FULLTEXT DEL 1 AV 2

Kvartalsrapport Q2 2024

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 130 mg concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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
murine myeloma cell line using recombinant DNA technology.

Excipient with known effect

Each mL contains 0.4 mg polysorbate 80.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

The solution is clear and colourless to slightly yellow and practically free of visible particles.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adult Crohn’s Disease

Uzpruvo 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

Uzpruvo 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.

4.2 Posology and method of administration

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

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Posology

Adults
Crohn’s Disease
Uzpruvo 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 Uzpruvo 130 mg as specified in Table 1 (see
section 6.6 for preparation).

Table 1 Initial intravenous dosing of Uzpruvo
Body weight of patient at the
time of dosing
Recommended dosea Number of 130 mg
Uzpruvo 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 Uzpruvo solution for
injection (vial) and 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)
Uzpruvo 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 Uzpruvo 130 mg as specified in Table 2 (see
section 6.6 for preparation).

Table 2 Initial intravenous dosing of Uzpruvo
Body weight of patient at the time of
dosing
Recommended dosea Number of 130 mg
Uzpruvo 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 safety and efficacy of Uzpruvo for the treatment of Crohn’s disease for paediatric patients
weighing less than 40 kg have not yet been established. No data are available.

Method of administration

Uzpruvo 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.

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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 name 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 Uzpruvo in patients with a chronic infection
or a history of recurrent infection (see section 4.3).

Prior to initiating treatment with Uzpruvo, patients should be evaluated for tuberculosis infection.
Uzpruvo must not be given to patients with active tuberculosis (see section 4.3). Treatment of latent
tuberculosis infection should be initiated prior to administering Uzpruvo. Anti-tuberculosis therapy
should also be considered prior to initiation of Uzpruvo in patients with a history of latent or active
tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving
Uzpruvo 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 Uzpruvo
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 Uzpruvo 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 (psoralen and ultraviolet A)
treatment, should be monitored for the appearance of skin cancer (see section 4.8).

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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 Uzpruvo 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
ustekinumab.

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 Uzpruvo. 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 Uzpruvo 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 Uzpruvo may receive concurrent inactivated or non-live vaccinations.

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

Concomitant immunosuppressive therapy

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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 Uzpruvo 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 Uzpruvo 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. Uzpruvo 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 age 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

Uzpruvo contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’. Uzpruvo
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).

Polysorbates

This medicinal product contains 10.4 mg of polysorbate 80 in each vial 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 Uzpruvo (see section 4.4).

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.

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In the population pharmacokinetic analyses of the ustekinumab 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 Uzpruvo 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

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therapy with Uzpruvo must be made taking into account the benefit of breast-feeding to the child and
the benefit of Uzpruvo 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

Uzpruvo 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

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System Organ Class Frequency: Adverse reaction
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).

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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 cancer, 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 the national reporting system
listed in Appendix V.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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Uzpruvo is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency https://www.ema.europa.eu.

Mechanism of action

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared
p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the
bioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor
protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is
already bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute to
complement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and
IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophages
and dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer
(NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-
23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 has
been associated with immune mediated diseases, such as psoriasis, psoriatic arthritis 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 are central to the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatory
markers including C-Reactive Protein (CRP) and faecal calprotectin during the induction phase, which
were then maintained throughout the maintenance phase. CRP was assessed during the study extension
and the reductions observed during maintenance were generally sustained through week 252.

Immunisation

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

Clinical efficacy

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 program
consisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44-week
subcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks of
therapy.

The induction studies included 1,409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary
endpoint for both induction studies was the proportion of subjects in clinical response (defined as a
reduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analysed
through 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 one
of these medications. In both studies, patients were randomised to receive a single intravenous
administration of either the recommended tiered dose of approximately 6 mg/kg (see Table 1, section
4.2), a fixed dose of 130 mg ustekinumab, or placebo at week 0.

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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-TNFα 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
and remission in the ustekinumab treated group compared to placebo (Table 4). Clinical response and
remission were significant as early as week 3 in ustekinumab treated patients and continued to
improve through week 8. In these induction studies, efficacy was higher and better sustained in the
tiered dose group compared to the 130 mg dose group, and tiered dosing is therefore the recommended
intravenous induction dose.

Table 4: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2
UNITI-1* UNITI-2**
Placebo
N = 247
Recommended
dose of
ustekinumab
N = 249
Placebo
N = 209
Recommended
dose of
ustekinumab
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%)a
70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a
70 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 least 100
points or being in clinical remission
70 point response is defined as reduction in CDAI score by at least 70 points
* Anti-TNFα failures
** Conventional therapy failures
a p < 0.001
b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical response
at week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomised
to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mg
ustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance posology, see
section 4.2 of the Uzpruvo 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 treated groups compared to the placebo group at week 44 (see Table 5).

Table 5: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from
initiation of the induction dose)
Placebo*
N = 131†
90 mg
ustekinumab
every 8 weeks
N = 128†
90 mg
ustekinumab
every
12 weeks
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:

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13
Placebo*
N = 131†
90 mg
ustekinumab
every 8 weeks
N = 128†
90 mg
ustekinumab
every
12 weeks
N = 129†
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 least 100 points or
being in clinical remission
* The placebo group consisted of patients who were in response to ustekinumab and were randomised to receive placebo 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/intolerant
a p < 0.01
b p < 0.05
c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every
12 weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response
was 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-randomised 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 dosing every 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 initially responded to ustekinumab induction.

Of 131 patients who responded to ustekinumab induction, and were randomised to the placebo group
at the start of the maintenance study, 51 subsequently lost response and received 90 mg ustekinumab
subcutaneously every 8 weeks. The majority of patients who lost response and resumed ustekinumab
did so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinical
response and 39.2% percent achieved clinical remission 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 study extension. 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
disease 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 the
ustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, mean
change = -0.7, p = 0.012).

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Fistula response
In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of
ustekinumab-treated patients achieved a fistula response over 44 weeks (defined as ≥ 50% reduction
from 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 significantly
greater 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 in
ustekinumab-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 through
week 252.

Immunogenicity

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

Paediatric population

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

Paediatric Crohn’s disease
The safety and efficacy of ustekinumab was evaluated in 48 paediatric patients weighing at least
40 kg, in an interim analysis of a multicentre phase 3 study (UNITI-Jr) for paediatric patients with
moderately to severely active Crohn's disease (defined by a Paediatric Crohn’s Disease Activity Index
[PCDAI] score > 30) through 52 weeks of treatment (8 weeks of induction and 44 weeks of
maintenance treatment). Patients included in the study either had not adequately responded to or had
not tolerated prior biologic therapy or conventional therapy for Crohn’s disease. The study included an
open-label induction treatment with a single ustekinumab intravenous dose, of approximately 6 mg/kg
(see section 4.2), followed by a randomised double-blind subcutaneous maintenance regimen of 90 mg
ustekinumab administered either every 8 weeks or every 12 weeks.

Efficacy results
The primary endpoint of the study was clinical remission at induction week 8 (defined as PCDAI score
≤ 10). The proportion of patients who achieved clinical remission was 52.1% (25/48) and is
comparable to that observed in the adult ustekinumab phase 3 studies.

Clinical response was observed as early as week 3. The proportion of patients in clinical response at
week 8 (defined as a reduction from baseline in the PCDAI score of > 12.5 points with a total PCDAI
score not more than 30) was 93.8% (45/48).

Table 6 presents the analyses for the secondary endpoints through maintenance week 44.

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15
Table 6: Summary of Secondary endpoints through Maintenance week 44
90 mg
ustekinumab
every 8 weeks
N = 23
90 mg
ustekinumab
every 12 weeks
N = 25
Total number of
patients
N = 48
Clinical Remission* 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)
Corticosteroid-free Clinical
Remission§
43.5% (10/23) 60.0% (15/25) 52.1% (25/48)
Clinical remission for patients who
were in clinical remission at
induction week 8*
64.3% (9/14) 54.5% (6/11) 60.0% (15/25)
Clinical Response† 52.2% (12/23) 60.0% (15/25) 56.3% (27/48)
Endoscopic response£ 22.7% (5/22) 28.0% (7/25) 25.5% (12/47)
* Clinical remission is defined as PCDAI score ≤ 10 points.
§ Corticosteroid-free remission is defined as PCDAI score of ≤ 10 points and not receiving corticosteroids for at least
90 days prior to Week M-44.
† Clinical response is defined as a reduction from baseline in the PCDAI score of ≥ 12.5 points with a total PCDAI score
not more than 30.
£ Endoscopic response is defined as a reduction in the SES-CD score of ≥ 50% or SES-CD score ≤ 2, in patients with a
baseline SES-CD score of ≥ 3.

The safety profile of the induction dose regimen and both maintenance dose regimens in the paediatric
population weighing at least 40 kg is comparable with that established in the adult Crohn’s disease
population (see section 4.8).

Serum and faecal inflammatory biomarkers
The mean change from baseline at maintenance week 44 in C-Reactive protein (CRP) and faecal
calprotectin concentrations were -11.17 mg/L (24.159) and -538.2 mg/kg (1,271.33), respectively.

Health-related quality of life
The total IMPACT-III scores and all subdomains (bowel symptoms, fatigue-related systemic
symptoms, and well-being) demonstrated clinically meaningful improvements after 52 weeks.

5.2 Pharmacokinetic properties

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.

Distribution

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

Biotransformation

The exact metabolic pathway for ustekinumab is unknown.

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16
Elimination

Dose linearity

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

Special populations

No pharmacokinetic data are available in patients with impaired renal or hepatic function. No specific
studies have been conducted with intravenous ustekinumab in elderly or paediatric patients weighing
less than 40 kg.

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 main
covariate affecting the volume of distribution. Additionally, in Crohn’s disease, clearance was affected
by C-reactive protein, TNF antagonist failure status and race (Asian versus non-Asian). The impact of
these covariates was within ±20% of the typical or reference value of the respective PK parameter,
thus dose adjustment is not warranted for these covariates. Concomitant use of immunomodulators did
not have a significant impact on ustekinumab disposition.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro
study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not
alter human CYP450 enzyme 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 of ustekinumab on cytochrome P450 enzyme activities following induction and maintenance
dosing in patients with active Crohn’s disease (n=18). No clinically significant changes in exposure of
caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate),
dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used
concomitantly with ustekinumab at the approved recommended dosing in patients with Crohn’s
disease (see section 4.5).

