PYZCHIVA 130mg perfusive solution concentrate medication leaflet

Pyzchiva 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 achinese hamster ovary (CHO) cell line using recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

The solution is clear, colourless to light yellow, and its formulated at pH 6.0 ± 0.3. The osmolality ofthe solution is 290 ± 30 mOsm/kg.

Crohn’s Disease

Pyzchiva is indicated for the treatment of adult patients with moderately to severely active Crohn’sdisease who have had an inadequate response with, lost response to, or were intolerant to eitherconventional therapy or a TNFα antagonist or have medical contraindications to such therapies.

Pyzchiva concentrate for solution for infusion is intended for use under the guidance and supervisionof physicians experienced in the diagnosis and treatment of Crohn's disease.

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

Crohn’s Disease

Pyzchiva treatment is to be initiated with a single intravenous dose based on body weight. Theinfusion solution is to be composed of the number of vials of Pyzchiva 130 mg as specified in Table 1(see section 6.6 for preparation).

Table 1: Initial intravenous dosing of Pyzchiva

Body weight of patient at the time of Recommended dosea Number of 130 mgdosing Pyzchiva 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 theposology of the subsequent subcutaneous dosing regimen, see section 4.2 of the Pyzchiva solution forinjection in pre-filled syringe or pre-filled pen SmPC.

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 bemade.

The safety and efficacy of ustekinumab for the treatment of Crohn’s disease in children less than18 years have not yet been established. No data are available.

Pyzchiva 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. Clinicallyimportant, active infection (e.g. active tuberculosis; see section 4.4).

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

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, andnocardiosis), opportunistic fungal infections, opportunistic viral infections (including encephalitiscaused by herpes simplex 2), and parasitic infections (including ocular toxoplasmosis) have beenreported in patients treated with ustekinumab.

Caution should be exercised when considering the use of ustekinumab in patients with a chronicinfection or a history of recurrent infection (see section 4.3).

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

Ustekinumab must not be given to patients with active tuberculosis (see section 4.3). Treatment oflatent tuberculosis infection should be initiated prior to administering ustekinumab. Anti-tuberculosistherapy should also be considered prior to initiation of ustekinumab in patients with a history of latentor active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patientsreceiving ustekinumab should be monitored closely for signs and symptoms of active tuberculosisduring and after treatment.

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

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Somepatients who received ustekinumab in clinical studies and in a post-marketing observational study inpatients with psoriasis developed cutaneous and non-cutaneous malignancies (see section 4.8). Therisk of malignancy may be higher in psoriasis patients who have been treated with other biologicsduring the course of their disease

No studies have been conducted that include patients with a history of malignancy or that continuetreatment in patients who develop malignancy while receiving ustekinumab. Thus, caution should beexercised when considering the use of ustekinumab in these patients.

All patients, in particular those greater than 60 years of age, patients with a medical history ofprolonged immunosuppressant therapy or those with a history of PUVA treatment, should bemonitored 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 casesseveral days after treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or otherserious hypersensitivity reaction occurs, appropriate therapy should be instituted and administration ofustekinumab should be discontinued (see section 4.8).

Infusion-Related Reactions

Infusion-related reactions were observed in clinical trials (see section 4.8). Serious infusion-relatedreactions including anaphylactic reactions to the infusion have been reported in the post-marketingsetting. If a serious or life-threatening reaction is observed, appropriate therapy should be institutedand ustekinumab should be discontinued.

Respiratory

Cases of allergic alveolitis, eosinophilic pneumonia, and non-infectious organising pneumonia havebeen reported during post-approval use of ustekinumab. Clinical presentations included cough,dyspnoea, and interstitial infiltrates following one to three doses. Serious outcomes have includedrespiratory failure and prolonged hospitalisation. Improvement has been reported after discontinuationof ustekinumab and also, in some cases, administration of corticosteroids. If infection has beenexcluded and diagnosis is confirmed, discontinue ustekinumab and institute appropriate treatment (seesection 4.8).

Cardiovascular events including myocardial infarction and cerebrovascular accident have beenobserved in patients with psoriasis exposed to ustekinumab in a post-marketing observational study.

