Stelara

Stelara

ustekinumab

Manufacturer:

Janssen

Distributor:

Zuellig Pharma

Marketer:

Johnson & Johnson
Full Prescribing Info
Contents
Ustekinumab.
Description
Solution for Injection for Subcutaneous Administration (Pre-filled Syringe): Each mL of STELARA contains 90 mg of ustekinumab, 1.0 mg L histidine and L histidine hydrochloride, 76 mg sucrose, 0.04 mg polysorbate 80, and Water for Injection, USP. STELARA does not contain preservatives.
The solution is clear to slightly opalescent, colorless to light yellow with a pH of approximately 6.0.
Concentrate for Solution for Intravenous Infusion (Single-use Vial): Each mL of STELARA contains 5.0 mg of ustekinumab, 0.8 mg L-histidine, 1.1 mg L-histidine hydrochloride monohydrate, 85 mg sucrose, 0.40 mg polysorbate 80, 0.40 mg L-methionine, and 0.02 mg EDTA disodium salt dihydrate. STELARA does not contain preservatives.
The solution is clear, colorless to light yellow with a pH of approximately 6.0.
Ustekinumab is a fully human IgG1κ monoclonal antibody with an approximate molecular weight of 148600 daltons. Ustekinumab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.
Excipients/Inactive Ingredients: Solution for Injection for Subcutaneous Administration (Pre-filled Syringe): L-histidine, L-histidine monohydrochloride monohydrate, Polysorbate 80, Sucrose, Water for injection.
Concentrate for Solution for Intravenous Infusion (Single-use Vial): EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, Polysorbate 80, Sucrose, Water for injection.
Action
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors. ATC code: L04AC05.
Pharmacology: Pharmacodynamics: Mechanism of Action: STELARA 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. STELARA 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. STELARA cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ1 cell surface receptors. Thus, STELARA is not likely to contribute to complement or antibody mediated cytotoxicity of cells expressing 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. IL-12 stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype and stimulates interferon gamma (IFNγ) production. IL-23 induces the T helper 17 (Th17) pathway and promotes secretion of IL-17A, IL-21, and IL-22. Levels of IL-12 and IL-23 are elevated in the skin and blood of patients with psoriasis, and serum IL12/23p40 distinguishes patients with psoriatic arthritis from healthy individuals, implicating IL-12 and IL-23 in the pathophysiology of psoriatic inflammatory diseases. Genetic polymorphisms in IL23A, IL23R, and IL-12B genes confer susceptibility to these disorders. Additionally, IL-12 and IL-23 are highly expressed in lesional psoriatic skin, and IL-12-mediated induction of IFNγ correlates with psoriasis disease activity. IL-23 responsive T-cells have been found in the entheses in a mouse model of inflammatory arthritis, where IL-23 drives entheseal inflammation. In addition, there is pre-clinical evidence implicating IL-23 and downstream pathways in bone erosion and destruction through up-regulation of receptor activator of nuclear factor-κB ligand (RANKL), which activates osteoclasts.
In patients with Crohn's disease, IL-12 and IL-23 are elevated in the intestines and lymph nodes. This is accompanied by increases in serum IFNγ and IL-17A levels, suggesting that IL-12 and IL-23 promote Th1 and Th17 activation in Crohn's disease. Both IL-12 and IL-23 can also stimulate TNFα production by T cells, resulting in chronic intestinal inflammation and epithelial cell injury. Significant associations have been found between Crohn's disease and genetic polymorphisms in the IL23R and IL12B genes, suggesting a potential causal role for IL-12/23 signaling in the disease. This is supported by pre-clinical data demonstrating that IL-12/23 signaling is required for intestinal injury in mouse models of inflammatory bowel disease.
By binding the shared p40 subunit of IL-12 and IL-23, STELARA may exert its clinical effects in both 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.
Pharmacodynamic Effects: Treatment with STELARA resulted in significant improvement in histological measures of psoriasis including epidermal hyperplasia and cell proliferation. These results are consistent with the clinical efficacy observed.
In patients with psoriasis and/or psoriatic arthritis, STELARA had no apparent effect on the percentages of circulating immune cell populations including memory and naive T cell subsets or circulating cytokine levels. Systemic markers of inflammation were measurable in the serum at baseline and 4 markers (MDC, VEGF, MCSF-1 and YKL-40) showed modest differences in concentration post-treatment in STELARA-treated patients as compared to placebo.
Treatment with STELARA resulted in a decrease in the gene expression of its molecular targets IL-12 and IL-23 as shown by analyses of mRNA obtained from lesional skin biopsies of psoriatic patients at baseline and up to 2 weeks post-treatment. In addition, STELARA down regulated the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8 in lesional skin biopsies. These results are consistent with the significant clinical benefit observed with STELARA treatment in psoriasis.
In psoriasis and psoriatic arthritis studies, clinical response (improvement in PASI or ACR measurements, respectively) appeared to be related to serum ustekinumab levels. Patients with psoriasis with higher PASI response had higher median serum concentrations of ustekinumab than those with lower clinical responses. In psoriasis studies, the proportion of patients who achieved PASI 75 response increased with increasing serum levels of ustekinumab. The proportion of patients who achieved PASI 75 response at Week 28 increased with increasing serum ustekinumab trough levels at Week 28. In psoriatic arthritis studies, patients achieving an ACR 20 response had higher median serum concentrations of ustekinumab than ACR 20 non-responders. The proportion of patients who achieved ACR 20 and ACR 50 response increased with increasing serum levels of ustekinumab.
In patients with Crohn's disease, treatment with STELARA resulted in a significant decrease in inflammatory markers including C-Reactive Protein (CRP) and fecal calprotectin. Reductions in serum IFNγ and IL-17A, which are IL-12 and IL-23 regulated pro-inflammatory cytokines, were achieved and maintained in STELARA treated patients through Week 44 compared to placebo. Expression of genes such as IL-12Rβ1 and IL-23 was reduced in inflamed colon tissue from Crohn’s disease patients, responders to STELARA treatment while no significant changes were observed in placebo treated patients at Week 6.
Immunization: During the long term extension of a Phase 3 psoriasis study (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.
Clinical Studies: Clinical Efficacy - Plaque Psoriasis (Adults): The safety and efficacy of STELARA was assessed in 2 Phase 3, multicenter, randomized, double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis (PHOENIX 1 and PHOENIX 2). A total of 1996 patients were enrolled in these studies.
The studies enrolled adults (≥ 18 years) with chronic (> 6 months) plaque psoriasis who had a minimum body surface area (BSA) involvement of 10%, and PASI score ≥ 12 and who were candidates for systemic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the studies. No concomitant antipsoriatic therapies were allowed during the study with the exception of low-potency topical corticosteroids on the face and groin after week 12.
The PASI is a composite score that assesses the fraction of body surface area involved with psoriasis and the severity of psoriatic changes within the affected regions (plaque thickness/induration, erythema, and scaling). PASI numeric scores range from 0 to 72, with higher scores representing more severe disease.
Patients achieving ≥ 75% improvement in PASI from baseline (PASI 75) were considered PASI 75 responders. Patients originally randomized to STELARA who were PASI 75 responders at both Weeks 28 and 40 were considered long-term PASI 75 responders. Patients achieving ≥ 90% improvement in PASI from baseline (PASI 90) were considered PASI 90 responders and patients with ≥ 50% improvement in PASI from baseline (PASI 50) were considered PASI 50 responders. Patients who achieved ≥ 50% but less than 75% improvement in PASI from baseline were considered partial responders. Patients with < 50% improvement in PASI from baseline were considered nonresponders.
Other key efficacy assessments included: The Physician's Global Assessment (PGA), a 6-category scale: 0 = cleared, 1 = minimal, 2 = mild, 3= moderate, 4 = marked and 5 = severe, that indicates the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. The PGA was assessed in PHOENIX 1 and 2.
The Dermatology Life Quality Index (DLQI), a dermatology-specific quality of life instrument designed to assess the impact of the disease on a patient's quality of life. DLQI scores range from 0 to 30, with a lower score representing a better quality of life. A decrease of 5 in the DLQI score from baseline is considered a clinically meaningful improvement. The DLQI was assessed in PHOENIX 1 and 2.
The SF-36, a health survey questionnaire consisting of multi-item scales measuring 8 health concepts. The SF-36 yields composite scores that provide a measure of disease impact on physical and mental health status. Higher SF-36 scores indicate a better quality of life. The SF-36 was assessed in PHOENIX 1.
The Nail Psoriasis Severity Index (NAPSI), a physician-assessed score that measures the severity of nail involvement. The scale consists of 4 components of nail matrix disease and 4 components of nail bed disease with scores from 0 to 8, with a lower scores representing milder disease. The NAPSI was assessed in PHOENIX 1.
The Hospital Anxiety and Depression Scale (HADS), a self-rating tool developed to evaluate psychological measures in patients with physical ailments. It consists of 2 subscales, one measuring anxiety (A-scale) and one measuring Depression (D-scale), which are scored separately. Lower HADS scores correspond to lesser psychological impairment. The HADS was assessed in PHOENIX 2.
The Work Limitations Questionnaire (WLQ), a 25-item, self-administered questionnaire that was used to measure the impact of chronic health conditions on job performance and work productivity among employed populations. The WLQ assesses four aspects of work and productivity: Physical Demands, Time Management, Mental-Interpersonal Demand, and Output Demand. The four subscales range from 0-100 with the lower score indicating fewer work limitations. The WLQ was assessed in PHOENIX 2.
The Itch Visual Analog Scale, used to assess the severity of itch at the time of the assessment. Itch is assessed using a 10 cm horizontal line, or a Visual Analog Scale (VAS), representing the range of itch severity, from 0 (no itch at all) to 10 (severe itch). The Itch VAS was assessed in PHOENIX 1.
PHOENIX 1: PHOENIX 1 evaluated the safety and efficacy of STELARA versus placebo in 766 patients with plaque psoriasis and the efficacy of every 12 week dosing for patients who were PASI 75 responders.
Patients randomized to STELARA received 45 mg or 90 mg doses at Weeks 0 and 4 followed by the same doses every 12 weeks. Patients randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA (either 45 mg or 90 mg) at Weeks 12 and 16 followed by the same dose every 12 weeks.
Maintenance Dosing (every 12 weeks): To evaluate the therapeutic benefit of maintenance dosing with STELARA, patients originally randomized to STELARA who were PASI 75 responders at both Weeks 28 and 40 were re-randomized to either maintenance dosing of STELARA every 12 weeks or to placebo (ie, withdrawal of therapy). Patients who were re-randomized to placebo at Week 40 reinitiated STELARA at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at Week 40.
Dose Adjustment (every 8 weeks): At Week 28, patients who were nonresponders discontinued treatment and patients who were partial responders were adjusted to every-8-week dosing.
PASI 75 responders at week 28 who became partial responders or nonresponders at Week 40 were adjusted to every-8-week dosing.
All patients were followed for up to 76 weeks following first administration of study treatment.
PHOENIX 2: PHOENIX 2 evaluated the safety and efficacy of STELARA versus placebo in 1230 patients with plaque psoriasis. Patients randomized to STELARA received 45 mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at Week 16. Patients randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA (either 45 mg or 90 mg) at Weeks 12 and 16 followed by the same dose every 12 weeks.
Dose Adjustment (every 8 weeks): At Week 28, patients who were nonresponders discontinued treatment and patients who were partial responders were re-randomized to continue every-12-week dosing or switch to every-8-week dosing.
PASI 75 responders at week 28 who became partial responders or nonresponders at Week 40 were adjusted to every-8-week dosing.
All patients were followed for up to 52 weeks following first administration of study agent.
Baseline Disease Characteristics: PHOENIX 1 and 2: Baseline disease characteristics across PHOENIX 1 and 2 were similar (Table 1). (See Table 1.)