Paediatric population
Serum ustekinumab concentrations in paediatric Crohn’s disease patients weighing at least 40 kg,
treated with the recommended weight-based dose were generally comparable to those in the adult
Crohn’s disease population treated with the adult weight-based dose.

5.3 Preclinical safety data

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

===== SIDA 17 =====

17
Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalent
dose intended to be administered to psoriasis patients and resulted in peak serum concentrations in
monkeys that were more than 100-fold higher than observed in humans.

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

EDTA disodium salt dihydrate
Histidine
Histidine monohydrochloride
Methionine
Polysorbate 80 (E433)
Sucrose
Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products. Uzpruvo should only be diluted with sodium chloride 9 mg/mL (0.9%) solution. Uzpruvo
should not be administered concomitantly in the same intravenous line with other medicinal products.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been demonstrated for 8 hours at 15-25 °C.

From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the product should be used immediately. If not used immediately, in-use storage times
and conditions are the responsibility of user.

The unopened vial may be stored at room temperature up to 30 °C for a maximum single period of up
to 7 days in the original carton in order to protect from light. Once a vial has been stored at room
temperature (up to 30 °C), it should not be returned to the refrigerator. Discard the vial if not used
within 7 days at room temperature storage or by the original expiry date, whichever is earlier.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

26 mL solution in a type I glass 30 mL vial closed with a coated bromobutyl rubber stopper. Uzpruvo
is available in a 1 vial pack.

6.6 Special precautions for disposal and other handling

The solution in the Uzpruvo vial should not be shaken. The solution should be visually inspected for
particulate matter or discolouration prior to administration. The solution is clear, colourless to light

===== SIDA 18 =====

18
yellow and practically free from visible particles. The medicinal product should not be used if the
solution is frozen, discoloured or cloudy, or if foreign particulate matter is present.

Dilution

Uzpruvo concentrate for solution for infusion must be diluted and prepared by a healthcare
professional using aseptic technique.

1. Calculate the dose and the number of Uzpruvo vials needed based on patient weight (see
section 4.2, Table 1). Each 26 mL vial of Uzpruvo contains 130 mg of ustekinumab. Only use
complete vials of Uzpruvo.
2. Withdraw and discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the
250 mL infusion bag equal to the volume of Uzpruvo to be added. (discard 26 mL sodium
chloride solution for each vial of Uzpruvo needed, for 2 vials- discard 52 mL, for 3 vials-
discard 78 mL, for 4 vials- discard 104 mL)
3. Withdraw 26 mL of Uzpruvo from each vial needed and add it to the 250 mL infusion bag. 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 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 be completed within eight 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 0.2 micrometer).
7. Each vial is for single use only and any unused medicinal product should be disposed of in
accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1784/005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 January 2024

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu

===== SIDA 19 =====

19
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 45 mg solution for injection
Uzpruvo 45 mg solution for injection in pre-filled syringe
Uzpruvo 90 mg solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Uzpruvo 45 mg solution for injection

Each vial contains 45 mg ustekinumab in 0.5 mL.

Uzpruvo 45 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 45 mg ustekinumab in 0.5 mL.

Uzpruvo 90 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 90 mg ustekinumab in 1 mL.

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

Excipient with known effect

Each mL contains 0.04 mg polysorbate 80.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection)

The solution is clear and colourless to slightly yellow and practically free of visible particles.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Plaque psoriasis

Uzpruvo is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed to
respond to, or who have a contraindication to, or are intolerant to other systemic therapies including
ciclosporin, methotrexate (MTX) or PUVA (psoralen and ultraviolet A) (see section 5.1).

===== SIDA 20 =====

20
Paediatric plaque psoriasis

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

Psoriatic arthritis (PsA)

Uzpruvo, alone or in combination with MTX, is indicated for the treatment of active psoriatic arthritis
in adult patients when the response to previous non-biological disease-modifying anti-rheumatic drug
(DMARD) therapy has been inadequate (see section 5.1).

Adult Crohn’s Disease

Paediatric Crohn's Disease

4.2 Posology and method of administration

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

Posology

Plaque psoriasis
The recommended posology of Uzpruvo is an initial dose of 45 mg administered subcutaneously,
followed by a 45 mg dose 4 weeks later, and then every 12 weeks thereafter.

Consideration should be given to discontinuing treatment in patients who have shown no response up
to 28 weeks of treatment.

Patients with body weight > 100 kg
For patients with a body weight > 100 kg the initial dose is 90 mg administered subcutaneously,
followed by a 90 mg dose 4 weeks later, and then every 12 weeks thereafter. In these patients, 45 mg
was also shown to be efficacious. However, 90 mg resulted in greater efficacy (see section 5.1,
Table 4).

Psoriatic arthritis (PsA)
The recommended posology of Uzpruvo is an initial dose of 45 mg administered subcutaneously,
followed by a 45 mg dose 4 weeks later, and then every 12 weeks thereafter. Alternatively, 90 mg may
be used in patients with a body weight > 100 kg.

Consideration should be given to discontinuing treatment in patients who have shown no response up
to 28 weeks of treatment.

Elderly (≥ 65 years)
No dose adjustment is needed for elderly patients (see section 4.4).

Renal and hepatic impairment
Uzpruvo has not been studied in these patient populations. No dose recommendations can be made.

===== SIDA 21 =====

Paediatric population
The safety and efficacy of Uzpruvo in children with psoriasis less than 6 years of age or in children
with psoriatic arthritis less than 18 years of age have not yet been established. No data are available.

Paediatric plaque psoriasis (6 years and older)
The recommended dose of Uzpruvo based on body weight is shown below (Tables 1 and 2). Uzpruvo
should be administered at weeks 0 and 4, then every 12 weeks thereafter.

Table 1 Recommended dose of Uzpruvo for paediatric psoriasis
Body weight at the time of dosing Recommended dose
< 60 kg 0.75 mg/kg
≥ 60 kg to ≤ 100 kg 45 mg
> 100 kg 90 mg

To calculate the volume of injection (mL) for patients < 60 kg, use the following formula: body weight
(kg) x 0.0083 (mL/kg) or see Table 2. The calculated volume should be rounded to the nearest
0.01 mL and administered using a 1 mL graduated syringe. A 45 mg vial is available for paediatric
patients who need to receive less than the full 45 mg dose.

Table 2 Injection volumes of Uzpruvo for paediatric psoriasis patients < 60 kg
Body weight at time of dosing (kg) Dose (mg) Volume of injection (mL)
15 11.3 0.12
16 12.0 0.13
17 12.8 0.14
18 13.5 0.15
19 14.3 0.16
20 15.0 0.17
21 15.8 0.17
22 16.5 0.18
23 17.3 0.19
24 18.0 0.20
25 18.8 0.21
26 19.5 0.22
27 20.3 0.22
28 21.0 0.23
29 21.8 0.24
30 22.5 0.25
31 23.3 0.26
32 24.0 0.27
33 24.8 0.27
34 25.5 0.28
35 26.3 0.29
36 27.0 0.30
37 27.8 0.31
38 28.5 0.32
39 29.3 0.32

===== SIDA 22 =====

22
Body weight at time of dosing (kg) Dose (mg) Volume of injection (mL)
40 30.0 0.33
41 30.8 0.34
42 31.5 0.35
43 32.3 0.36
44 33.0 0.37
45 33.8 0.37
46 34.5 0.38
47 35.3 0.39
48 36.0 0.40
49 36.8 0.41
50 37.5 0.42
51 38.3 0.42
52 39.0 0.43
53 39.8 0.44
54 40.5 0.45
55 41.3 0.46
56 42.0 0.46
57 42.8 0.47
58 43.5 0.48
59 44.3 0.49

Consideration should be given to discontinuing treatment in patients who have shown no response up
to 28 weeks of treatment.

Adults
Crohn’s disease
In the treatment regimen, the first dose of Uzpruvo is administered intravenously. For the posology of
the intravenous dosing regimen, see section 4.2 of the Uzpruvo 130 mg concentrate for solution for
infusion SmPC.

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

Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may
receive a second subcutaneous dose at this time (see section 5.1).

Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing
frequency to every 8 weeks (see sections 5.1 and 5.2).

Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment
(see section 5.1).

Consideration should be given to discontinuing treatment in patients who show no evidence of
therapeutic benefit 16 weeks after the IV induction dose or 16 weeks after switching to the 8-weekly
maintenance dose.

Immunomodulators and/or corticosteroids may be continued during treatment with Uzpruvo. In
patients who have responded to treatment with Uzpruvo, corticosteroids may be reduced or
discontinued in accordance with standard of care.

===== SIDA 23 =====

In Crohn’s disease, if therapy is interrupted, resumption of treatment with subcutaneous dosing every
8 weeks is safe and effective.

Elderly (≥ 65 years)
No dose adjustment is needed for elderly patients (see section 4.4).

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

Paediatric population
Paediatric Crohn's disease (patients weighing at least 40 kg)
In the treatment regimen, the first dose of Uzpruvo is administered intravenously. For the posology of
the intravenous dosing regimen, see section 4.2 of the Uzpruvo 130 mg Concentrate for solution for
infusion SmPC.

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

Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing
frequency to every 8 weeks (see section 5.1, section 5.2).

Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment
(see section 5.1).

Consideration should be given to discontinuing treatment in patients who show no evidence of
therapeutic benefit 16 weeks after the IV induction dose or 16 weeks after dose adjustment.

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

The safety and efficacy of Uzpruvo for the treatment of Crohn’s disease for paediatric patients
weighing less than 40 kg have not yet been established. No data are available.

Method of administration

Uzpruvo 45 mg vial or 45 mg and 90 mg pre-filled syringes are for subcutaneous injection only. If
possible, areas of the skin that show psoriasis should be avoided as injection sites.

