- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Plaque psoriasisSTELARA 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).
Psoriatic arthritis (PsA)STELARA, 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).
Plaque psoriasisThe recommended posology of STELARA 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 kgFor 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 2)
Psoriatic arthritis (PsA)The recommended posology of STELARA 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 patients (≥ 65 years)No dose adjustment is needed for elderly patients (see section 4.4).
Renal and hepatic impairmentSTELARA has not been studied in these patient populations. No dose recommendations can be made.
Paediatric populationThe safety and efficacy of STELARA in children less than 18 years have not yet been established. No data are available.
Method of administrationSTELARA is for subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites.After proper training in subcutaneous injection technique, patients may self-inject STELARA if a physician determines that it is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients should be instructed to inject the full amount of STELARA 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.
InfectionsUstekinumab may have the potential to increase the risk of infections and reactivate latent infections. In clinical studies, serious bacterial, fungal, and viral infections have been observed in patients receiving STELARA (see section 4.8).Caution should be exercised when considering the use of STELARA in patients with a chronic infection or a history of recurrent infection (see section 4.3).Prior to initiating treatment with STELARA, patients should be evaluated for tuberculosis infection. STELARA must 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 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, the patient should be closely monitored and STELARA should not be administered until the infection resolves.
MalignanciesImmunosuppressants like ustekinumab 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).No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving STELARA. Thus, caution should be exercised when considering the use of STELARA 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).
Hypersensitivity reactionsSerious 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 STELARA should be discontinued (see section 4.8).
Latex sensitivityThe needle cover on the syringe in the pre-filled syringe is manufactured from dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
VaccinationsIt is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin (BCG)) should not be given concurrently with STELARA. 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 STELARA. Before live viral or live bacterial vaccination, treatment with STELARA 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.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 (see section 5.1).
Concomitant immunosuppressive therapyIn psoriasis studies, the safety and efficacy of STELARA 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 STELARA. Caution should be exercised when considering concomitant use of other immunosuppressants and STELARA or when transitioning from other immunosuppressive biologics (see section 4.5).
ImmunotherapySTELARA has not been evaluated in patients who have undergone allergy immunotherapy. It is not known whether STELARA may affect allergy immunotherapy. Serious skin conditionsIn 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. STELARA should be discontinued if a drug reaction is suspected.
Elderly patients (≥ 65 years)No overall differences in efficacy or safety in patients age 65 and older who received STELARA were observed compared to younger patients, 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.
Women of childbearing potentialWomen of childbearing potential should use effective methods of contraception during treatment and for at least 15 weeks after treatment.
PregnancyThere 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 STELARA in pregnancy.
Breast-feedingIt is unknown whether ustekinumab is excreted in human breast milk. Animal studies have shown excretion of ustekinumab at low levels in breast milk. 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 STELARA must be made taking into account the benefit of breast-feeding to the child and the benefit of STELARA therapy to the woman.
FertilityThe effect of ustekinumab on human fertility has not been evaluated (see section 5.3).
Summary of the safety profileThe most common adverse reactions (> 5%) in controlled periods of the psoriasis and psoriatic arthritis clinical studies with ustekinumab were nasopharyngitis, headache and upper respiratory tract infection. 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).
Tabulated list of adverse reactionsThe safety data described below reflect exposure to ustekinumab in 7 controlled phase 2 and phase 3 studies in 4,135 patients with psoriasis and/or psoriatic arthritis, including 3,256 exposed for at least 6 months, 1,482 exposed for at least 4 years, and 838 exposed for at least 5 years.Table 1 provides a list of adverse reactions from psoriasis and psoriatic arthritis 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 1 List of adverse reactions
|System Organ Class||Frequency: Adverse reaction|
|Infections and infestations||Common: Dental infections, upper respiratory tract infection, nasopharyngitis Uncommon: Cellulitis, herpes zoster, viral upper respiratory tract infection|
|Immune system disorders||Uncommon: Hypersensitivity reactions (including rash, urticaria) Rare: Serious hypersensitivity reactions (including anaphylaxis, angioedema)|
|Psychiatric disorders||Uncommon: Depression|
|Nervous system disorders||Common: Dizziness, headache Uncommon: Facial palsy|
|Respiratory, thoracic and mediastinal disorders||Common: Oropharyngeal pain Uncommon: Nasal congestion|
|Gastrointestinal disorders||Common: Diarrhoea, nausea|
|Skin and subcutaneous tissue disorders||Common: Pruritus Uncommon: Pustular psoriasis, skin exfoliation Rare: Exfoliative dermatitis|
|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)|
Description of selected adverse reactions
InfectionsIn the placebo-controlled studies of patients with psoriasis and/or psoriatic arthritis, the rates of infection or serious infection were similar between ustekinumab-treated patients and those treated with placebo. In the placebo-controlled period of clinical studies of patients with psoriasis and patients with psoriatic arthritis, the rate of infection was 1.27 per patient-year of follow-up in ustekinumab-treated patients, and 1.17 in placebo-treated patients. Serious infections occurred in 0.01 per patient-year of follow-up in ustekinumab-treated patients (5 serious infections in 616 patient-years of follow-up) and 0.01 in placebo-treated patients (4 serious infections in 287 patient-years of follow-up) (see section 4.4).In the controlled and non-controlled periods of psoriasis and psoriatic arthritis clinical studies, representing 9,848 patient-years of exposure in 4,135 patients, the median follow up was 1.1 years; 3.2 years for psoriasis studies and 1.0 year for psoriatic arthritis studies. The rate of infection was 0.86 per patient-year of follow-up in ustekinumab-treated patients, and the rate of serious infections was 0.01 per patient-year of follow-up in ustekinumab-treated patients (107 serious infections in 9,848 patient-years of follow-up) and serious infections reported included diverticulitis, cellulitis, pneumonia, sepsis, appendicitis and cholecystitis.In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not develop tuberculosis.