Risk factors for cardiovascular disease should be regularly assessed during treatment withustekinumab.

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin(BCG)) should not be given concurrently with ustekinumab. Specific studies have not been conductedin patients who had recently received live viral or live bacterial vaccines. No data are available on thesecondary transmission of infection by live vaccines in patients receiving ustekinumab. Before liveviral or live bacterial vaccination, treatment with ustekinumab should be withheld for at least 15 weeksafter 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 guidanceon concomitant use of immunosuppressive agents post-vaccination.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumabis not recommended for twelve months following birth or until ustekinumab infant serum levels areundetectable (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 ustekinumabserum levels are undetectable.

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

Long term treatment with ustekinumab does not suppress the humoral immune response topneumococcal 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’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of ustekinumab. Caution should be exercised whenconsidering concomitant use of other immunosuppressants and ustekinumab or when transitioningfrom other immunosuppressive biologics (see section 4.5).

Immunotherapy

Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy. It is notknown 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 symptomsthat may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course oftheir disease. As part of the monitoring of the patient’s psoriasis, physicians should be alert forsymptoms of erythrodermic psoriasis or exfoliative dermatitis. If these symptoms occur, appropriatetherapy should be instituted. ustekinumab 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, includingcutaneous lupus erythematosus and lupus-like syndrome. If lesions occur, especially in sun exposedareas of the skin or if accompanied by arthralgia, the patient should seek medical attention promptly. Ifthe diagnosis of a lupus-related condition is confirmed, ustekinumab should be discontinued andappropriate treatment initiated.

No overall differences in efficacy or safety in patients age 65 and older who received ustekinumabwere observed compared to younger patients in clinical studies in approved indications, however thenumber of patients aged 65 and older is not sufficient to determine whether they respond differentlyfrom younger patients. Because there is a higher incidence of infections in the elderly population ingeneral, caution should be used in treating the elderly.

Ustekinumab contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.ustekinumab is however, diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. Thisshould be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Live vaccines should not be given concurrently with ustekinumab.

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumabis not recommended for twelve months following birth or until ustekinumab infant serum levels areundetectable (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 ustekinumabserum levels are undetectable.

No interaction studies have been performed in humans. In the population pharmacokinetic analyses ofthe phase 3 studies, the effect of the most frequently used concomitant medicinal products in patientswith psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin,levothyroxine) on pharmacokinetics of ustekinumab was explored. There were no indications of aninteraction with these concomitantly administered medicinal products. The basis for this analysis wasthat 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 notimpacted by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oralcorticosteroids in patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis, or priorexposure to anti-TNFα agents, in patients with psoriatic arthritis or Crohn’s disease or by priorexposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.

The results of an in vitro study do not suggest the need for dose adjustments in patients who arereceiving 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’sdisease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids didnot appear to influence the safety or efficacy of ustekinumab. (see section 4.4).

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

Data from a moderate number of prospectively collected pregnancies following exposure toustekinumab with known outcomes, including more than 450 pregnancies exposed during the firsttrimester, 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 toavoid the use of ustekinumab in pregnancy.

Ustekinumab crosses the placenta and has been detected in the serum of infants born to female patientstreated with ustekinumab during pregnancy. The clinical impact of this is unknown, however, the riskof infection in infants exposed in utero to ustekinumab may be increased after birth. Administration oflive 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 areundetectable (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 ustekinumabserum levels are undetectable.

Limited data from published literature suggests that ustekinumab is excreted in human breast milk invery small amounts. It is not known if ustekinumab is absorbed systemically after ingestion. Becauseof the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether todiscontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinuetherapy with ustekinumab must be made taking into account the benefit of breast-feeding to the childand the benefit of ustekinumab therapy to the woman.