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Efficacy at the Primary Endpoint, PHOENIX 1 and 2: In both the PHOENIX 1 and PHOENIX 2 studies, a significantly greater proportion of patients randomized to treatment with STELARA were PASI 75 responders compared with placebo at Week 12 (Table 2). In the PHOENIX 1 study, 67% and 66% of patients receiving STELARA 45 mg and 90 mg, respectively, achieved a PASI 75 response at Week 12 compared with 3% of patients receiving placebo. In the PHOENIX 2 study, 67% and 76% of patients receiving STELARA 45 mg and 90 mg respectively achieved a PASI 75 response at Week 12 compared with 4% of patients receiving placebo.
All 3 components of the PASI (plaque thickness/induration, erythema, and scaling) contributed comparably to the improvement in PASI.
The efficacy of STELARA was significantly superior (p<0.001) to placebo across all subgroups defined by baseline demographics, clinical disease characteristics (including patients with a history of psoriatic arthritis) and prior medication usage. While pharmacokinetic modeling suggested a trend towards higher CL/F in patients with diabetes, a consistent effect on efficacy was not observed.
Other Efficacy Measures at Week 12: In both PHOENIX 1 and PHOENIX 2, compared with placebo, significantly greater proportions of patients randomized to 45 mg or 90 mg STELARA achieved a cleared or minimal PGA score, and significantly greater proportions of patients randomized to 45 mg or 90 mg STELARA were PASI 90 and PASI 50 responders at Week 12 (Table 2). In the PHOENIX 1 study, 59% and 61% of the patients treated with 45 mg and 90 mg STELARA, respectively, achieved PGA scores of cleared or minimal compared with 4% of placebo-treated patients. In PHOENIX 2, 68% and 73% of patients receiving 45 mg or 90 mg STELARA, respectively, had cleared or minimal PGA scores compared with 4% of the placebo patients. In PHOENIX 1, PASI 90 was achieved by 42% and 37% of the patients treated with 45 mg and 90 mg STELARA, respectively, compared with 2% of placebo-treated patients. In PHOENIX 2, the percentage of patients achieving PASI 90 was 42% in the 45 mg STELARA group, 51% in the 90 mg STELARA group and 1% in the placebo group. The percentage of patients achieving PASI 50 in PHOENIX 1 was 84% and 86% in the 45 mg and 90 mg STELARA groups, respectively, compared with 10% in the placebo group. Similarly, 84% of patients treated with 45 mg STELARA, 89% of patients treated with 90 mg STELARA and 10% of patients treated with placebo reached PASI 50 in PHOENIX 2 (Table 2). (See Table 2.)

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Response Over Time: In PHOENIX 1, significantly greater proportions of STELARA-treated patients had PASI 50 responses (9% and 10% for the 45 mg and 90 mg groups, respectively) compared with placebo (2%) by Week 2 (p< 0.001). Significantly greater proportions of patients treated with STELARA achieved PASI 75 responses (9% and 12% for the 45 mg and 90 mg STELARA groups, respectively) compared with placebo (0.4%) by Week 4 (p< 0.001). Maximum response was generally achieved by Week 24 in the 45 mg and 90 mg-STELARA treatment groups, and response rates were generally sustained through Week 36 (Figure 1). In PHOENIX 1, PASI 75 rates at Week 24 were 76% for the 45 mg group, and 85% for the 90 mg group. Higher response rates were observed in patients receiving STELARA 90 mg than in those receiving STELARA 45 mg by Week 16 and these higher response rates were sustained through Week 36 (Figure 1). Similar results were observed in the PHOENIX 2 study through Week 28. (See Figure 1.)
In pre-specified analyses of efficacy by body weight in PHOENIX 1 and PHOENIX 2, no consistent pattern of dose response was seen in patients ≤ 100 kg. In patients who weighed >100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 2).

