Stelara a 130 Mg Solution

SCHEDULING STATUS Schedule 4

Crohnu2019s Disease STELARA is indicated for the treatment of adult patients with moderately to severely active Crohnu2019s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNFu03b1 antagonist or have medical contraindications to such therapies.

Ulcerative colitis STELARA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies.

Posology STELARA concentrate for solution for infusion is intended for use under the guidance and supervision of medical practitioners experienced in the diagnosis and treatment of Crohn's disease or ulcerative colitis. STELARA concentrate for solution for infusion should only be used for the intravenous induction dose.

Posology Crohnu2019s Disease and Ulcerative Colitis STELARA 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 STELARA 130 mg as specified in Table 1 (see section 6.6 for preparation).

Table 1 Initial intravenous dosing of STELARA Body weight of patient at the time of dosing Recommended dose a Number of 130 mg STELARA vials

• u2264 55 kg 260 mg 2
• > 55 kg to u2264 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 STELARA solution for injection (vial) and solution for injection in pre-filled syringe Professional Information.

Elderly (u2265 65 years) In clinical studies, no major age-related differences in clearance or volume of distribution were observed and no overall differences in safety and efficacy in patients age 65 and older who received STELARA were observed compared to younger patients. The number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. No dose adjustment is needed for elderly patients (see section 5.2).

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

Paediatric population The safety and efficacy of STELARA for the treatment of Crohnu2019s disease or ulcerative colitis in children less than 18 years have not yet been established. No data are available.

Method of administration STELARA 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, ustekinumab, or to any of the excipients listed in section 6.1. Active tuberculosis (see section 4.4).

Infections STELARA is a selective immunosuppressant and may have the potential to increase the risk of infections and reactivate latent infections. In clinical studies, serious bacterial, fungal, and viral infections were observed in patients receiving STELARA (see section 4.8: Infections). STELARA should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of STELARA in patients with a chronic infection or a history of recurrent infection. Prior to initiating treatment with STELARA, patients should be evaluated for tuberculosis infection. STELARA should not be given to patients with active tuberculosis (see section 4.3). Treatment of latent tuberculosis infection should be initiated prior to administering STELARA. Anti-tuberculosis therapy should also be considered prior to initiation of STELARA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

Patients receiving STELARA 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, they should be closely monitored and STELARA should not be administered until the infection resolves.

Malignancies STELARA is a selective immunosuppressant. Immunosuppressive medicines, such as STELARA, have the potential to increase the risk of malignancy. Some patients who received STELARA in clinical studies developed cutaneous and non-cutaneous malignancies (see section 4.8: Malignancies). STELARA has not been studied in patients with a history of malignancy. Caution should be exercised when considering the use of STELARA in patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy. All patients, in particular those older than 60 years of age, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the appearance of skin cancer (see section 4.8: Malignancies).

Hypersensitivity reactions In post-marketing experience, serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. If an anaphylactic or other serious hypersensitivity reaction occurs, institute appropriate therapy and administration of STELARA should be discontinued (see section 4.8: Hypersensitivity reactions).

Immunisations Live viral or live bacterial vaccines (such as Bacillus of Calmette and Guu00e9rin (BCG)) should not be given concurrently with STELARA. No data are available on the secondary transmission of infection by live vaccines in patients receiving STELARA. Caution is advised when administering some live vaccines to household contacts of patients receiving STELARA because of the potential risk for shedding from the household contact and transmission to the patient. Patients receiving STELARA may receive concurrent inactivated or non-live vaccinations. Long term treatment with STELARA does not suppress the humoral immune response to pneumococcal polysaccharide or tetanus vaccines. Infant exposure in utero For infants exposed in utero to ustekinumab, a six month waiting period following birth is recommended before the administration of live vaccines. Administration of a live vaccine prior to 6 months of age may be considered if ustekinumab dosing was limited to the first trimester of pregnancy when placental transport is minimal, or ustekinumab serum levels are undetectable in the infant, or the benefit of the vaccination clearly outweighs the theoretical risk of administration of live vaccines to the infant (see section 4.6 - Fertility, pregnancy and lactation).

Immunosuppression In Crohnu2019s disease and ulcerative colitis studies, concomitant use of immunomodulators (6-mercaptopurine (6-MP), azathioprine (AZA), methotrexate (MTX) or corticosteroids did not appear to influence the safety or efficacy of STELARA. Caution should be exercised when considering concomitant use of immunosuppressive medicines and STELARA or when transitioning from other biologic medicines (see section 4.5).

Immunotherapy STELARA has not been evaluated in patients who have undergone allergy immunotherapy. STELARA may affect allergy immunotherapy. Caution should be exercised in patients receiving or who have received allergy immunotherapy particularly for anaphylaxis.

Sucrose STELARA contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not use STELARA. In addition, sucrose may have an effect on the glycaemic control of patients with diabetes mellitus.

Live vaccines should not be given concurrently with STELARA. Recommendations for infants exposed to ustekinumab in utero are provided (see section 4.4).

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). Results from a Phase 1 study in subjects with active Crohnu2019s disease suggest no clinically relevant drug interactions are likely. These results do not suggest the need for dose adjustments in patients who are receiving concomitant CYP450 substrates (see 5.2). In a population pharmacokinetic analysis, the effect of the most frequently used concomitant medicines in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine, hydrochlorothiazide, and influenza vaccine) on pharmacokinetics of ustekinumab was explored. There were no indications of an interaction with these concomitantly administered medicines. The pharmacokinetics of STELARA was not impacted by the prior use of MTX, NSAIDs, and oral corticosteroids, or prior exposure to anti-TNFu03b1 medicines in patients with psoriatic arthritis, Crohnu2019s disease or in patients with ulcerative colitis. In psoriasis studies, the safety and efficacy of STELARA in combination with immunosuppressive medicines, including biologics, or phototherapy have not been evaluated. Caution should be exercised when considering concomitant use of immunosuppressive medicines and STELARA.

