any suspected adverse reactions via the national reporting system listed in Appendix V.

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

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

IMULDOSA is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40 proteinsubunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the bioactivity of human IL-12and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on the surface of immunecells. 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-12and/or IL-23 receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presentingcells, such as macrophages and dendritic cells, and both cytokines participate in immune functions; IL-12stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1)phenotype, IL- 23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 hasbeen associated with immune mediated diseases, such as psoriasis, psoriatic arthritis and Crohn’s disease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis,psoriatic arthritis and Crohn’s disease through interruption of the Th1 and Th17 cytokine pathways, which arecentral to the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatory markersincluding C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, which were thenmaintained throughout the maintenance phase. CRP was assessed during the study extension and the reductionsobserved during maintenance were generally sustained through week 252.

During the long term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated with ustekinumab forat least 3.5 years mounted similar antibody responses to both pneumococcal polysaccharide and tetanusvaccines as a non-systemically treated psoriasis control group. Similar proportions of adult patients developedprotective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers were similar amongustekinumab-treated and control patients.

Crohn’s Disease

The safety and efficacy of ustekinumab was assessed in three randomized, double-blind, placebo- controlled,multicenter studies in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease

Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical development program consisted of two 8-weekintravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 week subcutaneous randomizedwithdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.

The induction studies included 1409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary endpoint forboth induction studies was the proportion of subjects in clinical response (defined as a reduction in CDAI scoreof ≥ 100 points) at week 6. Efficacy data were collected and analyzed through week 8 for both studies.

Concomitant doses of oral corticosteroids, immunomodulators, aminosalicylates and antibiotics were permittedand 75% of patients continued to receive at least one of these medications. In both studies, patients wererandomised to receive a single intravenous administration of either the recommended tiered dose ofapproximately 6 mg/kg (see Table 1, section 4.2), a fixed dose of 130 mg ustekinumab, or placebo at week 0.

Patients in UNITI-1 had failed or were intolerant to prior anti-TNFα therapy. Approximately 48% of the patientshad failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies. In this study, 29.1%of the patients had an inadequate initial response (primary non-responders), 69.4% responded but lost response(secondary non-responders), and 36.4% were intolerant to anti-TNFα therapies.

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

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

Table 3: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1* UNITI-2**

Placebo Recommended Placebo Recommended dose

N = 247 dose of N = 209 ofustekinumab ustekinumab

N = 249 N = 209

Clinical Remission, week 8 18 (7.3%) 52 (20.9%)a 41 (19.6%) 84 (40.2%)a

Clinical Response (100 point), week 6 53 (21.5%) 84 (33.7%)b 60 (28.7%) 116 (55.5%)a

Clinical Response (100 point), week 8 50 (20.2%) 94 (37.8%)a 67 (32.1%) 121 (57.9%)a70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a70 Point Response, week 6 75 (30.4%) 109 (43.8%)b 81 (38.8%) 135 (64.6%)a

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least100 points or being in clinical remission70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failuresa p < 0.001b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical response at week 8of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomized to receive asubcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12weeks or placebo for 44 weeks (for recommended maintenance posology, see section 4.2 of the IMULDOSA

Solution for injection (vial) and Solution for injection in pre-filled syringe SmPC).

Significantly higher proportions of patients maintained clinical remission and response in the ustekinumab treatedgroups compared to the placebo group at week 44 (see Table 4).

Table 4: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from initiationof the induction dose)

Placebo* 90 mg 90 mg ustekinumabustekinumab everyevery 8 weeks 12 weeks

N = 129†

N = 131† N = 128†

Clinical Remission 36% 53%a 49%b

Clinical Response 44% 59%b 58%b

Corticosteroid-Free Clinical Remission 30% 47%a 43%c

Clinical Remission in patients:

in remission at the start of maintenance 46% (36/79) 67% (52/78)a 56% (44/78)therapywho entered from study CRD3002‡ 44% (31/70) 63% (45/72)c 57% (41/72)who are Anti-TNFα naïve 49% (25/51) 65% (34/52)c 57% (30/53)who entered from study CRD3001§ 26% (16/61) 41% (23/56) 39% (22/57)

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

* The placebo group consisted of patients who were in response to ustekinumab and were randomized to receive placebo at the start ofmaintenance therapy.† Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy‡ Patients who failed conventional therapy but not anti-TNFα therapy§ Patients who are anti-TNFα refractory/intoleranta p < 0.01b p < 0.05c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every 12 weeks andwere allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response was defined as a CDAIscore ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline. In these patients, clinicalremission was achieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and UNITI-2induction studies (476 patients) entered into the non-randomized portion of the maintenance study (IM-UNITI)and received a 90 mg subcutaneous injection of ustekinumab at that time.

Eight weeks later, 50.5% of the patients achieved clinical response and continued to receive maintenance dosingevery 8 weeks; among these patients with continued maintenance dosing, a majority maintained response (68.1%)and achieved remission (50.2%) at week 44, at proportions that were similar to the patients who initiallyresponded to ustekinumab induction.