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Therapeutic Benefit of Long-term Continuous Use: At Week 40 in PHOENIX 1, 162 patients were randomized to receive STELARA (maintenance) and 160 were randomized to receive placebo (treatment withdrawal). Maintenance of PASI 75 was significantly superior with continuous treatment compared with treatment withdrawal (p<0.001). Similar results were seen with each dose of STELARA (Figure 2). At 1 year (Week 52), 89% of patients re-randomized to maintenance treatment were PASI 75 responders compared with 63% of patients re-randomized to placebo (treatment withdrawal) (p<0.001). At 18 months (Week 76), 84% of patients re-randomized to maintenance treatment were PASI 75 responders compared with 19% of patients re-randomized to placebo (treatment withdrawal). At 3 years (Week 148), 82% of patients re-randomized to maintenance treatment were PASI 75 responders. At 5 years (Week 244), 80% of patients re-randomized to maintenance treatment were PASI 75 responders. (See Figure 2.)

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Efficacy of Retreatment: In PHOENIX 1, after withdrawal from therapy, patients reinitiated their original STELARA treatment regimen after loss of ≥ 50% of PASI improvement. Retreatment with STELARA resulted in 71% of evaluated patients regaining PASI 75 response within 8 weeks after reinitiating therapy and 85% of evaluated patients regaining PASI 75 response within 12 weeks after reinitiating therapy.
Dosing Interval Adjustment: In PHOENIX 1, Week 28 and Week 40 Partial Responders and Week 40 Nonresponders were adjusted from every 12 week to every 8 week dosing. Approximately 40%-50% of Week 28 Partial Responders to every 12 week dosing achieved PASI 75 response after adjustment to every 8 week dosing and this proportion of PASI 75 responders was maintained through Week 52. A similar proportion of patients who were PASI 75 responders at Week 28 and subsequently became partial responders or nonresponders at Week 40 achieved PASI 75 response following a dosing interval adjustment to every 8 weeks.
Quality of Life: In PHOENIX 1 and 2, the mean baseline DLQI scores ranged from 11 to 12. In PHOENIX 1, the mean baseline SF-36 Physical Component ranged from 47-49 and the mean baseline SF-36 Mental Component was approximately 50. Quality of life improved significantly in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo as evaluated by DLQI in PHOENIX 1 and 2 and SF-36 in PHOENIX 1 (Tables 3 and 4). Quality of life improvements were significant as early as 2 weeks in patients treated with STELARA and these improvements were maintained over time with continued dosing. (See Tables 3 and 4.)

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Nail Psoriasis: In PHOENIX 1, the median baseline NAPSI score for nail psoriasis was 4.0 and the median number of fingernails involved with psoriasis was 8.0. Nail psoriasis improved significantly in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo when measured by the NAPSI score (Tables 5 and 6). Nail psoriasis continued to improve over time through Week 52 in patients treated with STELARA. (See Tables 5 and 6.)

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Hospital Anxiety and Depression Scale: At baseline in PHOENIX 2, the mean HADS anxiety and depression scores were 6.9 and 5.1, respectively. Both anxiety and depression scores were reduced significantly in patients randomized to 45 mg or 90 mg STELARA at Week 12 compared with patients randomized to placebo (Table 7). HADS improvements were maintained through Week 24 (Table 8). (See Tables 7 and 8.)

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Work Limitations Questionnaire: The Work Limitations Questionnaire obtained at baseline showed impaired work productivity among patients with psoriasis evaluated in PHOENIX 2 for the Physical Demands, Time Management, Mental-Interpersonal and Output Demands component scores. Work productivity improved significantly more in patients randomized to STELARA at Week 12 compared with patients randomized to placebo as measured by the four WLQ subscales (Physical Demands, Time Management, Mental-Interpersonal, and Output Demands; Table 9). (See Table 9.)

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Itch VAS: Itch associated with psoriasis improved significantly (p<0.001) at Week 12 in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo as evaluated by Itch VAS in PHOENIX 1 (Table 10). (See Table 10.)

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ACCEPT: In addition, a multicenter, randomized, single-blind, active-controlled study (ACCEPT) compared the safety and efficacy of ustekinumab and etanercept in patients 18 years of age and older with chronic (>6 months) plaque psoriasis who had a minimum BSA involvement of 10%, PASI score ≥12, Physician Global Assessment (PGA) score ≥ 3, who were candidates for phototherapy or systemic therapy, and who had had an inadequate response to, intolerance to, or contraindication to cyclosporine, MTX, or PUVA therapy. A total of 903 patients were enrolled in the study.
The ACCEPT trial compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept in patients with moderate to severe psoriasis. The active-controlled portion of the study was from Week 0 to Week 12, during which patients were randomized 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. This trial was powered to test the superiority of each ustekinumab dose to etanercept on the primary endpoint of the proportion of patients who achieved a PASI 75 at week 12.
Significantly greater proportions of subjects treated with ustekinumab 45 mg (67%; p = 0.012) or 90 mg (74%; p < 0.001) were PASI 75 responders at Week 12 compared with the etanercept group (57%). PASI 90 response was observed in 36% and 45% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared with 23% of patients receiving etanercept (p<0.001 for each comparison versus etanercept). PASI 100 response was observed in 12% and 21% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared to 6% of patients receiving etanercept (Table 11). In addition, a greater proportion of patients in the ustekinumab 45 mg and 90 mg treatment groups achieved a PGA score of "cleared" or "minimal" (65% and 71%, respectively) compared with patients in the etanercept treatment group (49%) (p<0.001 for each comparison versus etanercept).
In pre-specified analyses of efficacy by body weight in ACCEPT, minimal dose response to ustekinumab was evident in patients ≤ 100 kg. In patients who weighed >100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 11). (See Table 11.)

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Clinical Efficacy - Psoriatic arthritis (PsA): The safety and efficacy of STELARA was assessed in two multicenter, randomized, double-blind, placebo-controlled, Phase 3 studies, PSUMMIT I and PSUMMIT II, in patients with active psoriatic arthritis. Patients were randomized to receive treatment with either STELARA 45 mg, 90 mg, or placebo subcutaneous injections at Weeks 0 and 4 followed by every 12 week (q12w) dosing. The primary endpoint in these studies was the reduction in the signs and symptoms of psoriatic arthritis (PsA) as measured by the percentage of ACR 20 responders at Week 24. Secondary endpoints included change from baseline in Disability Index of the Health Assessment Questionnaire (HAQ-DI), PASI 75, ACR 50, ACR 70 and change from baseline in total radiographic scores of the hands and feet, at Week 24. Efficacy data were collected and analyzed through Week 52 for both studies and through Week 100 for PSUMMIT I. These studies included 927 (PSUMMIT I, n=615; PSUMMIT II, n=312) adult patients (≥18 years) who had active psoriatic arthritis (≥5 swollen joints and ≥5 tender joints, despite disease modifying antirheumatic (DMARD) and/or nonsteroidal anti-inflammatory (NSAID) therapy). Methotrexate use was allowed during the studies but was not mandatory. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). In PSUMMIT I and PSUMMIT II, 80% and 86% of the patients, respectively, had been previously treated with DMARDs.
In PSUMMIT I patients, who had been previously treated with anti-TNFα therapy, prior to the first study dose, were excluded. In PSUMMIT II, the majority of patients (58%, n=180) had been previously treated with one or more anti-TNFα agent(s) for at least 8 weeks (14 weeks with infliximab) or had discontinued anti-TNFα for intolerance at any time. Among the patients who had been previously treated with an anti-TNFα agent, over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance.
Patients with each subtype of psoriatic arthritis were enrolled, including polyarticular arthritis with no evidence of rheumatoid nodules (39%, N=362), spondylitis with peripheral arthritis (28%, N=255), asymmetric peripheral arthritis (21%, N=193), distal interphalangeal (DIP) arthritis (12%, N=112) and arthritis mutilans (0.5%, N=5). Over 70% and 40% of the patients in both studies had enthesitis and dactylitis at baseline, respectively.
In both studies, a significantly greater proportion of patients achieved ACR 20 and ACR 50 responses at Week 24 in the STELARA 45 mg and 90 mg groups compared to placebo (see Table 12). In PSUMMIT I, a significantly greater proportion of patients and in PSUMMIT II a numerically greater proportion of patients (p=NS) achieved ACR 70 responses in the STELARA 45 mg and 90 mg groups compared to placebo (see Table 12).
In both studies, the proportion of patients achieving a modified PsA response criteria (PsARC) or a Disease Activity Index Score 28 using C-reactive protein (DAS28-CRP) response was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT I the proportion of patients achieving DAS28-CRP remission was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, the proportion of patients who achieved DAS28-CRP remission was significantly greater in the STELARA 90 mg group compared to placebo (see Table 12). DAS28-CRP and PsARC responses were maintained through Week 52 in both studies and through Week 100 in PSUMMIT I. (See Table 12.)