After proper training in subcutaneous injection technique, patients or their caregivers may inject
Uzpruvo if a physician determines that it is appropriate. However, the physician should ensure
appropriate follow-up of patients. Patients or their caregivers should be instructed to inject the
prescribed amount of Uzpruvo according to the directions provided in the package leaflet.
Comprehensive instructions for administration are given in the package leaflet.

For further instructions on preparation and special precautions for handling, see section 6.6.

4.3 Contraindications

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

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

===== SIDA 24 =====

24
4.4 Special warnings and precautions for use

Traceability

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

Infections

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

Malignancies

Systemic and respiratory hypersensitivity reactions

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25
serious hypersensitivity reaction occurs, appropriate therapy should be instituted and administration of
Uzpruvo should be discontinued (see section 4.8).

Cardiovascular events

Vaccinations

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

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

Concomitant immunosuppressive therapy

Immunotherapy

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

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26
Serious skin conditions

Lupus-related conditions

Special populations

Polysorbates

Uzpruvo 45 mg solution for injection
This medicinal product contains 0.02 mg of polysorbate 80 in each vial which is equivalent to
0.04 mg/mL. Polysorbates may cause allergic reactions.

Uzpruvo 45 mg solution for injection in pre-filled syringe
This medicinal product contains 0.02 mg of polysorbate 80 in each pre-filled syringe which is
equivalent to 0.04 mg/mL. Polysorbates may cause allergic reactions.

Uzpruvo 90 mg solution for injection in pre-filled syringe
This medicinal product contains 0.04 mg of polysorbate 80 in each pre-filled syringe which is
equivalent to 0.04 mg/mL. Polysorbates may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Live vaccines should not be given concurrently with Uzpruvo (see section 4.4).

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 ustekinumab 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,

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27
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.

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

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 Uzpruvo in pregnancy.

Breast-feeding

Fertility

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

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4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Tabulated list of adverse reactions

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29
System Organ Class Frequency: Adverse reaction
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

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).

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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 cancer, melanoma, colorectal, and breast cancers. The incidence
of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up for ustekinumab-treated
patients (69 patients in 15,165 patient-years of follow-up). The ratio of patients with basal versus
squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population (see
section 4.4).

Hypersensitivity reactions
During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of ustekinumab,
rash and urticaria have each been observed in < 1% of patients (see section 4.4).

Paediatric population

Reporting of suspected adverse reactions

4.9 Overdose

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Uzpruvo is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency https://www.ema.europa.eu.

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Mechanism of action

Immunisation

Clinical efficacy

Plaque psoriasis (Adults)
The safety and efficacy of ustekinumab was assessed in 1,996 patients in two randomised double
blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis and who were
candidates for phototherapy or systemic therapy. In addition, a randomised, blinded assessor, active-
controlled study compared ustekinumab and etanercept in patients with moderate to severe plaque
psoriasis who had had an inadequate response to, intolerance to, or contraindication to ciclosporin,
MTX, or PUVA.

Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of these patients were either non-
responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to
ustekinumab received 45 mg or 90 mg doses at weeks 0 and 4 and followed by the same dose every
12 weeks. Patients randomised to receive placebo at weeks 0 and 4 crossed over to receive
ustekinumab (either 45 mg or 90 mg) at weeks 12 and 16 followed by dosing every 12 weeks. Patients
originally randomised to ustekinumab who achieved Psoriasis Area and Severity Index 75 response
(PASI improvement of at least 75% relative to baseline) at both weeks 28 and 40 were re-randomised
to receive ustekinumab every 12 weeks or to placebo (i.e., withdrawal of therapy). Patients who were
re- randomised to placebo at week 40 reinitiated ustekinumab at their original dosing regimen when
they experienced at least a 50% loss of their PASI improvement obtained at week 40. All patients were
followed for up to 76 weeks following first administration of study treatment.

Psoriasis Study 2 (PHOENIX 2) evaluated 1,230 patients. 61% of these patients were either non-
responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to

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32
ustekinumab received 45 mg or 90 mg doses at weeks 0 and 4 followed by an additional dose at
16 weeks. Patients randomised to receive placebo at weeks 0 and 4 crossed over to receive
ustekinumab (either 45 mg or 90 mg) at weeks 12 and 16. All patients were followed for up to
52 weeks following first administration of study treatment.

Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis who
inadequately responded to, were intolerant to, or had a contraindication to other systemic therapy and
compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and
etanercept. During the 12-week active-controlled portion of the study, patients were randomised to
receive etanercept (50 mg twice a week), ustekinumab 45 mg at weeks 0 and 4, or ustekinumab 90 mg
at weeks 0 and 4.

Baseline disease characteristics were generally consistent across all treatment groups in Psoriasis
Studies 1 and 2 with a median baseline PASI score from 17 to 18, median baseline Body Surface Area
(BSA) ≥ 20, and median Dermatology Life Quality Index (DLQI) range from 10 to 12. Approximately
one third (Psoriasis Study 1) and one quarter (Psoriasis Study 2) of subjects had Psoriatic Arthritis
(PsA). Similar disease severity was also seen in Psoriasis Study 3.

The primary endpoint in these studies was the proportion of patients who achieved PASI 75 response
from baseline at week 12 (see Tables 4 and 5).

Table 4 Summary of clinical response in Psoriasis Study 1 (PHOENIX 1) and Psoriasis Study 2
(PHOENIX 2)
Week 12
2 doses (week 0 and week 4)
Week 28
3 doses (week 0, week 4 and
week 16)
PBO 45 mg 90 mg 45 mg 90 mg
Psoriasis Study 1
Number of patients randomised 255 255 256 250 243
PASI 50 response N (%) 26 (10%) 213 (84%)a 220 (86%)a 228 (91%) 234 (96%)
PASI 75 response N (%) 8 (3%) 171 (67%)a 170 (66%)a 178 (71%) 191 (79%)
PASI 90 response N (%) 5 (2%) 106 (42%)a 94 (37%)a 123 (49%) 135 (56%)
PGAb of cleared or minimal N
(%)
10 (4%) 151 (59%)a 156 (61%)a 146 (58%) 160 (66%)
Number of patients ≤ 100 kg 166 168 164 164 153
PASI 75 response N (%) 6 (4%) 124 (74%) 107 (65%) 130 (79%) 124 (81%)
Number of patients > 100 kg 89 87 92 86 90
PASI 75 response N (%) 2 (2%) 47 (54%) 63 (68%) 48 (56%) 67 (74%)
Psoriasis Study 2
Number of patients randomised 410 409 411 397 400
PASI 50 response N (%) 41 (10%) 342 (84%)a 367 (89%)a 369 (93%) 380 (95%)
PASI 75 response N (%) 15 (4%) 273 (67%)a 311 (76%)a 276 (70%) 314 (79%)
PASI 90 response N (%) 3 (1%) 173 (42%)a 209 (51%)a 178 (45%) 217 (54%)
PGAb of cleared or minimal N
(%)
18 (4%) 277 (68%)a 300 (73%)a 241 (61%) 279 (70%)
Number of patients ≤ 100 kg 290 297 289 287 280
PASI 75 response N (%) 12 (4%) 218 (73%) 225 (78%) 217 (76%) 226 (81%)
Number of patients > 100 kg 120 112 121 110 119
PASI 75 response N (%) 3 (3%) 55 (49%) 86 (71%) 59 (54%) 88 (74%)
a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with placebo (PBO).
b PGA = Physician Global Assessment

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33
Table 5 Summary of clinical response at week 12 in Psoriasis Study 3 (ACCEPT)
Psoriasis Study 3
Etanercept
24 doses
(50 mg twice a week)
Ustekinumab
2 doses (week 0 and week 4)
45 mg 90 mg
Number of patients randomised 347 209 347
PASI 50 response N (%) 286 (82%) 181 (87%) 320 (92%)a
PASI 75 response N (%) 197 (57%) 141 (67%)b 256 (74%)a
PASI 90 response N (%) 80 (23%) 76 (36%)a 155 (45%)a
PGA of cleared or minimal N
(%)
170 (49%) 136 (65%)a 245 (71%)a
Number of patients ≤ 100 kg 251 151 244
PASI 75 response N (%) 154 (61%) 109 (72%) 189 (77%)
Number of patients > 100 kg 96 58 103
PASI 75 response N (%) 43 (45%) 32 (55%) 67 (65%)
a p < 0.001 for ustekinumab 45 mg or 90 mg in comparison with etanercept.
b p = 0.012 for ustekinumab 45 mg in comparison with etanercept.

In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatment
compared with treatment withdrawal (p < 0.001). Similar results were seen with each dose of
ustekinumab. At 1 year (week 52), 89% of patients re-randomised to maintenance treatment were
PASI 75 responders compared with 63% of patients re-randomised to placebo (treatment withdrawal)
(p< 0.001). At 18 months (week 76), 84% of patients re-randomised to maintenance treatment were
PASI 75 responders compared with 19% of patients re-randomised to placebo (treatment withdrawal).
At 3 years (week 148), 82% of patients re-randomised to maintenance treatment were PASI 75
responders. At 5 years (week 244), 80% of patients re-randomised to maintenance treatment were
PASI 75 responders.

In patients re-randomised to placebo, and who reinitiated their original ustekinumab treatment regimen
after loss of ≥ 50% of PASI improvement 85% regained PASI 75 response within 12 weeks after re
initiating therapy.

In Psoriasis Study 1, at week 2 and week 12, significantly greater improvements from baseline were
demonstrated in the DLQI in each ustekinumab treatment group compared with placebo. The
improvement was sustained through week 28. Similarly, significant improvements were seen in
Psoriasis Study 2 at week 4 and 12, which were sustained through week 24. In Psoriasis Study 1,
improvements in nail psoriasis (Nail Psoriasis Severity Index), in the physical and mental component
summary scores of the SF-36 and in the Itch Visual Analogue Scale (VAS) were also significant in
each ustekinumab treatment group compared with placebo. In Psoriasis Study 2, the Hospital Anxiety
and Depression Scale (HADS) and Work Limitations Questionnaire (WLQ) were also significantly
improved in each ustekinumab treatment group compared with placebo.

Psoriatic arthritis (PsA) (Adults)
Ustekinumab has been shown to improve signs and symptoms, physical function and health-related
quality of life, and reduce the rate of progression of peripheral joint damage in adult patients with
active PsA.