Pregnancy Data from prospectively collected pregnancies following exposure to STELARA resulting in live birth with known outcomes, including more than 450 pregnancies exposed during the first trimester, do not indicate an increased risk of malformations in the newborn. Overall, data from observational studies, pharmacovigilance, and published case reports and cohort studies do not indicate an increase in the risk of major birth defects, pattern of major or minor anomalies, miscarriage, or adverse infant outcomes. STELARA should not be given to a pregnant woman except if the benefit clearly outweighs the risk.

Lactation Limited data from published literature suggests that ustekinumab is excreted in human breast milk in very small amounts. While systemic exposure to the breastfed infant is expected to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract, it is not known if STELARA is absorbed systemically after ingestion. Because of the potential for adverse reactions in breastfeeding infants from STELARA, a decision should be made whether to discontinue breastfeeding or to discontinue STELARA.

Fertility The effect of STELARA on human fertility has not been evaluated (see section 5.3). It is not known whether STELARA can affect reproductive potential.

No studies on the effects on the ability to drive and use machines have been performed.

Clinical studies experience in adult patients Summary of safety profile The most common adverse reactions (> 5 %) in controlled periods of the adult psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis clinical studies with STELARA 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 STELARA is serious hypersensitivity reactions including anaphylaxis (see section 4.4). The overall safety profile was similar for patients with psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis.

Tabulated list of adverse reactions The safety data described below reflect exposure in adults to STELARA in 14 phase 2 and phase 3 studies in 6 710 patients (4 135 with psoriasis and/or psoriatic arthritis, 1 749 with Crohnu2019s disease and 826 patients with ulcerative colitis). This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies for at least 6 months or 1 year (4 577 and 3648 patients respectively with psoriasis, psoriatic arthritis, Crohnu2019s disease or ulcerative colitis) and exposure for at least 4 or 5 years (2194 and 1148 patients with psoriasis respectively). Table 2 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis clinical studies. The adverse reactions are classified by System Organ Class and frequency, using the following convention:

Very common (u2265 1/10), Common (u2265 1/100 to < 1/10), Uncommon (u2265 1/1 000 to < 1/100), Rare (u2265 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: Summary of Adverse Reactions in Clinical Studies System Organ Class Frequency: Adverse reaction Infections and infestations Common: Upper respiratory tract infection, nasopharyngitis, sinusitis Uncommon: Cellulitis, dental infections, herpes zoster, viral upper respiratory tract infection, vulvovaginal mycotic infection Psychiatric disorders Uncommon: Depression Nervous system disorders Common: Dizziness, headache Respiratory, thoracic and mediastinal disorders Common: Oropharyngeal pain Uncommon: Nasal congestion Gastrointestinal disorders Common: Diarrhoea, nausea, vomiting Skin and subcutaneous tissue disorders Common: Pruritus Uncommon: Acne Musculoskeletal and connective tissue disorders Common: Back pain, myalgia, arthralgia 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

Physicians should consider the local disease background when treating patients with STELARA (see section 4.4).

Description of selected adverse reactions Infections In the placebo-controlled period of clinical studies of patients with psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis, the rate of infection was 1,36 per patient-year of follow-up in STELARA-treated patients, and 1,34 per patient follow-up in placebo-treated patients. Serious infections occurred at the same rate of 0,03 per patient-year of follow-up in STELARA and placebo treated patients (see section 4.4: Infections). In the controlled and non-controlled portions of psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis clinical studies, the rates of infection and serious infection were 0, 85 and 0,02, respectively, per patient-year of follow-up in STELARA-treated patients. Serious infections included anal abscess, cellulitis, pneumonia, 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, Crohnu2019s 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 STELARA-treated patients compared with 0,23 per 100 patient years of follow up for placebo-treated patients. The incidence of non-melanoma skin cancer was 0,43 per 100 patient-years of follow-up for STELARA-treated patients compared with 0,46 per 100 patient-years of follow up for placebo-treated patients. In the controlled and non-controlled periods of psoriasis, psoriatic arthritis, Crohnu2019s disease and ulcerative colitis clinical studies malignancies, excluding non-melanoma skin cancers were reported with an incidence of 0,50 per 100 patient-years of follow-up for STELARA-treated patients. This was comparable to the incidence expected in the general population (standardised incidence ratio = 0, 94 [95% confidence interval: 0,73,1, 18]). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal and breast. The incidence of non-melanoma skin cancer was 0,49 per 100 patient-years of follow-up for STELARA-treated patients (see section 4.4: Malignancies). The ratio of patients with basal versus squamous cell skin cancers (3:1) is comparable with the ratio expected in the general population.

Hypersensitivity and infusion reactions In Crohnu2019s 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 STELARA reported adverse events occurring during or within an hour of the infusion.

Postmarketing experience Table 3: Adverse Reactions Identified During Postmarketing Experience with STELARA Immune system disorders Hypersensitivity reactions (including rash, urticaria) Serious hypersensitivity reactions (including anaphylaxis, angioedema) Infections and infestations Lower respiratory tract infection Respiratory, thoracic and mediastinal disorders Allergic alveolitis, eosinophilic pneumonia Skin and subcutaneous tissue disorders Pustular psoriasis, exfoliative dermatitis, erythrodermic psoriasis, hypersensitivity vasculitis 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 medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who - umc.org) found on SAHPRA website.

In case of overdose, although no dose-dependent toxicity has been observed, theoretically, side effects could be exacerbated or exaggerated. It is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.