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The time course for ACR 20 response rates during the first 24 weeks in both studies for patients receiving STELARA or placebo are summarized in Figure 3. ACR 20 responses showed improvement at the first assessment (Week 4). ACR 20, 50 and 70 responses continued to improve or were maintained through Week 52 (see Table 13). In PSUMMIT I, ACR responses were maintained through Week 100. (See Figure 3 and Table 13.)

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In PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 153 continued the same dose and were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 99 (64.7%), 57 (37.3%) and 34 (22.2%) subjects respectively. Of 204 subjects randomized to STELARA 90 mg, 185 were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 120 (64.9%), 74 (40%) and 41 (22.2%) subjects respectively.
In PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 138 continued the same dose and were available for evaluation at Week 100. Among those, ACR 20, 50 and 70 responses were achieved by 89 (64.5%), 63 (45.7%) and 41 (29.7%) subjects respectively. Of 204 subjects randomized to STELARA 90 mg, 166 were available for evaluation at Week 100. Among those, ACR 20, 50 and 70 responses were achieved by 116 (69.9%), 84 (50.6%) and 41 (24.7%) subjects respectively.
In PSUMMIT II, of 103 subjects randomized to STELARA 45 mg, 68 continued the same dose and were available for evaluation at Week 52. Among those, ACR 20, 50, and 70 responses were achieved by 41 (60.3%), 23 (33.8%) and 11 (16.2%) subjects respectively. Of 105 subjects randomized to STELARA 90 mg, 83 were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 49 (59%), 26 (31.3%) and 17 (20.5%) subjects respectively.
Additionally, within each weight group (≤100 kg and >100 kg), ACR 20, ACR 50 and ACR 70 responses were consistently higher in the STELARA 45 and 90 mg groups than in the placebo group (see Table 14).

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STELARA treatment resulted in significantly greater improvement compared with placebo for each ACR component (see Table 15).

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Methotrexate Use: The proportion of patients achieving ACR responses were consistently greater in patients treated with STELARA than those treated with placebo regardless of concomitant MTX use (see Table 16). Responses observed in the STELARA groups were similar in patients receiving or not receiving concomitant MTX. ACR responses were maintained through Week 52 in PSUMMIT I and II and through Week 100 in PSUMMIT I. (See Table 16.)

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Prior Anti-TNFα therapy: PSUMMIT II evaluated 180 patients who were previously treated with one or more anti-TNFα agents for at least 8 weeks (14 weeks with infliximab), or had documented intolerance of anti-TNFα therapy at any time in the past.
Among patients previously treated with anti-TNFα agents, a significantly greater proportion of STELARA-treated patients achieved an ACR 20 response at Week 24 compared to placebo (see Table 17). ACR 20, 50 and 70 responses were generally maintained through Week 52. (See Table 17.)

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Enthesitis and Dactylitis: For patients with enthesitis and/or dactylitis at baseline, in PSUMMIT I, a significant improvement in enthesitis and dactylitis score was observed in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, a significant improvement in enthesitis score and numerical improvement in dactylitis score were observed in the 90 mg group (p=NS) compared with the placebo group (see Table 18). In both studies, improvement in enthesitis score and dactylitis score were maintained at Week 52. In PSUMMIT I, the improvement in enthesitis score and dactylitis score was maintained through Week 100. (See Table 18.)

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A higher proportion of patients treated with STELARA, that have spondylitis with peripheral arthritis as their primary presentation, demonstrated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 and 70 percent improvement in BASDAI scores at Week 24 compared with placebo (see Table 19).

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PASI Response: In PSUMMIT I and PSUMMIT II, the proportion of patients with psoriasis involvement of ≥3% BSA at baseline who achieved a ≥75% improvement in the PASI assessment at Week 24 was significantly greater in the STELARA 45 mg and 90 mg groups compared with the placebo group (see Table 20). In both studies the proportion of patients achieving the PASI 75 response was maintained through Week 52 (PSUMMIT I, STELARA 45 mg-70.1% and 90 mg-68.1%; PSUMMIT II, STELARA 45 mg-56.5% and 90 mg-64.4%). In PSUMMIT I, the PASI 75 response was maintained through Week 100.
The proportion of patients who achieved both a PASI 75 response and an ACR 20 response was evaluated for those patients with ≥3% BSA psoriasis skin involvement at baseline. A significantly higher proportion of patients achieved the combined response in the STELARA 45 mg and 90 mg groups compared with the placebo group at Week 24 (see Table 20). In both studies the proportion of patients achieving both a PASI 75 response and an ACR20 response was maintained through Week 52 (PSUMMIT I, STELARA 45 mg-44.8% and 90 mg-44.3%; PSUMMIT II, STELARA 45 mg-36.8% and 90 mg-43.1%). In PSUMMIT I, the proportion of patients achieving the combined PASI 75 and ACR20 response was maintained through Week 100. (See Table 20.)

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Additionally, within each weight group (≤100 kg and >100 kg), PASI 75, 90 and 100 responses were consistently higher in the STELARA 45 and 90 mg groups than in the placebo group (see Table 21).

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Methotrexate Use: In both studies, the proportion of patients who achieved a PASI 75 response at Week 24 was consistently higher in STELARA 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use. PASI 75 responses were maintained through Week 52 in both PSUMMIT I and II. In PSUMMIT I, PASI 75 response was maintained at Week 100.
Prior Anti-TNFα Therapy: In PSUMMIT II, the proportion of patients who achieved a PASI 75 response at Week 24 was significantly greater in STELARA 45 mg and 90 mg groups compared with placebo in patients previously treated with an anti-TNFα agent.
Radiographic Response: Structural damage in both hands and feet was assessed by readers unaware of treatment group and order of visits, and expressed as change in total van der Heijde-Sharp score (vdH-S score), modified for PsA by addition of hand distal interphalangeal (DIP) joints, compared to baseline. A pre-specified integrated analysis combining data from 927 subjects in both PSUMMIT I & II was performed. At Week 24, based on this integrated analysis, the STELARA 45 mg or 90 mg treatment significantly inhibited progression of structural damage, when compared to placebo (see Table 22). Beyond Week 24, STELARA treatment continued to inhibit the progression of structural damage through Week 52. The mean change from Week 24 to 52 in total modified vdH-S score (0.18 and 0.26 in the STELARA 45 mg and 90 mg groups respectively) was less than the mean change from Week 0 to 24 (see Table 22). In PSUMMIT I, the effect of STELARA on inhibition of structural damage progression was maintained through Week 100. Among subjects treated with STELARA 45 mg and 90 mg with no radiographic progression from baseline to Week 52 (n=103, and 113, respectively), 81.5% and 88.8% continued to show no radiographic progression at Week 100. (See Table 22.)