The safety and efficacy of ustekinumab was assessed in 927 patients in two randomised, double-blind,
placebo-controlled studies in patients with active PsA (≥ 5 swollen joints and ≥ 5 tender joints) despite
non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy.
Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of
PsA were enrolled, including polyarticular arthritis with no evidence of rheumatoid nodules (39%),
spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal
interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients in
both studies had enthesitis and dactylitis at baseline, respectively. Patients were randomised to receive
treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at weeks 0 and 4 followed by

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every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX
(≤ 25 mg/week).

In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of the patients,
respectively, had been previously treated with DMARDs. In Study 1 previous treatment with anti-
tumour necrosis factor (TNF)α agent was not allowed. In Study 2, the majority of patients (58%,
n = 180) had been previously treated with one or more anti-TNFα agent(s), of whom over 70% had
discontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.

Signs and symptoms
Treatment with ustekinumab resulted in significant improvements in the measures of disease activity
compared to placebo at week 24. The primary endpoint was the percentage of patients who achieved
American College of Rheumatology (ACR) 20 response at week 24. The key efficacy results are
shown in Table 6 below.

Table 6 Number of patients who achieved clinical response in Psoriatic arthritis Study 1
(PSUMMIT I) and Study 2 (PSUMMIT II) at week 24
Psoriatic arthritis Study 1 Psoriatic arthritis Study 2
PBO 45 mg 90 mg PBO 45 mg 90 mg
Number of patients
randomised 206 205 204 104 103 105
ACR 20 response,
N (%) 47 (23%) 87 (42%)a 101 (50%)a 21 (20%) 45 (44%)a 46 (44%)a
ACR 50 response,
N (%) 18 (9%) 51 (25%)a 57 (28%)a 7 (7%) 18 (17%)b 24 (23%)a
ACR 70 response,
N (%) 5 (2%) 25 (12%)a 29 (14%)a 3 (3%) 7 (7%)c 9 (9%)c
Number of patients
with ≥ 3% BSAd 146 145 149 80 80 81
PASI 75 response,
N (%) 16 (11%) 83 (57%)a 93 (62%)a 4 (5%) 41 (51%)a 45 (56%)a
PASI 90 response,
N (%) 4 (3%) 60 (41%)a 65 (44%)a 3 (4%) 24 (30%)a 36 (44%)a
Combined PASI
75 and ACR 20
response, N (%)
8 (5%) 40 (28%)a 62 (42%)a 2 (3%) 24 (30%)a 31 (38%)a
Number of patients
≤ 100 kg 154 153 154 74 74 73
ACR 20 response,
N (%) 39 (25%) 67 (44%) 78 (51%) 17 (23%) 32 (43%) 34 (47%)
Number of patients
with ≥ 3% BSAd 105 105 111 54 58 57
PASI 75 response,
N (%) 14 (13%) 64 (61%) 73 (66%) 4 (7%) 31 (53%) 32 (56%)
Number of patients
> 100 kg 52 52 50 30 29 31
ACR 20 response,
N (%) 8 (15%) 20 (38%) 23 (46%) 4 (13%) 13 (45%) 12 (39%)
Number of patients
with ≥ 3% BSAd 41 40 38 26 22 24
PASI 75 response,
N (%) 2 (5%) 19 (48%) 20 (53%) 0 10 (45%) 13 (54%)
a p < 0.001
b p < 0.05
c p = NS
d Number of patients with ≥ 3% BSA psoriasis skin involvement at baseline

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ACR 20, 50 and 70 responses continued to improve or were maintained through week 52 (PsA Study 1
and 2) and week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at week 100 were achieved by
57% and 64%, for 45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at week 52 were
achieved by 47% and 48%, for 45 mg and 90 mg, respectively.

The proportion of patients achieving a modified PsA response criteria (PsARC) response was also
significantly greater in the ustekinumab groups compared to placebo at week 24. PsARC responses
were maintained through weeks 52 and 100. A higher proportion of patients treated with ustekinumab
who had spondylitis with peripheral arthritis as their primary presentation, demonstrated 50 and 70
percent improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores
compared with placebo at week 24.

Responses observed in the ustekinumab treated groups were similar in patients receiving and not
receiving concomitant MTX, and were maintained through weeks 52 and 100. Patients previously
treated with anti-TNFα agents who received ustekinumab achieved a greater response at week 24 than
patients receiving placebo (ACR 20 response at week 24 for 45 mg and 90 mg was 37% and 34%,
respectively, compared with placebo 15%; p< 0.05), and responses were maintained through week 52.

For patients with enthesitis and/or dactylitis at baseline, in PsA Study 1 significant improvement in
enthesitis and dactylitis score was observed in the ustekinumab groups compared with placebo at
week 24. In PsA Study 2 significant improvement in enthesitis score and numerical improvement (not
statistically significant) in dactylitis score was observed in the ustekinumab 90 mg group compared
with placebo at week 24. Improvements in enthesitis score and dactylitis score were maintained
through weeks 52 and 100.

Radiographic response
Structural damage in both hands and feet was expressed as change in total van der Heijde-Sharp score
(vdH-S score), modified for PsA by addition of hand distal interphalangeal joints, compared to
baseline. A pre-specified integrated analysis combining data from 927 subjects in both PsA Study 1
and 2 was performed. Ustekinumab demonstrated a statistically significant decrease in the rate of
progression of structural damage compared to placebo, as measured by change from baseline to
week 24 in the total modified vdH-S score (mean ± SD score was 0.97 ± 3.85 in the placebo group
compared with 0.40 ± 2.11 and 0.39 ± 2.40 in the ustekinumab 45 mg (p< 0.05) and 90 mg (p< 0.001)
groups, respectively). This effect was driven by PsA Study 1. The effect is considered demonstrated
irrespective of concomitant MTX use and was maintained through weeks 52 (integrated analysis)
and 100 (PsA Study 1).

Physical function and health-related quality of life
Ustekinumab-treated patients showed significant improvement in physical function as assessed by the
Disability Index of the Health Assessment Questionnaire (HAQ-DI) at week 24. The proportion of
patients achieving a clinically meaningful ≥ 0.3 improvement in HAQ-DI score from baseline was also
significantly greater in the ustekinumab groups when compared with placebo. Improvement in HAQ
DI score from baseline was maintained through weeks 52 and 100.

There was significant improvement in DLQI scores in the ustekinumab groups as compared with
placebo at week 24, which was maintained through weeks 52 and 100. In PsA Study 2 there was a
significant improvement in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
scores in the ustekinumab groups when compared with placebo at week 24. The proportion of patients
achieving a clinically significant improvement in fatigue (4 points in FACIT-F) was also significantly
greater in the ustekinumab groups compared with placebo. Improvements in FACIT scores were
maintained through week 52.

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36
Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with the
reference medicinal product containing ustekinumab in one or more subsets of the paediatric
population with juvenile idiopathic arthritis (see section 4.2 for information on paediatric use).

Paediatric plaque psoriasis
Ustekinumab has been shown to improve signs and symptoms, and health-related quality of life in
paediatric patients 6 years and older with plaque psoriasis.

Adolescent patients (12-17 years)
The efficacy of ustekinumab was studied in 110 paediatric patients aged 12 to 17 years with moderate
to severe plaque psoriasis in a multicentre, phase 3, randomised, double-blind, placebo-controlled
study (CADMUS). Patients were randomised to receive either placebo (n = 37), or the recommended
dose of ustekinumab (see section 4.2; n = 36) or half of the recommended dose of ustekinumab
(n = 37) by subcutaneous injection at weeks 0 and 4 followed by every 12 weeks (q12w) dosing. At
week 12, placebo-treated patients crossed over to receive ustekinumab.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for
systemic therapy or phototherapy, were eligible for the study. Approximately 60% of the patients had
prior exposure to conventional systemic therapy or phototherapy. Approximately 11% of the patients
had prior exposure to biologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or
minimal (1) at week 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in
Children’s Dermatology Life Quality Index (CDLQI), change from baseline in the total scale score of
PedsQL (Paediatric Quality of Life Inventory) at week 12. At week 12, subjects treated with
ustekinumab showed significantly greater improvement in their psoriasis and health-related quality of
life compared with placebo (Table 7).

All patients were followed for efficacy for up to 52 weeks following first administration of study
agent. The proportion of patients with a PGA score of cleared (0) or minimal (1) and the proportion
achieving PASI 75 showed separation between the ustekinumab treated group and placebo at the first
post-baseline visit at week 4, reaching a maximum by week 12. Improvements in PGA, PASI, CDLQI
and PedsQL were maintained through week 52 (Table 7).

Table 7 Summary of primary and secondary endpoints at week 12 and week 52
Paediatric psoriasis study (CADMUS) (Age 12-17)
Week 12 Week 52
Placebo Recommended dose of
Ustekinumab
Recommended dose of
Ustekinumab
N (%) N (%) N (%)
Patients randomised 37 36 35
PGA
PGA of cleared (0) or
minimal (1)
2 (5.4%) 25 (69.4%)a 20 (57.1%)
PGA of cleared (0) 1 (2.7%) 17 (47.2%)a 13 (37.1%)

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PASI
PASI 75 responders 4 (10.8%) 29 (80.6%)a 28 (80.0%)
PASI 90 responders 2 (5.4%) 22 (61.1%)a 23 (65.7%)
PASI 100 responders 1 (2.7%) 14 (38.9%)a 13 (37.1%)
CDLQI
CDLQI of 0 or 1b 6 (16.2%) 18 (50.0%)c 20 (57.1%)
PedsQL
Change from baseline
Mean (SD)d
3.35 (10.04) 8.03 (10.44)e 7.26 (10.92)
a p < 0.001
b CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality of life in the
paediatric population. CDLQI of 0 or 1 indicates no effect on child’s quality of life.
c p = 0.002
d PedsQL: The PedsQL Total Scale Score is a general health-related quality of life measure developed for use in children and adolescent
populations. For the placebo group at week 12, N = 36
e p = 0.028

During the placebo-controlled period through week 12, the efficacy of both the recommended and half
of the recommended dose groups were generally comparable at the primary endpoint (69.4% and
67.6% respectively) although there was evidence of a dose response for higher level efficacy criteria
(e.g. PGA of cleared (0), PASI 90). Beyond week 12, efficacy was generally higher and better
sustained in the recommended dose group compared with half of the recommended dosage group in
which a modest loss of efficacy was more frequently observed toward the end of each 12 week dosing
interval. The safety profiles of the recommended dose and half of the recommended dose were
comparable.