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

Ustekinumab 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, psoriaticarthritis, Crohn’s disease and ulcerative colitis clinical studies with ustekinumab were nasopharyngitisand headache. Most were considered to be mild and did not necessitate discontinuation of studytreatment. The most serious adverse reaction that has been reported for ustekinumab is serioushypersensitivity reactions including anaphylaxis (see section 4.4). The overall safety profile wassimilar for patients with psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

The safety data described below reflect exposure in adults to ustekinumab in 14 phase 2 and phase 3studies in 6,709 patients (4,135 with psoriasis and/or psoriatic arthritis, 1,749 with Crohn’s disease,and 825 patients with ulcerative colitis). This includes exposure to ustekinumab in the controlled andnon-controlled periods of the clinical studies for at least 6 months or 1 year (4,577 and 3,253 patientsrespectively with psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis) and exposure for atleast 4 or 5 years (1,482 and 838 patients with psoriasis respectively).

Table 2 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-marketingexperience. The adverse reactions are classified by System Organ Class and frequency, using thefollowing 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 fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing 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, lowerrespiratory 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

System Organ Class Frequency: Adverse reaction

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 lupuserythematosus

Musculoskeletal and Common: Back pain, myalgia, arthralgiaconnective tissue 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.

Description of selected adverse reactions Infections

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis, Crohn’s disease andulcerative colitis, the rates of infection or serious infection were similar between ustekinumab-treatedpatients and those treated with placebo. In the placebo-controlled period of these clinical studies, therate of infection was 1.36 per patient-year of follow-up in ustekinumab-treated patients, and 1.34 inplacebo-treated patients. Serious infections occurred at the rate of 0.03 per patient-year of follow-up inustekinumab-treated patients (30 serious infections in 930 patient-years of follow-up) and 0.03 inplacebo-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 andulcerative colitis clinical studies, representing 11,581 patient-years of exposure in 6,709 patients, themedian follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 year for Crohn’s diseasestudies and 1.0 years for ulcerative colitis studies. The rate of infection was 0.91 per patient-year offollow-up in ustekinumab-treated patients, and the rate of serious infections was 0.02 per patient-yearof follow-up in ustekinumab-treated patients (199 serious infections in 11,581 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 didnot develop tuberculosis.

In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn’s disease and ulcerativecolitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years offollow-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 forustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 forplacebo-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 andulcerative colitis clinical studies, representing 11,561 patient-years of exposure in 6,709 patients, themedian follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 year for Crohn’s diseasestudies and 1.0 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancerswere reported in 62 patients in 11,561 patient-years of follow-up (incidence of 0.54 per 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(standardised incidence ratio = 0.93 [95% confidence interval: 0.71, 1.20], adjusted for age, genderand race). The most frequently observed malignancies, other than non-melanoma skin cancer, wereprostate, colorectal, melanoma and breast cancers. The incidence of non-melanoma skin cancer was0.49 per 100 patient-years of follow-up for ustekinumab-treated patients (56 patients in 11,545 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (3:1) iscomparable 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 orother 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 ofustekinumab reported adverse events occurring during or within an hour of the infusion. Seriousinfusion-related reactions including anaphylactic reactions to the infusion have been reported in thepost-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 moderateto severe plaque psoriasis. The first study was in 110 patients from 12 to 17 years of age treated for upto 60 weeks and the second study was in 44 patients from 6 to 11 years of age treated for up to 56weeks. In general, the adverse events reported in these two studies with safety data up to 1 year weresimilar to those seen in previous studies in adults with plaque psoriasis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 orsymptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

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

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

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

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the sharedp40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits thebioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptorprotein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that isalready bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute tocomplement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and

IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophagesand dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer(NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 hasbeen associated with immune mediated diseases, such as psoriasis, psoriatic arthritis and Crohn’sdisease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects inpsoriasis, psoriatic arthritis and Crohn’s disease through interruption of the Th1 and Th17 cytokinepathways, which are central to the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatorymarkers including C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, whichwere then maintained throughout the maintenance phase. CRP was assessed during the study extensionand the reductions observed during maintenance were generally sustained through Week 252.

During the long term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated withustekinumab for at least 3.5 years mounted similar antibody responses to both pneumococcalpolysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similarproportions of adult patients developed protective levels of anti-pneumococcal and anti-tetanusantibodies and antibody titres were similar among ustekinumab-treated and control patients.