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At Week 24, patients treated with STELARA demonstrated less progression of structural damage compared to placebo, irrespective of concomitant MTX use.
The effect of STELARA on progression of structural damage in patients with prior anti-TNFα experience has not been established although it has not been adequately studied.
Physical Function and Health-Related Quality of Life: In PSUMMIT I and PSUMMIT II, physical function and health-related quality of life were assessed using the Disability Index of the Health Assessment Questionnaire (HAQ-DI), Dermatology Life Quality Index (DLQI) and the SF-36 health survey.
Patients treated with STELARA showed significant improvement in physical function as assessed by the HAQ-DI at Week 24. The proportion of patients achieving a clinically meaningful ≥0.3 improvement in HAQ-DI score from baseline at Week 24 was also significantly greater in the STELARA groups when compared with placebo (see Table 23). Improvement was observed at the first assessment (Week 4), reached maximum at Week 12 and was maintained through Week 24. Improvement in HAQ-DI score from baseline was maintained in both studies at Week 52 and through Week 100 in PSUMMIT I.
In both studies, the improvement in HAQ-DI at Week 24 was consistently greater in the STELARA 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use.
In PSUMMIT II, the improvement in HAQ-DI at Week 24 was significantly greater in the STELARA 45 mg and 90 mg groups compared with placebo in patients previously treated with anti-TNFα agents. (See Table 23.)

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In PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 153 continued the same dose and were available for evaluation at Week 52. Among those, the HAQ-DI response was achieved by 83 (54.2%) subjects. Of 204 subjects randomized to STELARA 90 mg, 185 were available for evaluation at Week 52. Among those, HAQ-DI response was achieved by 102 (55.1%) subjects.
In PSUMMIT II, of 103 subjects randomized to STELARA 45 mg, 68 continued the same dose and were available for evaluation at Week 52. Among those, the HAQ-DI response was achieved by 29 (42.6%) subjects. Of 105 subjects randomized to STELARA 90 mg, 83 were available for evaluation at Week 52. Among those, HAQ-DI response was achieved by 44 (53%) subjects.
The DLQI was assessed by comparing the change in DLQI scores from baseline for those patients with ≥3% BSA at baseline. In both studies at Week 24, there was a significant improvement from baseline in DLQI scores in both the STELARA 45 mg and 90 mg groups as compared with placebo (see Table 24) and the improvement was maintained at Week 52. In PSUMMIT I, the improvement from baseline in DLQI scores was maintained through Week 100.
In both PSUMMIT I and PSUMMIT II, at Week 24, the change from baseline in the SF-36 physical component summary (PCS) scores was significantly greater in the STELARA 45 mg and 90 mg groups compared with the placebo group. In both studies, the change from baseline in the SF-36 mental component summary (MCS) scores at Week 24 was greater in both STELARA groups compared with the placebo group (p<0.001 for PSUMMIT I - 90 mg group, p=NS for other groups) (see Table 24). The change from baseline in the SF-36 PCS and MCS scores was maintained at Week 52 in both studies, and at Week 100 in PSUMMIT I.
In PSUMMIT II, a significant change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores was observed at Week 24 in the STELARA 45 mg and 90 mg groups compared with the placebo group (median improvement, all 3.0 vs 0.0; p<0.007). Similarly, the percentage of patients with clinically significant improvement in fatigue from baseline (4 points in FACIT-F) was significantly greater in the STELARA 45 mg (49% [p<0.001]) and 90 mg groups (49% [p<0.001]) compared with the placebo group (25.8%). The change from baseline in the FACIT-F scores was maintained at Week 52. (See Table 24.)

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Health Economics: Health economics data on time lost from work, employability, and daily productivity at work, school, or home were collected through questionnaires at baseline and Week 24. To assess productivity, patients were asked to indicate how much their disease affected their productivity at work, school or at home in the past 4 weeks, using a 10 cm Visual Analogue Scale (VAS) (not at all affected [0] to affected very much [10]).
The improvement in self-reported productivity was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo at Week 24. The improvement in self-reported productivity was maintained in both studies at Week 52 and through Week 100 in PSUMMIT I.
Clinical Efficacy - Crohn's Disease: The safety and efficacy of STELARA were evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). The clinical development program consisted of two 8-week IV induction studies (UNITI-1 and UNITI-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.
Induction of Clinical Response and Remission: UNITI-1 and UNITI-2 studies included 1409 (UNITI-1, n=769; UNITI-2, n=640) patients. In both studies, patients were permitted to concomitantly receive oral 5-ASA compounds, immunomodulators, corticosteroids, and/or antibiotics. Patients were randomized to receive a single IV administration of either 130 mg STELARA, or approximately 6 mg/kg STELARA designed as a tiered dose based on patient body weight (Table 27) or placebo at Week 0. The primary endpoint was clinical response (defined as a reduction in CDAI score of ≥100 points or CDAI score <150) at Week 6. Secondary endpoints included clinical remission at Week 8, clinical response at Week 8, 70-point response at Week 3, and 70-point response at Week 6. Efficacy data were collected and analyzed through Week 8 for both studies.
In UNITI-1, patients had failed or were intolerant to prior anti-TNFα therapy. At baseline, approximately 46% (n=340) patients were receiving corticosteroids (including budesonide) and 31.4% of patients were receiving immunomodulators. Approximately 48% had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies (40.8% and 10.4%, respectively). In this study, 29.1% patients had an inadequate initial response (primary non responders), 69.4% responded but subsequently 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 (corticosteroids or immunomodulators) and were either anti-TNFα naive (68.6%) or had previously received but not failed anti-TNFα therapy (31.4%). At baseline, approximately 40% patients were receiving corticosteroids (including budesonide) and 35% patients were receiving immunomodulators.
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 IV induction dose. In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response and remission in the group treated with STELARA, compared to placebo (Table 25, Figure 4). Clinical response and remission were significant as early as Week 3 in STELARA treated patients and continued to improve through Week 8 (Figure 4). (See Table 25 and Figure 4.)

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Maintenance of Response and Remission: The maintenance study (IM-UNITI) evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 of induction with STELARA in UNITI-1 or UNITI-2. Of those, approximately 60% of the patients entered the maintenance study in remission. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA every 8 weeks, 90 mg STELARA every 12 weeks or placebo for 44 weeks.
Concomitant doses of oral 5-ASA compounds, immunomodulators corticosteroids and antibiotics were permitted. Corticosteroids were tapered at the start of the maintenance trial. The primary endpoint was clinical remission (CDAI < 150) at Week 44. Secondary endpoints assessed at Week 44 included clinical response, clinical remission among STELARA treated patients in clinical remission after induction, corticosteroid-free remission, and clinical remission in the subset of patients who were refractory or intolerant to anti-TNFα treatment.
Significantly higher proportions of patients maintained clinical remission and response in the STELARA treated groups as compared to placebo at Week 44 (Table 26, Figure 5). A higher proportion of STELARA treated patients compared to placebo achieved sustained clinical remission (clinical remission at Week 36, 40 and 44). (See Table 26 and Figure 5.)