Children (6-11 years)
The efficacy of ustekinumab was studied in 44 paediatric patients aged 6 to 11 years with moderate to
severe plaque psoriasis in an open label, single arm, multicentre, phase 3, study (CADMUS Jr.).
Patients were treated with the recommended dose of ustekinumab (see section 4.2; n = 44) by
subcutaneous injection at weeks 0 and 4 followed by every 12 weeks (q12w) dosing.

Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for
systemic therapy or phototherapy, were eligible for the study. Approximately 43% of the patients had
prior exposure to conventional systemic therapy or phototherapy. Approximately 5% of the patients
had prior exposure to biologics.

The primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or
minimal (1) at week 12. Secondary endpoints included PASI 75, PASI 90, and change from baseline
in Children’s Dermatology Life Quality Index (CDLQI) at week 12. At week 12, subjects treated with
ustekinumab showed clinically meaningful improvements in their psoriasis and health-related quality
of life (Table 8).

All patients were followed for efficacy for up to 52 weeks following first administration of study
agent. The proportion of patients with a PGA score of cleared (0) or minimal (1) at week 12 was
77.3%. Efficacy (defined as PGA 0 or 1) was observed as early as the first post-baseline visit at
week 4 and the proportion of subjects who achieved a PGA score of 0 or 1 increased through week 16
and then remained relatively stable through week 52. Improvements in PGA, PASI, and CDLQI were
maintained through week 52 (Table 8).

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38
Table 8 Summary of primary and secondary endpoints at week 12 and week 52
Paediatric psoriasis study (CADMUS Jr.) (Age 6-11)
week 12 week 52
Recommended dose of
Ustekinumab
Recommended dose of
Ustekinumab
N (%) N (%)
Patients enrolled 44 41
PGA
PGA of cleared (0) or minimal (1) 34 (77.3%) 31 (75.6%)
PGA of cleared (0) 17 (38.6%) 23 (56.1%)
PASI
PASI 75 responders 37 (84.1%) 36 (87.8%)
PASI 90 responders 28 (63.6%) 29 (70.7%)
PASI 100 responders 15 (34.1%) 22 (53.7%)
CDLQIa
Patients with a CDLQI > 1 at baseline (N=39) (N=36)
CDLQI of 0 or 1 24 (61.5%) 21 (58.3%)
a CDLQI: The CDLQI is a dermatology instrument to assess the effect of a skin problem on the health-related quality of life in the
paediatric population. CDLQI of 0 or 1 indicates no effect on child’s quality of life.

The induction studies included 1,409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary
endpoint for both induction studies was the proportion of subjects in clinical response (defined as a
reduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analysed
through 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 one
of these medications. In both studies, patients were randomised to receive a single intravenous
administration of either the recommended tiered dose of approximately 6 mg/kg (see section 4.2 of the
Uzpruvo 130 mg concentrate for solution for infusion SmPC), 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 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.

In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response
and remission in the ustekinumab treated group compared to placebo (Table 9). Clinical response and
remission were significant as early as week 3 in ustekinumab treated patients and continued to
improve through week 8. In these induction studies, efficacy was higher and better sustained in the
tiered dose group compared to the 130 mg dose group, and tiered dosing is therefore the recommended
intravenous induction dose.

===== SIDA 39 =====

39
Table 9: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2
UNITI-1* UNITI-2**
Placebo
N = 247
Recommended
dose of
ustekinumab
N = 249
Placebo
N = 209
Recommended
dose of
ustekinumab
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%)a
70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a
70 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 least
100 points or being in clinical remission
70 point response is defined as reduction in CDAI score by at least 70 points
* Anti-TNFα failures
** Conventional therapy failures
a p < 0.001
b p < 0.01

Significantly higher proportions of patients maintained clinical remission and response in the
ustekinumab treated groups compared to the placebo group at week 44 (see Table 10).

Table 10: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from
initiation of the induction dose)
Placebo* 90 mg
ustekinumab
every 8 weeks
90 mg
ustekinumab
every
12 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 least
100 points or being in clinical remission
* The placebo group consisted of patients who were in response to ustekinumab and were randomised to receive placebo 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/intolerant
a p < 0.01
b p < 0.05

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40
c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every
12 weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response
was 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-randomised 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
dosing every 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 initially responded to ustekinumab induction.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment
in a study extension. 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.

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41
Immunogenicity

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

Paediatric population

Table 11 presents the analyses for the secondary endpoints through maintenance week 44.

Table 11: Summary of Secondary endpoints through Maintenance week 44
90 mg
ustekinumab
every 8 weeks
N = 23
90 mg
ustekinumab
every 12 weeks
N = 25
Total number of
patients
N = 48
Clinical Remission* 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)
Corticosteroid-free Clinical
Remission§
43.5% (10/23) 60.0% (15/25) 52.1% (25/48)
Clinical remission for patients who
were in clinical remission at
induction week 8*
64.3% (9/14) 54.5% (6/11) 60.0% (15/25)
Clinical Response† 52.2% (12/23) 60.0% (15/25) 56.3% (27/48)
Endoscopic response£ 22.7% (5/22) 28.0% (7/25) 25.5% (12/47)
* Clinical remission is defined as PCDAI score ≤ 10 points.
§ Corticosteroid-free remission is defined as PCDAI score of ≤ 10 points and not receiving corticosteroids for at least 90 days prior to
Week M-44.
† Clinical response is defined as a reduction from baseline in the PCDAI score of ≥ 12.5 points with a total PCDAI score not more than
30.
£ Endoscopic response is defined as a reduction in the SES-CD score of ≥ 50% or SES-CD score ≤ 2, in patients with a baseline SES-CD
score of ≥ 3.

===== SIDA 42 =====

Dosing frequency adjustment
Patients who entered the maintenance regimen and experienced loss of response (LOR) based on
PCDAI score were eligible for dose adjustment. Patients were either switched from treatment every
12 weeks to every 8 weeks or stayed on treatment every 8 weeks (sham adjustment). 2 patients were
dose adjusted to the shorter dosing interval. In these patients, clinical remission was achieved in 100%
(2/2) of patients 8 weeks after dose adjustment.
The safety profile of the induction dose regimen and both maintenance dose regimens in the paediatric
population weighing at least 40 kg is comparable with that established in the adult Crohn’s disease
population (see section 4.8).
Serum and faecal inflammatory biomarkers
The mean change from baseline at maintenance week 44 in C-Reactive protein (CRP) and faecal
calprotectin concentrations were -11.17 mg/L (24.159) and -538.2 mg/kg (1,271.33), respectively.
Health-related quality of life
The total IMPACT-III scores and all subdomains (bowel symptoms, fatigue-related systemic
symptoms, and well-being) demonstrated clinically meaningful improvements after 52 weeks.

5.2 Pharmacokinetic properties

Absorption

The median time to reach the maximum serum concentration (tmax) was 8.5 days after a single 90 mg
subcutaneous administration in healthy subjects. The median tmax values of ustekinumab following a
single subcutaneous administration of either 45 mg or 90 mg in patients with psoriasis were
comparable to those observed in healthy subjects.

The absolute bioavailability of ustekinumab following a single subcutaneous administration was
estimated to be 57.2% in patients with psoriasis.

Distribution

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

Biotransformation

The exact metabolic pathway for ustekinumab is unknown.

Elimination

Median systemic clearance (CL) following a single intravenous administration to patients with
psoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t1/2) of ustekinumab was
approximately 3 weeks in patients with psoriasis, psoriatic arthritis or Crohn’s disease, ranging
from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokinetic
analysis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/day
and 15.7 L, respectively, in patients with psoriasis. The CL/F of ustekinumab was not impacted by
gender. Population pharmacokinetic analysis showed that there was a trend towards a higher clearance
of ustekinumab in patients who tested positive for antibodies to ustekinumab.

Dose linearity

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

===== SIDA 43 =====

43
4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately
24 mg to 240 mg in patients with psoriasis.

Single dose versus multiple doses

Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple
subcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations of
ustekinumab were achieved by week 28 after initial subcutaneous doses at weeks 0 and 4 followed by
doses every 12 weeks. The median steady-state trough concentration ranged from 0.21 μg/mL to
0.26 μg/mL (45 mg) and from 0.47 μg/mL to 0.49 μg/mL (90 mg). There was no apparent
accumulation in serum ustekinumab concentration over time when given subcutaneously every
12 weeks.
In patients with Crohn’s disease, following an intravenous dose of ~6 mg/kg, starting at week 8,
subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks.
Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. In
patients with Crohn’s disease, median steady-state trough concentrations ranged from 1.97 μg/mL to
2.24 μg/mL and from 0.61 μg/mL to 0.76 μg/mL for 90 mg ustekinumab every 8 weeks or every
12 weeks respectively. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumab
every 8 weeks were associated with higher clinical remission rates as compared to the steady-state
trough levels following 90 mg every 12 weeks.

Impact of weight on pharmacokinetics

In a population pharmacokinetic analysis using data from patients with psoriasis, body weight was
found to be the most significant covariate affecting the clearance of ustekinumab. The median CL/F in
patients with weight > 100 kg was approximately 55% higher compared to patients with weight
≤ 100 kg. The median V/F in patients with weight > 100 kg was approximately 37% higher as
compared to patients with weight ≤ 100 kg. The median trough serum concentrations of ustekinumab
in patients with higher weight (> 100 kg) in the 90 mg group were comparable to those in patients with
lower weight (≤ 100 kg) in the 45 mg group. Similar results were obtained from a confirmatory
population pharmacokinetic analysis using data from patients with psoriatic arthritis.

Dosing frequency adjustment

In patients with Crohn’s disease, based on observed data and population PK analyses, randomised
subjects who lost response to treatment had lower serum ustekinumab concentrations over time
compared with subjects who did not lose response. In Crohn’s disease, dose adjustment from 90 mg
every 12 weeks to 90 mg every 8 weeks was associated with an increase in trough serum ustekinumab
concentrations and an accompanying increase in efficacy.