Crohn’s Disease

The safety and efficacy of ustekinumab was assessed in three randomised, double-blind, placebo-controlled, multicentre 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 programconsisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 weeksubcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks oftherapy.

The induction studies included 1,409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primaryendpoint for both induction studies was the proportion of subjects in clinical response (defined as areduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analysedthrough week 8 for both studies. Concomitant doses of oral corticosteroids, immunomodulators,aminosalicylates and antibiotics were permitted and 75% of patients continued to receive at least oneof these medications. In both studies, patients were randomised to receive a single intravenousadministration of either the recommended tiered dose of approximately 6 mg/kg (see Table 1, section4.2), 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% ofthe patients had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies.

In this study, 29.1% of the patients had an inadequate initial response (primary non-responders),69.4% responded but lost response (secondary non-responders), and 36.4% were intolerant to anti-

TNFα therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids orimmunomodulators, and were either anti-TNF-α naïve (68.6%) or had previously received but notfailed anti-TNFα therapy (31.4%).

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

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

UNITI-1* UNITI-2**

Placebo Recommended Placebo Recommended

N = 247 dose of N = 209 dose 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 atleast 100 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 failuresap < 0.001bp < 0.01

The maintenance study (IM-UNITI) evaluated 388 patients who achieved 100 point clinical responseat week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomisedto receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mgustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance posology, seesection 4.2 of the ustekinumab Solution for injection in pre-filled syringe SmPC or pre-filled pen

SmPC).

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

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

Placebo* 90 mg 90 mgustekinumab ustekinumabevery 8 weeks every12 weeks

N = 131† N = 128† N = 129†

Clinical Remission 36% 53%a 49%b

Clinical Response 44% 59%b 58%b

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

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

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least100 points or being in clinical remission

*The placebo group consisted of patients who were in response to ustekinumab and were randomised to receiveplacebo at the start of maintenance therapy.†Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy‡Patients who failed conventional therapy but not anti-TNFα therapy§Patients who are anti-TNFα refractory/intolerantap < 0.01bp < 0.05cnominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every12 weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of responsewas defined as a CDAI score ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline.

In these patients, clinical remission was achieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and

UNITI-2 induction studies (476 patients) entered into the non-randomized portion of the maintenancestudy (IM-UNITI) and received a 90 mg subcutaneous injection of ustekinumab at that time. Eightweeks later, 50.5% of the patients achieved clinical response and continued to receive maintenancedosing every 8 weeks; among these patients with continued maintenance dosing, a majoritymaintained response (68.1%) and achieved remission (50.2%) at week 44, at proportions that weresimilar to the patients who initially responded to ustekinumab induction.

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

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatmentin a study extension. Among the 567 patients who entered on and were treated with ustekinumab in thestudy extension, clinical remission and response were generally maintained through week 252 for bothpatients 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 inpatients with Crohn’s Disease.

Endoscopy

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

Endoscopic Disease Severity Score for Crohn’s Disease (SES-CD), a composite score across 5 ileo-colonic segments of presence/size of ulcers, proportion of mucosal surface covered by ulcers,proportion of mucosal surface affected by any other lesions and presence/type of narrowing/strictures.

At week 8, after a single intravenous induction dose, the change in SES-CD score was greater in theustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

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

Health-Related Quality of Life

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and

SF-36 questionnaires. At week 8, patients receiving ustekinumab showed statistically significantlygreater and clinically meaningful improvements on IBDQ total score and SF-36 Mental Component

Summary Score in both UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in

UNITI-2, when compared to placebo. These improvements were generally better maintained inustekinumab-treated patients in the IM-UNITI study through week 44 when compared to placebo.

Improvement in health-related quality of life was generally maintained during the extension throughweek 252.

Antibodies to ustekinumab may develop during ustekinumab treatment and most are neutralising. Theformation of anti-ustekinumab antibodies is associated with increased clearance of ustekinumab inpatients with Crohn’s disease. No reduced efficacy was observed. There is no apparent correlationbetween 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 withustekinumab in one or more subsets of the paediatric population in Crohn’s Disease (see section 4.2for information on paediatric use).

