Pyzchiva 130 mg concentrate for solution for infusion

Crohn's Disease

Pyzchiva 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 or have medical contraindications to such therapies.

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

Posology

Crohn's Disease

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

Table 1 Initial intravenous dosing of Pyzchiva

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 Pyzchiva 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

The safety and efficacy of ustekinumab for the treatment of Crohn's disease in children less than 18 years have not yet been established. No data are available.

Method of administration

Pyzchiva 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.

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

Traceability

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

Infections

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

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

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

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

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

Systemic and respiratory hypersensitivity reactions

Systemic

Serious hypersensitivity reactions have been reported in the postmarketing setting, in some cases several days after treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or other serious hypersensitivity reaction occurs, appropriate therapy should be instituted and administration of ustekinumab 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 Gué rin (BCG)) should not be given concurrently with ustekinumab. 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 ustekinumab 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 six 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 ustekinumab may receive concurrent inactivated or non-live vaccinations.

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

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of ustekinumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. Caution should be exercised when considering concomitant use of other immunosuppressants and ustekinumab or when transitioning from other immunosuppressive biologics (see section 4.5).

Immunotherapy

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

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see section 4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may be clinically indistinguishable from exfoliative dermatitis, as part of the natural course of their disease. As part of the monitoring of the patient's psoriasis, physicians should be alert for symptoms of erythrodermic psoriasis or exfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted. ustekinumab should be discontinued if a drug reaction is suspected.

Lupus-related conditions

Cases of lupus-related conditions have been reported in patients treated with ustekinumab, 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

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

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

Administration of live vaccines (such as the BCG vaccine) to infants exposed in utero to ustekinumab is not recommended for six 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.

No interaction studies have been performed in humans. In the population pharmacokinetic analyses of the phase 3 studies, the effect of the most frequently used concomitant medicinal products in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on pharmacokinetics of ustekinumab was explored. There were no indications of an interaction with these concomitantly administered medicinal products. The basis for this analysis was that at least 100 patients (> 5% of the studied population) were treated concomitantly with these medicinal products for at least 90% of the study period. The pharmacokinetics of ustekinumab was not impacted by concomitant use of MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids in patients with psoriatic arthritis, Crohn's disease or ulcerative colitis, or prior exposure to anti-TNFα agents, in patients with psoriatic arthritis or Crohn's disease or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.

The results of an in vitro study 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).

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

There are no adequate data from the use of ustekinumab in pregnant women. 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). As a precautionary measure, it is preferable to avoid the use of ustekinumab 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 6 months following birth or until ustekinumab infant serum levels are undetectable (see sections 4.4 and 4.5). If there is a clear clinical benefit for the individual infant, administration of a live vaccine might be considered at an earlier timepoint, if infant ustekinumab serum levels are undetectable.

Breast-feeding

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

Fertility

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

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

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 6,709 patients (4,135 with psoriasis and/or psoriatic arthritis, 1,749 with Crohn's disease and 825 patients with ulcerative colitis). This includes exposure to ustekinumab in the controlled and non- controlled periods of the clinical studies for at least 6 months or 1 year (4,577 and 3,253 patients respectively with psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis) and exposure for at least 4 or 5 years (1,482 and 838 patients with psoriasis respectively).

Table 2 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies as well as adverse reactions reported from post-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 2 List of adverse reactions

* 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 11,581 patient-years of exposure in 6,709 patients, the median follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 year for Crohn's disease studies and 1.0 years for ulcerative colitis studies. The rate of infection was 0.91 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 (199 serious infections in 11,581 patient-years of follow-up) and serious infections reported included pneumonia, anal abscess, cellulitis, diverticulitis, gastroenteritis and viral infections.

In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis.

Malignancies

In the placebo-controlled period of the psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.11 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 929 patient-years of follow-up) compared with 0.23 for placebo-treated patients (1 patient in 434 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.43 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 929 patient-years of follow-up) compared to 0.46 for placebo-treated patients (2 patients in 433 patient-years of follow-up).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies, representing 11,561 patient-years of exposure in 6,709 patients, the median follow-up was 1.0 years; 1.1 years for psoriatic disease studies, 0.6 year for Crohn's disease studies and 1.0 years for ulcerative colitis studies. Malignancies excluding non-melanoma skin cancers were reported in 62 patients in 11,561 patient-years of follow-up (incidence of 0.54 per 100 patient-years of follow-up for ustekinumab-treated patients). The incidence of malignancies reported in ustekinumab-treated patients was comparable to the incidence expected in the general population (standardised incidence ratio = 0.93 [95% confidence interval: 0.71, 1.20], adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, colorectal, melanoma and breast cancers. The incidence of non-melanoma skin cancer was 0.49 per 100 patient-years of follow-up for ustekinumab-treated patients (56 patients in 11,545 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (3:1) 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

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

Pyzchiva is a biosimilar medicinal product.

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-12Rβ 1 receptor protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ 1 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 fecal 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 1409 (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.

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.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids or immunomodulators, and were either anti-TNF-α naï ve (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 3). 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 3 Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

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 ustekinumab 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 4).

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

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).

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 ustekinumab in one or more subsets of the paediatric population in Crohn's Disease (see section 4.2 for information on paediatric use).

Following the recommended intravenous induction dose, median peak serum ustekinumab concentration, observed 1 hour after the infusion, was 126.1 μ g/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.

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

Dose linearity

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

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).

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.

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.

Histidine

Histidine hydrochloride monohydrate

Methionine

Disodium edetate

Sucrose

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Pyzchiva should be diluted with sodium chloride 9 mg/mL (0.9%) solution. Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.

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

Before dilution

24 months

Do not freeze.

After dilution

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

From a microbiological point of view, the infusion solution should be administered immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8° C, unless dilution has taken place in controlled and validated aseptic conditions.

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

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

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

26 mL solution in a type I glass 30 mL vial closed with a chlorobutyl rubber stopper. Pyzchiva is available in a 1 vial pack.

The solution in the Pyzchiva vial should not be shaken. The solution should be visually inspected for particulate matter or discoloration prior to administration. The solution is clear, colourless to light yellow. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreign particulate matter is present.

Dilution

Pyzchiva 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 Pyzchiva vials needed based on patient weight (see section 4.2, Table 1). Each 26 mL vial of Pyzchiva contains 130 mg of ustekinumab. Only use complete vials of Pyzchiva.

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 Pyzchiva to be added. (discard 26 mL sodium chloride for each vial of Pyzchiva needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, for 4 vials- discard 104 mL) Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used.

3. Withdraw 26 mL of Pyzchiva from each vial needed and add it to the 250 mL 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, discoloration 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 72 hours at room temperature up to 30° C of the dilution in the infusion bag. If necessary, the diluted infusion solution may be kept at 2° C to 8° C for up to 1 month and at room temperature up to 30° C for an additional 72 hours after removal from refrigeration including the infusion period.

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.