MalignanciesIn the placebo-controlled period of the psoriasis and psoriatic arthritis clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.16 per 100 patient-years of follow-up for ustekinumab-treated patients (1 patient in 615 patient-years of follow-up) compared with 0.35 for placebo-treated patients (1 patient in 287 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.65 per 100 patient-years of follow-up for ustekinumab-treated patients (4 patients in 615 patient-years of follow-up) compared to 0.70 for placebo-treated patients (2 patients in 287 patient-years of follow-up).In the controlled and non-controlled periods of psoriasis and psoriatic arthritis clinical studies, representing9,848 patient-years of exposure in 4,135 patients, the median follow-up was 1.1 years; 3.2 years for psoriasis studies and 1.0 year for psoriatic arthritis studies. Malignancies excluding non-melanoma skin cancers were reported in 55 patients in 9,830 patient-years of follow-up (incidence of 0.56 per 100 patient-years of follow-up for ustekinumab-treated patients). This incidence of malignancies reported in ustekinumab-treated patients was comparable to the incidence expected in the general population (standardized incidence ratio = 0.92 [95% confidence interval: 0.69, 1.20], adjusted for age, gender and race). The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, melanoma, colorectal and breast cancers. The incidence of non-melanoma skin cancer was 0.50 per 100 patient-years of follow-up for ustekinumab-treated patients (49 patients in 9,815 patient-years of follow-up). The ratio of patients with basal versus squamous cell skin cancers (4:1) is comparable with the ratio expected in the general population (see section 4.4).
Hypersensitivity reactionsDuring 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).
ImmunogenicityIn clinical studies less than 8% of ustekinumab-treated patients developed antibodies to ustekinumab. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was observed. The majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. Efficacy tended to be lower in patients positive for antibodies to ustekinumab; however, antibody positivity did not preclude a clinical response.
Reporting of suspected adverse reactionsReporting 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: United KingdomYellow Card Scheme Website: www.mhra.gov.uk/yellowcardIrelandHPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ieE-mail: email@example.com
Mechanism of actionUstekinumab 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 and psoriatic arthritis.By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in both psoriasis and psoriatic arthritis through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology of these diseases.
ImmunizationDuring the long term extension of Psoriasis Study 2 (PHOENIX 2), patients treated with STELARA 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 patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers were similar among STELARA-treated and control patients.
Plaque psoriasisThe 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 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 2 and 3).
Table 2 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%)|
Table 3 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%)|
Psoriatic arthritis (PsA)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 randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by 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 symptomsTreatment 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 4 below.Table 4 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 randomized||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%)|
Radiographic ResponseStructural 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 lifeUstekinumab-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.
Paediatric populationThe 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 moderate to severe plaque psoriasis and juvenile idiopathic arthritis (see section 4.2 for information on paediatric use).
AbsorptionThe 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.
DistributionMedian volume of distribution during the terminal phase (Vz) following a single intravenous administration to patients with psoriasis ranged from 57 to 83 ml/kg.
BiotransformationThe exact metabolic pathway for ustekinumab is unknown.
EliminationMedian 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 and/or psoriatic arthritis, 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 linearityThe 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 or following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis.
Single dose versus multiple dosesSerum concentration-time profiles of ustekinumab were generally predictable after single or multiple subcutaneous dose administrations. 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) in patients with psoriasis. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Impact of weight on pharmacokineticsIn 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.
Special populationsNo 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 the population pharmacokinetic analysis, there were no indications of an effect of tobacco or alcohol on the pharmacokinetics of ustekinumab.
Regulation of CYP450 enzymesThe 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).
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