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Delayed Response: Patients who were not in clinical response to STELARA induction received a 90 mg subcutaneous injection of STELARA upon entry into the maintenance study. 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 achieved levels of response (68.1%) and remission (50.2%) similar to the patients who initially responded to STELARA induction.
Dosing in Patients with a Lower Inflammatory Burden: In patients with a lower inflammatory burden as reflected by CRP ≤ 10 mg/L at initiation of induction or initiation of maintenance therapy, the efficacy of the every 12 week dosing regimen was similar to that of the every 8 week dosing regimen.
Dosing Frequency Adjustment: In IM-UNITI, patients who did not maintain response to STELARA when treated every 12 weeks were allowed to increase the frequency of dosing and receive STELARA 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 dosing frequency adjustment.
Resumption of Treatment: Patients that responded to STELARA induction and who were randomized to the placebo group at the start of the maintenance study received 90 mg STELARA subcutaneously every 8 weeks at time of loss of response. Of these patients, 70.6% achieved clinical response and 39.2% achieved clinical remission 16 weeks after receiving the first subcutaneous dose of STELARA.
Long-Term Maintenance: In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension, clinical remission and response were generally maintained through week 92. Results were consistent between patients who failed TNF-therapies versus those who did not.
No new safety concerns were identified in this study extension with up to 2 years of treatment in patients with Crohn's Disease.
Corticosteroid Use in Maintenance: In patients that were in clinical response to STELARA induction therapy, a greater proportion of patients in the STELARA treated group were in remission and corticosteroid-free compared to the placebo group after 44 weeks of maintenance treatment (Table 26). In addition, a higher proportion of patients were in clinical response and not receiving corticosteroids in the STELARA treated group compared to placebo.
Endoscopic Healing of the Mucosa: Endoscopic healing of the mucosa was evaluated in 252 patients with baseline endoscopic disease activity in a substudy. At Week 8, after a single IV induction dose, reduction in mucosal inflammation, as measured by the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), was greater in patients treated with STELARA (n=83) compared with patients treated with placebo (n=97) (-3.0 vs -0.7, p=0.009). Similar reductions in histologic inflammation were also observed.
Reduction in endoscopic and histologic inflammation was observed in patients treated with STELARA in maintenance. However, due to the small number of patients, the efficacy of STELARA in the maintenance of endoscopic healing could not be definitively established.
Fistula Response: In patients with draining fistulas at baseline (8.8%), a numerically greater proportion of STELARA treated patients achieved a fistula response (defined as ≥ 50% reduction from baseline of the induction study in the number of draining fistulas) compared with placebo over 44 weeks (p=NS). The proportion of patients in fistula response at Week 44 was 45.5% (5/11) for placebo group, 71.4% (5/7) for STELARA 90 mg every 12 week dosing group, and 87.5% (7/8) for STELARA 90 mg every 8 week dosing group.
Health-Related Quality of Life Measures: Improvement in general and disease specific health-related quality of life was assessed using the SF-36 and Inflammatory Bowel Disease Questionnaire (IBDQ) respectively.
SF-36: A higher proportion of patients treated with STELARA showed clinically meaningful improvements in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and these improvements were significantly greater at week 8 compared with the placebo group in UNITI-1 (MCS) and UNITI-2 (PCS, MCS and all subscores). These improvements in the PCS and MCS scores were maintained in STELARA treated patients in the IM-UNITI maintenance study through Week 44.
IBDQ: At Week 8 in UNITI-1 and UNITI-2, significant improvement from baseline in the inflammatory bowel disease questionnaire (IBDQ) total score and all subscales, was observed in the patients treated with STELARA compared to placebo. In both studies, a higher proportion of patients with clinically meaningful improvement in IBDQ total scores were observed in patients treated with STELARA compared to placebo. These improvements in the IBDQ total scores were maintained in STELARA treated patients in the IM-UNITI maintenance study through Week 44.
Long-term Maintenance of Health-related Quality of Life Measures: Improvement in health related quality of life as measured by IBDQ and SF-36 was generally maintained during the extension through week 92.
Pharmacokinetics: Absorption: The median time to reach the maximum serum concentration (tmax) was 8.5 days after a single 90 mg subcutaneous administration in healthy subjects. The median tmax values of ustekinumab following a single subcutaneous administration of either 45 mg or 90 mg in patients with psoriasis were comparable to that observed in healthy subjects.
The absolute bioavailability of ustekinumab following a single subcutaneous administration was estimated to be 57.2% in patients with psoriasis. Following the recommended intravenous induction dose, median peak serum ustekinumab concentration was 126.1 mcg/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. In a population pharmacokinetic analysis of ustekinumab, the volume of distribution at steady-state was 4.62 L in patients with Crohn's disease.
Metabolism: 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 (t½) 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. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day while the half-life was approximately 19 days in patients with Crohn's disease.
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 or following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis.
Single Dose vs. Multiple Doses: Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple subcutaneous dose administrations. In patients with psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28 after initial subcutaneous doses at Weeks 0 and 4 followed by doses every 12 weeks. The median steady-state trough concentration ranged from 0.21 mcg/mL to 0.26 mcg/mL (45 mg) and from 0.47 mcg/mL to 0.49 mcg/mL (90 mg).
Following the recommended IV induction dose, median peak serum ustekinumab concentration was 126.1 mcg/mL in patients with Crohn's disease. Starting at Week 8, subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 8 or 12 weeks.
Following subcutaneous maintenance dosing of 90 mg ustekinumab every 8 weeks, median steady-state trough concentrations ranged from 1.97 mcg/mL to 2.24 mcg/mL in patients with Crohn's disease. Following subcutaneous maintenance dosing of 90 mg ustekinumab every 12 weeks, median steady state trough concentrations ranged from 0.61 mcg/mL to 0.76 mcg/mL in patients with Crohn's disease. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumab every 8 weeks were associated with higher clinical remission rates as compared to the steady state trough levels following 90 mg every 12 weeks.
Dosing Frequency Adjustment: In patients with Crohn's disease, based on observed data and population PK analyses, randomized subjects who lost response to treatment had lower serum ustekinumab concentrations over time compared with subjects who did not lose response. In Crohn’s disease, dose adjustment from 90 mg every 12 weeks to 90 mg every 8 weeks was associated with an increase in trough serum ustekinumab concentrations and an accompanying increase in efficacy.
Impact of Weight on Pharmacokinetics: Serum ustekinumab concentrations were affected by weight in patients with psoriasis and/or psoriatic arthritis. Within each dose (45 mg or 90 mg), patients of higher weight (> 100 kg) had lower median serum ustekinumab concentrations compared with those in patients of lower weight (≤ 100 kg). However, across doses, 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.
Population Pharmacokinetic Analysis: In a population pharmacokinetic analysis using data from patients with psoriasis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/d and 15.7 L, respectively, and the t½ was approximately 3 weeks in patients with psoriasis. The CL/F of ustekinumab was not impacted by sex, age, or race. The CL/F was impacted by body weight, with a trend toward higher CL/F in patients with higher body weight. The median CL/F in patients with weight > 100 kg was approximately 55% higher compared with patients with weight ≤ 100 kg. The median V/F in patients with weight > 100 kg was approximately 37% higher as compared with patients with weight ≤ 100 kg. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.
In the population pharmacokinetic analysis using data from patients with psoriasis, the effect of comorbidities (past and current history of diabetes, hypertension, and hyperlipidemia) on pharmacokinetics of ustekinumab was evaluated. The pharmacokinetics of ustekinumab were impacted by the comorbidity of diabetes, with a trend towards higher CL/F in patients with diabetes. The mean CL/F in patients with diabetes was approximately 29% higher compared with patients without diabetes.
Population pharmacokinetic analysis showed that there was a trend towards a higher clearance of ustekinumab in patients with positive immune response.
No specific drug-drug interaction studies have been conducted in healthy subjects or patients with psoriasis, psoriatic arthritis or Crohn's disease.
In the population pharmacokinetic analyses, the effect of the most frequently used concomitant medications in patients with psoriasis (including paracetamol/acetaminophen, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine, hydrochlorothiazide, and influenza vaccine) on pharmacokinetics of ustekinumab was explored and none of the concomitant medications exerted significant impact. The pharmacokinetics of ustekinumab was not impacted by the prior use of MTX, cyclosporine, or other biological therapeutics for the treatment of psoriasis. The pharmacokinetics of ustekinumab was not impacted by concomitant use of NSAIDs or prior exposure to anti-TNFα agents in patients with psoriatic arthritis; or by the use of MTX, oral corticosteroids, 6-MP, AZA in patients with psoriatic arthritis or Crohn's disease.
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 Interactions).
Special Populations: Pediatrics: The pharmacokinetics of ustekinumab in pediatric patients less than 18 years has not been established.
Elderly (65 years of age and older): No specific studies have been conducted in elderly patients. The population pharmacokinetic analysis indicated there were no apparent changes in CL/F and V/F estimates in patients ≥ 65 years.
Renal impairment: No pharmacokinetic data are available in patients with renal insufficiency.
Hepatic impairment: No pharmacokinetic data are available in patients with impaired hepatic function.
Other populations: The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asian patients with psoriasis.
The pharmacokinetics of ustekinumab were not impacted by the use of tobacco or alcohol.
Toxicology: Non-Clinical Information: In repeated-dose toxicity studies in juvenile cynomolgus monkeys, ustekinumab was well-tolerated following IV doses up to 45 mg/kg/week for up to 1 month and following twice-weekly SC doses up to 45 mg/kg for 6 months. There were no ustekinumab-related findings in the immunotoxicity and cardiovascular safety pharmacology evaluations. In histopathology evaluations there were no preneoplastic changes observed.
There were no adverse effects in monkeys at exposures that were 179-fold higher than the peak serum concentration in humans following 90 mg weekly subcutaneous injection and 29-fold higher than the peak serum concentration in humans following 6 mg/kg IV administration.
Carcinogenicity and Mutagenicity: 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.
Reproductive Toxicology: Three developmental toxicity studies were conducted in cynomolgus monkeys. No ustekinumab-related maternal toxicity, abortions, still-births, embryotoxicity, developmental delays, malformations or birth defects were observed at doses up to 45 mg/kg following weekly or twice weekly administration of ustekinumab via the IV or SC routes, respectively. In neonates born from pregnant monkeys treated with ustekinumab no adverse effects on growth or functional development were observed and no deficits were observed in immunotoxicity evaluations. In a male fertility study in cynomolgus monkeys no ustekinumab-related effects on mating behavior, sperm parameters, or serum concentrations of male hormones were observed following twice weekly subcutaneous administration of ustekinumab at doses up to 45 mg/kg.
A female fertility toxicity study was conducted in mice using an analogous antibody that binds to and inhibits IL-12 and IL-23 activity in mice. Twice weekly subcutaneous administration of the anti-mouse IL-12/23 antibody was well tolerated at doses up to 50 mg/kg and no adverse effects on female fertility parameters were observed.
Indications/Uses
Plaque Psoriasis (via subcutaneous administration only): STELARA 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 Pharmacology: Pharmacodynamics under Actions).
Psoriatic Arthritis (PsA) (via subcutaneous administration only): 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 Pharmacology: Pharmacodynamics under Actions).
Crohn's Disease (via intravenous administration for induction dosing, and via subcutaneous administration for maintenance dosing): STELARA 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 (see Pharmacology: Pharmacodynamics under Actions).
Dosage/Direction for Use
STELARA solution for subcutaneous injection (pre-filled syringe) is intended for use under the guidance and supervision of physicians experienced in the diagnosis and treatment of conditions for which STELARA is indicated.
STELARA concentrate for solution for intravenous infusion (single-use vial) is intended for use under the guidance and supervision of physicians experienced in the diagnosis and treatment of Crohn's disease. STELARA concentrate for solution for infusion should only be used for the intravenous induction dose.
Posology: Plaque Psoriasis: 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.
Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeks of treatment.
Patients with body weight > 100 kg: For patients with a body weight > 100 kg the initial dose is 90 mg administered subcutaneously, followed by a 90 mg dose 4 weeks later, and then every 12 weeks thereafter. In these patients, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy. (see Pharmacology: Pharmacodynamics under Actions, Table 1).
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.
Crohn's Disease: Intravenous Induction Dosing: 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 27 (see Special Precautions for Disposal and Other Handling for preparation under Cautions for Usage). (See Table 27.)