Special populations

No pharmacokinetic data are available in patients with impaired renal or hepatic function.
No specific studies have been conducted in elderly patients.

The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asian
patients with psoriasis.

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 main
covariate affecting the volume of distribution. Additionally, in Crohn’s disease, clearance was affected
by C-reactive protein, TNF antagonist failure status and race (Asian versus non-Asian). The impact of
these covariates was within ± 20% of the typical or reference value of the respective PK parameter,
thus dose adjustment is not warranted for these covariates. Concomitant use of immunomodulators did
not have a significant impact on ustekinumab disposition.

===== SIDA 44 =====

44
In the population pharmacokinetic analysis, there were no indications of an effect of tobacco or
alcohol on the pharmacokinetics of ustekinumab.

Serum ustekinumab concentrations in paediatric psoriasis patients 6 to 17 years of age, treated with the
recommended weight-based dose were generally comparable to those in the adult psoriasis population
treated with the adult dose. Serum ustekinumab concentrations in paediatric psoriasis patients 12-
17 years of age (CADMUS) treated with half of the recommended weight-based dose were generally
lower than those in adults.

The steady-state serum concentrations in paediatric patients with Crohn’s disease weighing at least
40 kg were comparable to those in the adult Crohn’s disease population.

Regulation of CYP450 enzymes

5.3 Preclinical safety data

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

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Histidine
Histidine monohydrochloride
Polysorbate 80 (E433)
Sucrose
Water for injections

6.2 Incompatibilities

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

===== SIDA 45 =====

6.3 Shelf life

Uzpruvo 45 mg solution for injection

18 months

Uzpruvo 45 mg solution for injection in pre-filled syringe

4 years

Uzpruvo 90 mg solution for injection in pre-filled syringe

4 years

Individual pre-filled syringes may be stored at room temperature up to 30 °C for a maximum single
period of up to 30 days in the original carton in order to protect from light. Once removed from the
refrigerator, record the discard date in the space provided on the outer carton. The discard date must
not exceed the original expiry date printed on the carton. Once a syringe has been stored at room
temperature (up to 30 °C), it should not be returned to the refrigerator. Discard the syringe if not used
within 30 days at room temperature storage or by the original expiry date, whichever is earlier.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Do not freeze.
Keep the vial or pre-filled syringe in the outer carton in order to protect from light.

If needed, individual pre-filled syringes may be stored at room temperature up to 30 °C (see
section 6.3).

6.5 Nature and contents of container

Uzpruvo 45 mg solution for injection

0.5 mL solution for injection in a type I glass 2 mL vial closed with a coated bromobutyl rubber
stopper.

Pack size: 1 vial

Uzpruvo 45 mg solution for injection in pre-filled syringe

0.5 mL solution for injection in a pre-filled type I glass 1 mL syringe with a fixed 29-gauge needle,
extended finger flanges and passive safety needle device, and a plunger stopper (bromobutyl rubber),
plunger rod and rigid needle shield (RNS).

Pack size: 1 pre-filled syringe

Uzpruvo 90 mg solution for injection in pre-filled syringe

1 mL solution for injection in a pre-filled type I glass 1 mL syringe with a fixed 29-gauge needle,
extended finger flanges and passive safety needle device and a plunger stopper (bromobutyl rubber),
plunger rod and rigid needle shield (RNS).

Pack sizes: 1 or 2 pre-filled syringe(s).

Not all pack sizes may be marketed.

===== SIDA 46 =====

46
6.6 Special precautions for disposal and other handling

The solution in the Uzpruvo vial or pre-filled syringe should not be shaken vigorously. The solution
should be visually inspected for particulate matter or discolouration prior to subcutaneous
administration. The solution is clear and colourless to slightly yellow and practically free from visible
particles. The medicinal product should not be used if the solution is frozen, discoloured or cloudy, or
has large particles. Before administration, Uzpruvo should be allowed to reach room temperature
(approximately half an hour). Detailed instructions for use are provided in the package leaflet.

Any unused medicinal product remaining in the vial and the syringe should not be used. Uzpruvo is
supplied as a sterile, single-use vial or single-use pre-filled syringe.

The syringe, needle and vial must never be re-used. Any unused medicinal product or waste material
should be disposed of in accordance with local requirements.

When using the single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch (13 mm) needle is
recommended.

7. MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

8. MARKETING AUTHORISATION NUMBER(S)

Uzpruvo 45 mg solution for injection
EU/1/23/1784/003

Uzpruvo 45 mg solution for injection in pre-filled syringe
EU/1/23/1784/001

Uzpruvo 90 mg solution for injection in pre-filled syringe
EU/1/23/1784/004 [1 pre-filled syringe]
EU/1/23/1784/002 [2 pre-filled syringes]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 January 2024

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.

===== SIDA 47 =====

ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE(S) AND MANUFACTURER(S)
RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT

===== SIDA 48 =====

48
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) of the biological active substance(s)

Alvotech Hf,
Saemundargata 15-19
Reykjavik, 102
Iceland

Name and address of the manufacturer(s) responsible for batch release

Alvotech Hf,
Saemundargata 15-19
Reykjavik, 102
Iceland

STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION

• Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the
marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.

===== SIDA 49 =====

ANNEX III

LABELLING AND PACKAGE LEAFLET

===== SIDA 50 =====

A. LABELLING

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51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

VIAL CARTON (130 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 130 mg concentrate for solution for infusion
ustekinumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 130 mg of ustekinumab in 26 mL.

3. LIST OF EXCIPIENTS

EDTA disodium salt dihydrate, histidine, histidine monohydrochloride, methionine, polysorbate 80,
sucrose, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion
130 mg/26 mL
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not shake.
Read the package leaflet before use.
For single use only.
Intravenous use after dilution.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

===== SIDA 52 =====

52
9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1784/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including in Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

===== SIDA 53 =====

53
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL (130 mg)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Uzpruvo 130 mg sterile concentrate
ustekinumab

2. METHOD OF ADMINISTRATION

For IV use after dilution
Do not shake.

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

130 mg/26 mL

6. OTHER

===== SIDA 54 =====

54
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

VIAL OUTER CARTON (45 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 45 mg solution for injection
ustekinumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 45 mg of ustekinumab in 0.5 mL.

3. LIST OF EXCIPIENTS

Sucrose, histidine, histidine monohydrochloride, polysorbate 80, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
45 mg/0.5 mL
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not shake.
Subcutaneous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

===== SIDA 55 =====

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1784/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

UZPRUVO 45 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

===== SIDA 56 =====

56
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL (45 mg)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Uzpruvo 45 mg injection
ustekinumab
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

45 mg/0.5 mL

6. OTHER

===== SIDA 57 =====

57
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

PRE-FILLED SYRINGE OUTER CARTON (45 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 45 mg solution for injection in pre-filled syringe
ustekinumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe contains 45 mg ustekinumab in 0.5 mL.

3. LIST OF EXCIPIENTS

Histidine, histidine monohydrochloride, polysorbate 80, sucrose, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
45 mg/0.5 mL
1 pre-filled syringe

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not shake.
Subcutaneous use.
Read the package leaflet before use.

QR code to be included
uzpruvopatients.com

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Discard date, if stored at room temperature:___________________

===== SIDA 58 =====

58
9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
Can be stored at room temperature (up to 30 °C) for a single period up to 30 days, but not exceeding
the original expiry date.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1784/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Uzpruvo 45 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

===== SIDA 59 =====

59
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE BLISTER (45 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 45 mg solution for injection in pre-filled syringe
ustekinumab

2. NAME OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

For storage information, see leaflet.

45 mg/0.5 mL

===== SIDA 60 =====

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE LABEL (45 mg)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Uzpruvo 45 mg injection
ustekinumab
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

45 mg/0.5 mL

6. OTHER

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61
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

PRE-FILLED SYRINGE OUTER CARTON (90 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 90 mg solution for injection in pre-filled syringe
ustekinumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe contains 90 mg ustekinumab in 1 mL.

3. LIST OF EXCIPIENTS

Histidine, histidine monohydrochloride, polysorbate 80, sucrose, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection
90 mg/1 mL
1 pre-filled syringe
2 pre-filled syringes

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Do not shake.
Subcutaneous use.
Read the package leaflet before use.

QR code to be included
uzpruvopatients.com

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Discard date, if stored at room temperature:___________________

===== SIDA 62 =====

62
9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/23/1784/004 [1 pre-filled syringe]
EU/1/23/1784/002 [2 pre-filled syringes]

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Uzpruvo 90 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

===== SIDA 63 =====

63
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE BLISTER (90 mg)

1. NAME OF THE MEDICINAL PRODUCT

Uzpruvo 90 mg solution for injection in pre-filled syringe
ustekinumab

2. NAME OF THE MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

For storage information, see leaflet.

90 mg/1 mL

===== SIDA 64 =====

64
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE LABEL (90 mg)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Uzpruvo 90 mg injection
ustekinumab
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

90 mg/1 mL

6. OTHER

===== SIDA 65 =====

B. PACKAGE LEAFLET

===== SIDA 66 =====

66
Package leaflet: Information for the user

Uzpruvo 130 mg concentrate for solution for infusion
ustekinumab

This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.

This leaflet has been written for the person taking the medicine.

- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Uzpruvo is and what it is used for
2. What you need to know before you use Uzpruvo
3. How Uzpruvo will be given
4. Possible side effects
5. How to store Uzpruvo
6. Contents of the pack and other information

1. What Uzpruvo is and what it is used for

What Uzpruvo is
Uzpruvo contains the active substance ‘ustekinumab’, a monoclonal antibody. Monoclonal antibodies
are proteins that recognise and bind specifically to certain proteins in the body.

Uzpruvo belongs to a group of medicines called ‘immunosuppressants’. These medicines work by
weakening part of the immune system.

What Uzpruvo is used for
Uzpruvo is used to treat the following inflammatory disease:
• Moderate to severe Crohn’s disease - in adults and children who weigh at least 40 kg

Crohn’s disease
Crohn’s disease is an inflammatory disease of the bowel. If you have Crohn’s disease you will first be
given other medicines. If you do not respond well enough or are intolerant to these medicines, you
may be given Uzpruvo to reduce the signs and symptoms of your disease.