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

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a studyextension. Among the 567 patients who entered on and were treated with ustekinumab in the study extension,clinical remission and response were generally maintained through week 252 for both patients who failed TNF-therapies and those who failed conventional therapies.

No new safety concerns were identified in this study extension with up to 5 years of treatment in patients with

Crohn’s Disease.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopic diseaseactivity in a substudy. The primary endpoint was change from baseline in Simplified Endoscopic Disease

Severity Score for Crohn’s Disease (SES-CD), a composite score across 5 ileo- colonic segments ofpresence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affectedby any other lesions and presence/type of narrowing/strictures. At week 8, after a single intravenous inductiondose, the change in SES-CD score was greater in the ustekinumab group (n = 155, mean change = -2.8) than inthe placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of ustekinumab-treatedpatients achieved a fistula response over 44 weeks (defined as ≥ 50% reduction from baseline of the inductionstudy in the number of draining fistulas) compared to 5/11 (45.5%) exposed to placebo.

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and SF-36questionnaires. At week 8, patients receiving ustekinumab showed statistically significantly greater andclinically meaningful improvements on IBDQ total score and SF-36 Mental Component Summary Score in both

UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in UNITI-2, when compared to placebo.

These improvements were generally better maintained in ustekinumab-treated patients in the IM-UNITI studythrough week 44 when compared to placebo. Improvement in health-related quality of life was generallymaintained during the extension through week 252.

Antibodies to ustekinumab may develop during ustekinumab treatment and most are neutralising. The formationof anti-ustekinumab antibodies is associated with increased clearance of ustekinumab in patients with Crohn’sdisease. No reduced efficacy was observed. There is no apparent correlation between the presence of anti-ustekinumab antibodies and the occurrence of injection site reactions.

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

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.

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

The exact metabolic pathway for ustekinumab is unknown.

Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis rangedfrom 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab was approximately 3 weeks in patients with

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

Dose linearity

The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximately dose-proportionalmanner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg.

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

No specific studies have been conducted with intravenous ustekinumab in elderly or paediatric patients.

In patients with Crohn’s disease, variability in ustekinumab clearance was affected by body weight, serumalbumin level, sex, and antibody to ustekinumab status while body weight was the main covariate affecting thevolume of distribution. Additionally in Crohn’s disease, clearance was affected by C-reactive protein, TNFantagonist failure status and race (Asian versus non-Asian). The impact of these covariates was within ±20% ofthe typical or reference value of the respective PK parameter, thus dose adjustment is not warranted for thesecovariates. Concomitant use of immunomodulators did not have a significant impact on ustekinumabdisposition.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study usinghuman hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).

A phase 1, open-label, drug interaction study, Study CNTO1275CRD1003, was conducted to evaluate the effect ofustekinumab on cytochrome P450 enzyme activities following induction and maintenance dosing in patients withactive Crohn’s disease (n=18). No clinically significant changes in exposure of caffeine (CYP1A2 substrate),warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), ormidazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approvedrecommended dosing in patients with Crohn’s disease (see section 4.5).

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

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

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

EDTA disodium salt dihydrate (E385)

L-histidine

L-histidine hydrochloride monohydrate

L-methionine

Polysorbate 80 (E433)

Sucrose

Water for injection

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

IMULDOSA should only be diluted with sodium chloride 9 mg/mL (0.9%) solution. IMULDOSA should not beadministered concomitantly in the same intravenous line with other medicinal products.

2 years.

Do not freeze.

After dilution, the chemical and physical in-use stability has been demonstrated for 24 hours at 23°C - 27°C or 7days at 2°C - 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-usestorage times and conditions prior to use are the responsibility of the user and would normally not be longer than24 hours at 2°C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

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

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

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

26 mL solution in a type I glass 30 mL vial closed with a coated butyl rubber stopper. IMULDOSA is availablein a 1 vial pack.

The solution in the IMULDOSA vial should not be shaken. The solution should be visually inspected forparticulate matter or discolouration prior to administration. The solution is colourless to slightly yellow and clearto slightly opalescent. The medicinal product should not be used if the solution is discoloured or cloudy, or ifforeign particulate matter is present.

IMULDOSA concentrate for solution for infusion must be diluted and prepared by a healthcare professional usingaseptic technique.

1. Calculate the dose and the number of IMULDOSA vials needed based on patient weight (see section 4.2,

Table 1). Each 26 mL vial of IMULDOSA contains 130 mg of ustekinumab. Only use complete vials of

IMULDOSA.

2. Withdraw and discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the 250 mLinfusion bag equal to the volume of IMULDOSA to be added. (discard 26 mL sodium chloride for eachvial of IMULDOSA needed, for 2 vials-discard 52 mL, for 3 vials- discard 78 mL, for 4 vials- discard104 mL)3. Withdraw 26 mL of IMULDOSA from each vial needed and add it to the 250 mL infusion bag. The finalvolume in the infusion bag should be 250 mL. Gently mix.

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

5. Administer the diluted solution over a period of at least one hour. Once diluted, the infusion should becompleted within 24 hours of the dilution in the infusion bag.

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

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

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

EU/1/24/1872/003

Date of first authorization: 12 December 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/