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After the initial IV induction dose, STELARA should then be administered subcutaneously.
Subcutaneous Maintenance Dosing: The first subcutaneous administration of 90 mg STELARA should take place at week 8 after the intravenous dose. After this, dosing every 12 weeks is recommended.
Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may receive a second subcutaneous dose at this time (see Pharmacology: Pharmacodynamics under Actions).
Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks (see Pharmacology: Pharmacodynamics under Actions).
Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment (see Pharmacology: Pharmacodynamics under Actions).
Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit by week 16 or 16 weeks after switching to the 8-weekly dose.
Immunomodulators and/or corticosteroids may be continued during treatment with STELARA. In patients who have responded to treatment with STELARA, corticosteroids may be reduced or discontinued in accordance with standard of care.
If therapy is interrupted, resumption of treatment with subcutaneous dosing every 8 weeks is safe and effective.
Elderly (≥ 65 years): No dose adjustment is needed for elderly patients (see Precautions).
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 in children less than 18 years have not yet been established. No data are available.
Method of Administration: Solution for Injection for Subcutaneous Administration (Pre-filled Syringe): STELARA 45 mg and 90 mg pre-filled syringes are for subcutaneous injection only. If possible, areas of the skin that show psoriasis should be avoided as injection sites.
After proper training in subcutaneous injection technique, patients or their caregivers may inject STELARA if a physician determines that it is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients or their caregivers should be instructed to inject the prescribed amount of 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 Special Precautions for Disposal and Other Handling under Cautions for Usage.
Concentrate for Solution for Intravenous Infusion (Single-use Vial): 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 Special Precautions for Disposal and Other Handling under Cautions for Usage.
Contraindications
Severe hypersensitivity to ustekinumab or to any of the excipients (see Precautions).
Special Precautions
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 have been observed in patients receiving STELARA.
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. 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 (see Adverse Reactions).
Malignancies: STELARA is a selective immunosuppressant. Immunosuppressive agents have the potential to increase the risk of malignancy. Some patients who received STELARA in clinical studies developed cutaneous and noncutaneous malignancies (see Adverse Reactions).
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 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 Adverse Reactions).
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 Adverse Reactions).
Immunizations: It is recommended that live viral or live bacterial vaccines 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 (see Pharmacology: Pharmacodynamics under Actions).
Immunosuppression: In psoriasis studies, the safety and efficacy of STELARA in combination with immunosuppressive agents or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA. In Crohn's disease studies, concomitant use of immunomodulators (6-mercaptopurine (6-MP), azathioprine (AZA), MTX) or corticosteroids did not appear to influence the safety or efficacy of STELARA. Caution should be exercised when considering concomitant use of immunosuppressive agents and STELARA or when transitioning from other biologic agents.
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.
Serious Skin Conditions: In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see Adverse Reactions). 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.
General: The needle cover on the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
Use In Pregnancy & Lactation
Pregnancy: There is no evidence from animal studies of teratogenicity, birth defects or developmental delays at exposures up to approximately 150-fold higher compared to Cmax following 4 weekly 90mg subcutaneous injections or up to 21-fold higher compared to serum concentrations 1h following 6mg/kg IV administration (see Pharmacology: Toxicology: Non-Clinical Information under Actions). However, animal reproductive and developmental studies are not always predictive of human response.
It is not known whether STELARA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. STELARA should be given to a pregnant woman only if the benefit clearly outweighs the risk.
Breast-feeding: STELARA is excreted in the milk of lactating monkeys administered STELARA. It is not known if STELARA is absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from STELARA, a decision should be made whether to discontinue nursing or to discontinue the drug.
Fertility: The effect of STELARA on human fertility has not been evaluated. No adverse effects on female fertility parameters were identified in a female fertility toxicity study conducted in mice (see Pharmacology: Toxicology: Non-Clinical Information under Actions).
Adverse Reactions
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of ustekinumab based on the comprehensive assessment of the available adverse event information. A causal relationship with ustekinumab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Studies Experience in Adult Patients with Psoriasis, Psoriatic Arthritis and Crohn's Disease: The safety data described as follows reflect exposure to STELARA in 12 Phase 2 and Phase 3 studies in 5884 patients (4135 with psoriasis and/or psoriatic arthritis and 1749 for Crohn's disease), with duration of exposure to STELARA presented in Table 28. (See Table 28.)