2. What you need to know before you use Uzpruvo

Do not use Uzpruvo
• If you are allergic to ustekinumab or any of the other ingredients of this medicine (listed in
section 6).
• If you have an active infection which your doctor thinks is important.

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67
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using
Uzpruvo.

Warnings and precautions
Talk to your doctor or pharmacist before using Uzpruvo. Your doctor will check how well you are
before treatment. Make sure you tell your doctor about any illness you have before treatment. Also tell
your doctor if you have recently been near anyone who might have tuberculosis. Your doctor will
examine you and do a test for tuberculosis, before you have Uzpruvo. If your doctor thinks you are at
risk of tuberculosis, you may be given medicines to treat it.

Look out for serious side effects
Uzpruvo can cause serious side effects, including allergic reactions and infections. You must look out
for certain signs of illness while you are taking Uzpruvo. See ‘Serious side effects’ in section 4 for a
full list of these side effects.

Before you use Uzpruvo tell your doctor
• If you ever had an allergic reaction to Uzpruvo. Ask your doctor if you are not sure.
• If you have ever had any type of cancer – this is because immunosuppressants like Uzpruvo
weaken part of the immune system. This may increase the risk of cancer.
• If you have been treated for psoriasis with other biologic medicines (a medicine produced
from a biological source and usually given by injection) – the risk of cancer may be higher.
• If you have or have had a recent infection or if you have any abnormal skin openings
(fistulae).
• If you have any new or changing lesions within psoriasis areas or on normal skin.
• If you are having any other treatment for psoriasis and/or psoriatic arthritis – such as
another immunosuppressant or phototherapy (when your body is treated with a type of
ultraviolet (UV) light). These treatments may also weaken part of the immune system. Using
these therapies together with Uzpruvo has not been studied. However, it is possible it may
increase the chance of diseases related to a weaker immune system.
• If you are having or have ever had injections to treat allergies – it is not known if Uzpruvo
may affect these.
• If you are 65 years of age or over – you may be more likely to get infections.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using
Uzpruvo.

Some patients have experienced lupus-like reactions including skin lupus or lupus-like syndrome
during treatment with ustekinumab. Talk to your doctor right away if you experience a red, raised,
scaly rash sometimes with a darker border, in areas of the skin that are exposed to the sun or with joint
pains.

Heart attack and strokes
Heart attack and strokes have been observed in a study in patients with psoriasis treated with
ustekinumab. Your doctor will regularly check your risk factors for heart disease and stroke in order to
ensure that they are appropriately treated. Seek medical attention right away if you develop chest pain,
weakness or abnormal sensation on one side of your body, facial droop, or speech or visual
abnormalities.

Children and adolescents
Uzpruvo is not recommended for use in children who weigh less than 40 kg with Crohn’s disease
because it has not been studied in this age group.

Other medicines, vaccines and Uzpruvo
Tell your doctor or pharmacist
• If you are taking, have recently taken or might take any other medicines.

===== SIDA 68 =====

68
• If you have recently had or are going to have a vaccination. Some types of vaccines (live
vaccines) should not be given while using Uzpruvo.
• If you received Uzpruvo while pregnant, tell your baby’s doctor about your Uzpruvo treatment
before the baby receives any vaccine, including live vaccines, such as the BCG vaccine (used to
prevent tuberculosis). Live vaccines are not recommended for your baby in the first twelve
months after birth if you received Uzpruvo during the pregnancy unless your baby’s doctor
recommends otherwise.

Pregnancy and breast-feeding
• If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor
for advice before taking this medicine.
• A higher risk of birth defects has not been seen in babies exposed to ustekinumab in the womb.
However, there is limited experience with ustekinumab in pregnant women. It is therefore
preferable to avoid the use of Uzpruvo in pregnancy.
• If you are a woman of childbearing potential, you are advised to avoid becoming pregnant and
must use adequate contraception while using Uzpruvo and for at least 15 weeks after the last
Uzpruvo treatment.
• Ustekinumab can pass across the placenta to the unborn baby. If you received Uzpruvo during
your pregnancy, your baby may have a higher risk for getting an infection.
• It is important that you tell your baby’s doctors and other health care professionals if you
received Uzpruvo during your pregnancy before the baby receives any vaccine. Live vaccines
such as the BCG vaccine (used to prevent tuberculosis) are not recommended for your baby in
the first twelve months after birth if you received Uzpruvo during the pregnancy unless your
baby’s doctor recommends otherwise.
• Ustekinumab may pass into breast milk in very small amounts. Talk to your doctor if you are
breast-feeding or are planning to breast-feed. You and your doctor should decide if you should
breast-feed or use Uzpruvo - do not do both.

Driving and using machines
Uzpruvo has no or negligible influence on the ability to drive and use machines.

Uzpruvo contains sodium and polysorbate 80
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. However, before Uzpruvo is given to you, it is mixed with a solution that contains sodium. Talk
to your doctor if you are on a low salt diet.

This medicine contains 0.4 mg of polysorbate 80 in each mL. Polysorbates may cause allergic
reactions. Tell your doctor if you have any known allergies.

3. How Uzpruvo will be given

Uzpruvo is intended for use under the guidance and supervision of a doctor experienced in the
diagnosis and treatment of Crohn’s disease.

Uzpruvo 130 mg concentrate for solution for infusion will be given to you by your doctor, through a
drip in the vein of your arm (intravenous infusion) over at least one hour. Talk to your doctor about
when you will have your injections and follow-up appointments.

How much Uzpruvo is given
Your doctor will decide how much Uzpruvo you need to receive and for how long.

Adults aged 18 years or older
• The doctor will work out the recommended intravenous infusion dose for you based on your
body weight.

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69
Your body weight Dose
≤ 55 kg 260 mg
> 55 kg to ≤ 85 kg 390 mg
> 85 kg 520 mg
• After the starting intravenous dose, you will have the next dose of 90 mg Uzpruvo by an
injection under your skin (subcutaneous injection) 8 weeks later, and then every 12 weeks
therafter.

Children with Crohn’s disease who weigh at least 40 kg
• The doctor will work out the recommended intravenous infusion dose for you based on your
body weight.

Your body weight Dose
≥ 40 to ≤ 55 kg 260 mg
> 55 kg to ≤ 85 kg 390 mg
> 85 kg 520 mg
• After the starting intravenous dose, you will have the next dose of 90 mg Uzpruvo by an
injection under your skin (subcutaneous injection) 8 weeks later, and then every 12 weeks
thereafter.

How Uzpruvo is given
• The first dose of Uzpruvo for treatment of Crohn’s disease is given by a doctor as a drip in the
vein of an arm (intravenous infusion).
Talk to your doctor if you have any questions about receiving Uzpruvo.

If you forget to use Uzpruvo
If you forget or miss the appointment for receiving the dose, contact your doctor to reschedule your
appointment.

If you stop using Uzpruvo
It is not dangerous to stop using Uzpruvo. However, if you stop, your symptoms may come back.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

Some patients may have serious side effects that may need urgent treatment.

Allergic reactions – these may need urgent treatment. Tell your doctor or get emergency medical
help straight away if you notice any of the following signs.
• Serious allergic reactions (‘anaphylaxis’) are rare in people taking ustekinumab (may affect up
to 1 in 1,000 people). Signs include:
o difficulty breathing or swallowing
o low blood pressure, which can cause dizziness or light-headedness
o swelling of the face, lips, mouth or throat.
• Common signs of an allergic reaction include skin rash and hives (may affect up to 1 in 100
people).

===== SIDA 70 =====

70
Infusion-related reactions – If you are being treated for Crohn’s disease , the first dose of
Uzpruvo is given through a drip into a vein (intravenous infusion). Some patients have
experienced serious allergic reactions during the infusion.

In rare cases, allergic lung reactions and lung inflammation have been reported in patients who
receive ustekinumab. Tell your doctor right away if you develop symptoms such as cough,
shortness of breath, and fever.

If you have a serious allergic reaction, your doctor may decide that you should not use Uzpruvo again.

Infections – these may need urgent treatment. Tell your doctor straight away if you notice any of
the following signs.
• Infections of the nose or throat and common cold are common (may affect up to 1 in 10 people)
• Infections of the chest are uncommon (may affect up to 1 in 100 people)
• Inflammation of tissue under the skin (‘cellulitis’) is uncommon (may affect up to 1 in
100 people)
• Shingles (a type of painful rash with blisters) are uncommon (may affect up to 1 in 100 people)

Uzpruvo may make you less able to fight infections. Some infections could become serious and may
include infections caused by viruses, fungi, bacteria (including tuberculosis), or parasites, including
infections that mainly occur in people with a weakened immune system (opportunistic infections).
Opportunistic infections of the brain (encephalitis, meningitis), lungs, and eye have been reported in
patients receiving treatment with ustekinumab.

You must look out for signs of infection while you are using Uzpruvo. These include:
• fever, flu-like symptoms, night sweats, weight loss
• feeling tired or short of breath; cough which will not go away
• warm, red and painful skin, or a painful skin rash with blisters
• burning when passing water
• diarrhoea
• visual disturbance or vision loss
• headache, neck stiffness, light sensitivity, nausea or confusion

Tell your doctor straight away if you notice any of these signs of infection. These may be signs of
infections such as chest infections, skin infections, shingles or opportunistic infections that could have
serious complications. Tell your doctor if you have any kind of infection that will not go away or
keeps coming back. Your doctor may decide that you should not use Uzpruvo until the infection goes
away. Also tell your doctor if you have any open cuts or sores as they might get infected.

Shedding of skin – increase in redness and shedding of skin over a larger area of the body may
be symptoms of erythrodermic psoriasis or exfoliative dermatitis, which are serious skin
conditions. You should tell your doctor straight away if you notice any of these signs.