Following the recommended intravenous induction dose, median peak serum ustekinumabconcentration, 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 intravenousadministration to patients 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 withpsoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab wasapproximately 3 weeks in patients with Crohn’s disease, psoriasis and/or psoriatic arthritis, rangingfrom 15 to 32 days across all psoriasis and psoriatic arthritis studies.

Dose linearity

The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximately dose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kg to4.5 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 paediatricpatients.

In patients with Crohn’s disease, variability in ustekinumab clearance was affected by body weight,serum albumin level, sex, and antibody to ustekinumab status while body weight was the maincovariate affecting the volume of distribution. Additionally in Crohn’s disease, clearance was affectedby C-reactive protein, TNF antagonist failure status and race (Asian versus non-Asian). The impact ofthese covariates was within ±20% of the typical or reference value of the respective PK parameter,thus dose adjustment is not warranted for these covariates. Concomitant use of immunomodulators didnot have a significant impact on ustekinumab disposition.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitrostudy using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did notalter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).

Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies ofrepeated-dose toxicity and developmental and reproductive toxicity, including safety pharmacologyevaluations. In developmental and reproductive toxicity studies in cynomolgus monkeys, neitheradverse effects on male fertility indices nor birth defects or developmental toxicity were observed. Noadverse effects on female fertility indices were observed using an analogous antibody to IL-12/23 inmice.

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

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

Histidine

Histidine hydrochloride monohydrate

Methionine

Disodium edetate

Sucrose

Polysorbate 80 (E 433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. Pyzchiva should be diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion.

Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.

Pyzchiva should not be administered concomitantly in the same intravenous line with other medicinalproducts.

Before dilution2 years

Do not freeze.

Chemical and physical in-use stability has been demonstrated for up to 72 hours at 30°C. If necessary,the diluted infusion solution may be kept at 2 °C to 8 °C for up to 1 month and at room temperature upto 30°C for an additional 72 hours after removal from refrigeration including the infusion period.

From a microbiological point of view, the infusion solution should be administered immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place incontrolled 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 chlorobutyl rubber stopper. Pyzchiva isavailable in a 1 vial pack.

The solution in the Pyzchiva vial should not be shaken. The solution should be visually inspected forparticulate matter or discoloration prior to administration. The solution is clear, colourless to lightyellow. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreignparticulate matter is present.

Pyzchiva concentrate for solution for infusion must be diluted and prepared by a healthcareprofessional using aseptic technique.

1. Calculate the dose and the number of Pyzchiva vials needed based on patient weight (seesection 4.2, Table 1). Each 26 mL vial of Pyzchiva contains 130 mg of ustekinumab. Onlyuse complete vials of Pyzchiva.

2. Withdraw and discard a volume of the sodium chloride 9 mg/mL (0.9%) solution fromthe 250 mL infusion bag equal to the volume of Pyzchiva to be added. (discard 26 mLsodium chloride for each vial of Pyzchiva needed, for 2 vials-discard 52 mL, for 3 vials-discard 78 mL, for 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bagcontaining 0.45% Sodium Chloride Injection, USP may be used.

3. Withdraw 26 mL of Pyzchiva from each vial needed and add it to the 250 mL infusionbag. The final volume in the infusion bag should be 250 mL. Gently mix.

4. Visually inspect the diluted solution before administration. Do not use if visiblyopaque particles, discoloration or foreign particles are observed.

5. Administer the diluted solution over a period of at least one hour. Once diluted, the infusionshould be completed within 72 hours at room temperature up to 30°C of the dilution in theinfusion bag. If necessary, the diluted infusion solution may be kept at 2°C to 8°C for up to1 month and at room temperature up to 30°C for an additional 72 hours after removal fromrefrigeration including the infusion period.

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

7. Each vial is for single use only and any unused medicinal product should be disposed ofin accordance with local requirements.

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

EU/1/24/1801/003

Date of first authorisation: 19 April 2024

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

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