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The most common adverse reactions (> 5%) in controlled periods of the clinical studies with STELARA among all indications were nasopharyngitis and headache. Most were considered to be mild and did not necessitate drug discontinuation. The overall safety profile of STELARA was similar for patients among all indications.
Table 29 provides a summary of Adverse Reactions from the clinical studies. The frequency of these adverse reactions was based on those that occurred during the initial controlled periods of the clinical studies. The adverse reactions are ranked by frequency, using the following convention: Very common (≥ 1/10); Common (frequent) (≥ 1/100, < 1/10); Uncommon (infrequent) (≥ 1/1000, < 1/100); Rare (≥ 1/10000, < 1/1000). (See Table 29.)

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Infections: In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis and Crohn's disease, the rates of infection or serious infection were similar between STELARA-treated patients and those treated with placebo. In the placebo-controlled period of the clinical studies of patients with psoriasis, patients with psoriatic arthritis and patients with Crohn's disease, the rate of infection was 1.38 per patient-year of follow-up in STELARA-treated patients, and 1.35 per patient-year of follow-up in placebo-treated patients. Serious infections occurred at a rate of 0.03 per patient-year of follow-up in STELARA-treated patients (27 serious infections in 829 patient-years of follow-up) and 0.03 per patient-year of follow-up in placebo-treated patients (11 serious infections in 385 patient-years of follow-up) (see Precautions).
In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical studies representing 10953 patient-years of exposure in 5884 patients, the median follow-up was 0.99 years; 3.2 years for psoriasis studies and 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's disease studies. The rate of infection was 0.91 per patient-year of follow-up in STELARA-treated patients. The rate of serious infections was 0.02 per patient-year of follow-up in STELARA-treated patients (178 serious infections in 10953 patient-years of follow-up) and 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.
Malignancy: In the placebo-controlled period of the psoriasis, psoriatic arthritis and Crohn's disease clinical studies, the incidence of malignancies excluding non-melanoma skin cancer was 0.12 per 100 patient-years of follow-up for STELARA-treated patients (1 patient in 829 patient-years of follow-up) compared with 0.26 per 100 patient-years of follow-up for placebo-treated patients (1 patient in 385 patient-years of follow-up). The incidence of non-melanoma skin cancer was 0.48 per 100 patient-years of follow-up for STELARA-treated patients (4 patients in 829 patient-years of follow-up) compared with 0.52 per 100 patient-years of follow-up for placebo-treated patients (2 patients in 385 patient-years of follow-up).
In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical studies representing 10935 patient-years of exposure in 5884 patients, the median follow up was 1.0 years; 3.2 years for psoriasis studies and 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's disease studies. Malignancies, excluding non-melanoma skin cancers, were reported in 58 patients in 10935 patient-years of follow up (incidence of 0.53 per 100 patient-years of follow up for STELARA-treated patients). The incidence of malignancies, reported in STELARA-treated patients was comparable to the incidence expected in the general population (standardized incidence ratio = 0.87 [95% confidence interval: 0.66, 1.14], adjusted for age, gender and race)1. The most frequently observed malignancies, other than non-melanoma skin cancer, were prostate, colorectal, melanoma, and breast. The incidence of non-melanoma skin cancer was 0.49 per 100 patient-years of follow up for STELARA-treated patients (53 patients in 10919 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 Precautions).
1Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973-2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission.
Hypersensitivity and Infusion Reactions: Subcutaneous Administration: During the controlled periods of the psoriasis and psoriatic arthritis clinical studies of STELARA, rash and urticaria have each been observed in <1% of patients.
IV Administration: In Crohn's disease intravenous induction studies, no events of anaphylaxis or other serious infusion reactions were reported. In Crohn's disease studies, 2.4% of 466 placebo treated patients and 2.6% of 470 patients treated with the recommended dose of STELARA reported adverse events occurring during or within an hour of the infusion.
Immunogenicity: In psoriasis and psoriatic arthritis clinical studies, up to 12.4% of patients treated with STELARA developed antibodies to ustekinumab. Patients positive for antibodies to ustekinumab tended to have lower efficacy, however, antibody positivity did not preclude a clinical response. The majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. In Crohn’s disease clinical studies, 2.9% of patients developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was observed.
Overdose: Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, 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.
Post Marketing Experience: The adverse reactions in Table 30 are ranked by frequency* using the following convention: Very common: ≥1/10; Common: ≥1/100 and <1/10; Uncommon: ≥1/1000 and <1/100; Rare: ≥1/10000 and <1/1000; Very rare: <1/10000, including isolated reports. (See Table 30.)

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Drug Interactions
Drug interaction studies have not been conducted in humans with STELARA (see Pharmacology: Pharmacokinetics under Actions).
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). These results do not suggest the need for dose adjustments in patients who are receiving concomitant CYP450 substrates (see Pharmacology: Pharmacokinetics under Actions).
Live vaccines should not be given concurrently with STELARA (see Precautions).
Caution For Usage
Instructions for dilution of STELARA 130 mg for IV infusion (Crohn's disease): STELARA 130 mg solution must be diluted and prepared for IV infusion by a healthcare professional using aseptic technique.
Calculate the dose and the number of STELARA vials needed based on patient’s body weight (see Table 27). Each 26 mL vial of STELARA contains 130 mg of ustekinumab.
Withdraw and then discard a volume of the 0.9% w/v sodium chloride solution from the 250 mL infusion bag equal to the volume of STELARA to be added. (discard 26 mL sodium chloride for each vial of STELARA 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% w/v sodium chloride solution may be used.
Withdraw 26 mL of STELARA 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.
Visually inspect the diluted solution before administration. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
Administer the diluted solution over a period of at least one hour. Once diluted, the infusion solution may be stored for up to four hours prior to infusion.
Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
Do not infuse STELARA concomitantly in the same intravenous line with other agents.
Each vial is for single use only and any unused medicinal product should be disposed of in accordance with local requirements.
Storage: If necessary, the diluted infusion solution may be stored for up to 4 hours at room temperature up to 25°C. Do not freeze. Discard any unused portion of the infusion solution.
Special Precautions for Disposal and Other Handling: Solution for Injection for Subcutaneous Administration (Pre-filled Syringe): The solution in the STELARA pre-filled syringe should not be shaken. The solution should be visually inspected for particulate matter or discoloration prior to subcutaneous administration. The solution is clear to slightly opalescent, colourless to light yellow and may contain a few small translucent or white particles of protein. This appearance is not unusual for proteinaceous solutions. The medicinal product should not be used if the solution is discoloured or cloudy, or if foreign particulate matter is present. Before administration, STELARA should be allowed to reach room temperature (approximately half an hour). Detailed instructions for use are provided in the package leaflet.
STELARA does not contain preservatives; therefore any unused product remaining in the syringe should not be used. STELARA is supplied as a sterile, single-use syringe. The syringe and needle must never be re-used. Any unused product or waste material should be disposed of in accordance with local requirements.
Concentrate for Solution for Intravenous Infusion (Single-use Vial): Following administration of STELARA, discard any unused portion. The syringe should be disposed of with accepted medical practices for used syringes. The syringe, needle and vial must never be re-used.
Incompatibilities: Not applicable.
Storage
Store in a refrigerator (2°C - 8°C).
Store in original carton until time of use.
Protect from light.
Do not freeze.
Do not shake.
Shelf-Life: 36 months.
ATC Classification
L04AC05 - ustekinumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.
Presentation/Packing
Soln for inj (clear to slightly opalescent, colorless to light yellow solution in pre-filled syringe) 45 mg/0.5 mL x 1's. 90 mg/mL x 1's. Infusion conc (clear, colorless to light yellow solution in vial) 130 mg/26 mL x 1's.
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