Other side effects

Common (may affect up to 1 in 10 people)
• Diarrhoea
• Nausea
• Vomiting
• Feeling tired
• Feeling dizzy
• Headache
• Itching (‘pruritus’)
• Back, muscle or joint pain
• Sore throat
• Redness and pain where the injection is given

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71
• Sinus infection

Uncommon (may affect up to 1 in 100 people)
• Tooth infections
• Vaginal yeast infection
• Depression
• Blocked or stuffy nose
• Bleeding, bruising, hardness, swelling and itching where the injection is given
• Feeling weak
• Drooping eyelid and sagging muscles on one side of the face (‘facial palsy’ or ‘Bell’s palsy’),
which is usually temporary
• A change in psoriasis with redness and new tiny, yellow or white skin blisters, sometimes
accompanied by fever (pustular psoriasis)
• Peeling of the skin (skin exfoliation)
• Acne

Rare (may affect up to 1 in 1,000 people)
• Redness and shedding of skin over a larger area of the body, which may be itchy or painful
(exfoliative dermatitis). Similar symptoms sometimes develop as a natural change in the type of
psoriasis symptoms (erythrodermic psoriasis)
• Inflammation of small blood vessels, which can lead to a skin rash with small red or purple
bumps, fever or joint pain (vasculitis)

Very rare (may affect up to 1 in 10,000 people)
• Blistering of the skin that may be red, itchy, and painful (Bullous pemphigoid)
• Skin lupus or lupus-like syndrome (red, raised scaly rash on areas of the skin exposed to the sun
possibly with joint pains)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Uzpruvo

• Uzpruvo 130 mg concentrate for solution for infusion is given in a hospital or clinic and patients
should not need to store or handle it.
• Keep this medicine out of the sight and reach of children.
• Store in a refrigerator (2 °C–8 °C). Do not freeze.
• Keep the vial in the outer carton in order to protect from light.
• If needed, an unopened vial may also be stored at room temperature up to 30 °C for a maximum
single period of up to 7 days in the original carton in order to protect from light. Once a vial has
been stored at room temperature (up to 30 °C), it should not be returned to the refrigerator.
Discard the vial if not used within 7 days at room temperature storage or by the original expiry
date, whichever is earlier.
• Do not shake the Uzpruvo vials. Prolonged vigorous shaking may damage the medicine.

Do not use this medicine
• After the expiry date which is stated on the label and the carton after ‘EXP’. The expiry date
refers to the last day of that month.
• If the liquid is discoloured, cloudy or has large particles floating in it (see section 6 ‘What
Uzpruvo looks like and contents of the pack’).
• If you know, or think that it may have been exposed to extreme temperatures (such as
accidentally frozen or heated).

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72
• If the product has been shaken vigorously.
• If the seal is broken.

Uzpruvo is for single use only. Any diluted infusion solution or unused product remaining in the vial
and the syringe should be thrown away in accordance with local requirements.

6. Contents of the pack and other information

What Uzpruvo contains
• The active substance is ustekinumab. Each vial contains130 mg ustekinumab in 26 mL.
• The other ingredients are EDTA disodium salt dihydrate, histidine, histidine
monohydrochloride, methionine, polysorbate 80 (E433), sucrose and water for injections.

What Uzpruvo looks like and contents of the pack
Uzpruvo is a clear, colourless to light yellow and practically free from visible particles concentrate for
solution for infusion (sterile concentrate). It is supplied as a carton pack containing 1 single-dose, glass
30 mL vial. Each vial contains 130 mg ustekinumab in 26 mL of concentrate for solution for infusion
(sterile concentrate).

Marketing Authorisation Holder
STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

Manufacturers
Alvotech Hf
Sæmundargata 15-19
Reykjavik, 102
Iceland

STADA Arzneimittel AG
Stadastrasse 2–18
61118 Bad Vilbel
Germany

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien
EG (Eurogenerics) NV
Tél/Tel: +32 24797878

Lietuva
UAB „STADA Baltics“
Tel: +370 52603926

България
STADA Bulgaria EOOD
Teл.: +359 29624626

Luxembourg/Luxemburg
EG (Eurogenerics) NV
Tél/Tel: +32 24797878

Česká republika
STADA PHARMA CZ s.r.o.
Tel: +420 257888111

Magyarország
STADA Hungary Kft
Tel.: +36 18009747

Danmark
STADA Nordic ApS
Tlf: +45 44859999

Malta
Pharma.MT Ltd
Tel: +356 21337008

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73
Deutschland
STADAPHARM GmbH
Tel: +49 61016030

Nederland
Centrafarm B.V.
Tel.: +31 765081000

Eesti
UAB „STADA Baltics“
Tel: +372 53072153

Norge
STADA Nordic ApS
Tlf: +45 44859999

Ελλάδα
DEMO S.A. Pharmaceutical Industry
Τηλ: +30 2108161802

Österreich
STADA Arzneimittel GmbH
Tel: +43 136785850

España
Laboratorio STADA, S.L.
Tel: +34 934738889

Polska
STADA Pharm Sp. z o.o.
Tel: +48 227377920

France
EG LABO - Laboratoires EuroGenerics
Tél: +33 146948686

Portugal
Stada, Lda.
Tel: +351 211209870

Hrvatska
STADA d.o.o.
Tel: +385 13764111

România
STADA M&D SRL
Tel: +40 213160640

Ireland
Clonmel Healthcare Ltd.
Tel: +353 526177777

Slovenija
Stada d.o.o.
Tel: +386 15896710

Ísland
STADA Arzneimittel AG
Sími: +49 61016030

Slovenská republika
STADA PHARMA Slovakia, s.r.o.
Tel: +421 252621933

Italia
EG SpA
Tel: +39 028310371

Suomi/Finland
STADA Nordic ApS, Suomen sivuliike
Puh/Tel: +358 207416888

Κύπρος
DEMO S.A. Pharmaceutical Industry
Τηλ: +30 2108161802

Sverige
STADA Nordic ApS
Tel: +45 44859999

Latvija
UAB „STADA Baltics“
Tel: +371 28016404

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

===== SIDA 74 =====

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The following information is intended for healthcare professionals only:

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.

Instructions for dilution:
Uzpruvo concentrate for solution for infusion must be diluted, prepared and infused by a healthcare
professional using aseptic technique.

1. Calculate the dose and the number of Uzpruvo vials needed based on patient weight (see
section 3, Table 1, Table 2). Each 26 mL vial of Uzpruvo contains 130 mg of ustekinumab.
2. Withdraw and then discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the
250 mL infusion bag equal to the volume of Uzpruvo to be added (discard 26 mL sodium
chloride for each vial of Uzpruvo needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL,
for 4 vials- discard 104 mL).
3. Withdraw 26 mL of Uzpruvo from each vial needed and add it to the 250 mL infusion bag. The
final volume in the infusion bag should be 250 mL. Gently mix.
4. Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles,
discolouration or foreign particles are observed.
5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should
be completed within eight 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 0.2 micrometer).
7. Each vial is for single use only and any unused medicinal product should be disposed of in
accordance with local requirements.

Storage

If necessary, the diluted infusion solution may be stored at room temperature. The infusion should be
completed within 8 hours of the dilution in the infusion bag. Do not freeze.

===== SIDA 75 =====

75
Package leaflet: Information for the user

Uzpruvo 45 mg solution for injection
ustekinumab

Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.

This leaflet has been written for the person taking the medicine. If you are the parent or
caregiver who will give Uzpruvo to a child, please read this information carefully.

- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Uzpruvo is and what it is used for
2. What you need to know before you use Uzpruvo
3. How to use Uzpruvo
4. Possible side effects
5. How to store Uzpruvo
6. Contents of the pack and other information

1. What Uzpruvo is and what it is used for

Uzpruvo belongs to a group of medicines called ‘immunosuppressants’. These medicines work by
weakening part of the immune system.

What Uzpruvo is used for
Uzpruvo is used to treat the following inflammatory diseases:
• Plaque psoriasis - in adults and children aged 6 years and older
• Psoriatic arthritis - in adults
• Moderate to severe Crohn’s disease - in adults and children who weigh at least 40 kg

Plaque psoriasis
Plaque psoriasis is a skin condition that causes inflammation affecting the skin and nails. Uzpruvo will
reduce the inflammation and other signs of the disease.

Uzpruvo is used in adults with moderate to severe plaque psoriasis, who cannot use ciclosporin,
methotrexate or phototherapy, or where these treatments did not work.

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76
Uzpruvo is used in children and adolescents aged 6 years and older with moderate to severe plaque
psoriasis who are unable to tolerate phototherapy or other systemic therapies or where these treatments
did not work.

Psoriatic arthritis
Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis. If you
have active psoriatic arthritis you will first be given other medicines. If you do not respond well
enough to these medicines, you may be given Uzpruvo to:
• Reduce the signs and symptoms of your disease.
• Improve your physical function.
• Slow down the damage to your joints.

2. What you need to know before you use Uzpruvo

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using
Uzpruvo.

Warnings and precautions
Talk to your doctor or pharmacist before using Uzpruvo. Your doctor will check how well you are
before each treatment. Make sure you tell your doctor about any illness you have before each
treatment. Also tell your doctor if you have recently been near anyone who might have tuberculosis.
Your doctor will examine you and do a test for tuberculosis, before you have Uzpruvo. If your doctor
thinks you are at risk of tuberculosis, you may be given medicines to treat it.

Before you use Uzpruvo tell your doctor
• If you ever had an allergic reaction to Uzpruvo. Ask your doctor if you are not sure.
• If you have ever had any type of cancer – this is because immunosuppressants like Uzpruvo
weaken part of the immune system. This may increase the risk of cancer.
• If you have been treated for psoriasis with other biologic medicines (a medicine produced
from a biological source and usually given by injection) – the risk of cancer may be higher.
• If you have or have had a recent infection.
• If you have any new or changing lesions within psoriasis areas or on normal skin.
• If you are having any other treatment for psoriasis and/or psoriatic arthritis – such as
another immunosuppressant or phototherapy (when your body is treated with a type of
ultraviolet (UV) light). These treatments may also weaken part of the immune system. Using
these therapies together with Uzpruvo has not been studied. However, it is possible it may
increase the chance of diseases related to a weaker immune system.
• If you are having or have ever had injections to treat allergies – it is not known if Uzpruvo
may affect these.
• If you are 65 years of age or over – you may be more likely to get infections.

===== SIDA 77 =====