Stelara

Stelara

ustekinumab

Manufacturer:

Janssen-Cilag

Distributor:

DKSH
Full Prescribing Info
Contents
Ustekinumab.
Description
Each mL also contains the following excipients: L-histidine and L-histidine HCl 1 mg, sucrose 76 mg, polysorbate 80 0.04 mg and water for injection. Stelara does not contain preservatives.
Stelara is a single-use, sterile solution. It is clear to slightly opalescent, colorless to light yellow with a pH of approximately 6.
Ustekinumab is a fully human IgG1κ monoclonal antibody with an approximate molecular weight of 148,600 daltons. It 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.
Action
ATC Code: L04AC05.
Pharmacology: Pharmacodynamics: Mechanism of Action: Stelara is a fully human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit of the human cytokines interleukin (IL)-12 and IL-23. Stelara inhibits the bioactivity of human IL-12 and IL-23 by preventing these cytokines from binding to their IL-12Rβ1 receptor protein expressed on the surface of immune cells. Stelara cannot bind to IL-12 or IL-23 that is pre-bound to IL-12Rβ1 cell surface receptors. Thus, Stelara is not likely to contribute to complement or antibody-mediated cytotoxicity of the receptor-bearing cell.
IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells eg, macrophages and dendritic cells. IL-12 and IL-23 participate in immune function by contributing to NK cell activation and CD4+ T cell differentiation and activation. However, abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases eg, psoriasis. Stelara prevents IL-12 and IL-23 contributions to immune cell activation eg, intracellular signaling and cytokine secretion. Thus, Stelara is believed to interrupt signaling and cytokine cascades that are central to psoriasis pathology.
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.
Stelara had no apparent effect on the percentages of circulating immune cell populations including memory and naive T cell subsets or circulating cytokine levels.
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 downregulated the gene expression of inflammatory cytokines and chemokines eg, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, interferon-γ-inducible protein (IP)-10 and interleukin (IL)-8 in lesional skin biopsies. These results are consistent with the significant clinical benefit observed with Stelara treatment.
Clinical response [improvement in psoriasis area and severity index (PASI)] appeared to be related to serum ustekinumab levels. Patients with psoriasis with higher clinical responses as measured by PASI response had higher median serum concentrations of ustekinumab than those with lower clinical responses. Overall, the proportion of patients with psoriasis 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.
Clinical Efficacy: 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 2). A total of 1996 patients were enrolled in these studies. The safety and efficacy of Stelara beyond 3 years have not been established.
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 BSA involved with psoriasis and the severity of psoriatic changes within the affected regions (plaque thickness/induration, erythema and scaling). PASI numeric scores range from 0-72, 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 <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 0-30, 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 0-8, with 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 4 aspects of work and productivity: Physical demands, time management, mental-interpersonal demand and output demand. The 4 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 (VAS), used to assess the severity of itch at the time of the assessment. Itch is assessed using a 10-cm horizontal line, or 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 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 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 1st administration of study treatment.
Phoenix 2: Phoenix 2 evaluated the safety and efficacy of Stelara versus placebo in 1,230 patients with plaque psoriasis. Patients randomized to Stelara received 45 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 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 1st administration of study agent.
Baseline Disease Characteristics: Phoenix 1 and 2: Baseline disease characteristics across Phoenix 1 and 2 were similar (see Table 1).

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Efficacy at the Primary Endpoint, Phoenix 1 and 2: In both the Phoenix 1 and 2 studies, a significantly greater proportion of patients randomized to treatment with Stelara were PASI 75 responders compared with placebo at week 12 (see 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 (PsA)] 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 2, compared with placebo, significantly greater proportions of patients randomized to 45 or 90 mg Stelara achieved a cleared or minimal PGA score, and significantly greater proportions of patients randomized to 45 or 90 mg Stelara were PASI 90 and PASI 50 responders at week 12 (see Table 2). In the Phoenix 1 study, 59% and 61% of the patients treated with 45 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 or 90 mg Stelara, respectively, had cleared or minimal PGA scores compared with 5% of the placebo patients. In Phoenix 1, PASI 90 was achieved by 42% and 37% of the patients treated with 45 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 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 (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 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. 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. Similar results were observed in the Phoenix 2 study through week 28.
In prespecified analyses of efficacy by body weight in Phoenix 1 and 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 (see Table 2).
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. At 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 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).
Efficacy of Re-Treatment: In Phoenix 1, after withdrawal from therapy, patients reinitiated their original Stelara treatment regimen after loss of ≥50% of PASI improvement. Re-treatment 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 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 11-12. 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 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 (see 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.

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Nail Psoriasis: In Phoenix 1, the median baseline NAPSI score for nail psoriasis was 4 and the median number of fingernails involved with psoriasis was 8. Nail psoriasis improved significantly in patients randomized to 45 or 90 mg Stelara compared with patients randomized to placebo when measured by the NAPSI score (See Tables 5 and 6). Nail psoriasis continued to improve over time through week 52 in patients treated with Stelara.

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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 or 90 mg Stelara at week 12 compared with patients randomized to placebo (see Table 7). HADS improvements were maintained through week 24 (see Table 8).

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Work Limitations Questionnaire: The work limitations questionnaire obtained at baseline showed impaired work productivity among psoriasis patients 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 4 WLQ subscales (physical demands, time management, mental-interpersonal and output demands; 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 or 90 mg Stelara compared with patients randomized to placebo as evaluated by itch VAS in Phoenix 1 (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 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, methotrexate or psoralen plus ultraviolet A (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 moderate to severe psoriasis patients. The active-controlled portion of the study was from week 0-12, 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 and 90 mg groups, respectively, compared with 23% of patients receiving etanercept (p<0.001 for each comparison vs etanercept). PASI 100 response was observed in 12% and 21% of patients in the ustekinumab 45 and 90 mg groups, respectively, compared to 6% of patients receiving etanercept (see Table 11). In addition, a greater proportion of patients in the ustekinumab 45 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 vs 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 (see Table 11).

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Clinical Efficacy-Psoriatic Arthritis (PsA): The safety and efficacy of Stelara was assessed in 2 multicenter, randomized, double-blind, placebo-controlled, phase 3 studies, PSUMMIT I and PSUMMIT II, in patients with active PsA. Patients were randomized to receive treatment with either Stelara 45 mg, 90 mg or placebo SC injections at weeks 0 and 4, followed by every 12-week dosing. The primary endpoint in these studies was the reduction in the signs and symptoms of PsA as measured by the percentage of American College of Rheumatology (ACR) 20 responders at week 24. Secondary endpoints included change from baseline in Disability Index of 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.
The 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 not mandatory. Approximately 50% of patients continued on stable doses of methotrexate (≤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-TNF-α therapy, prior to the 1st study dose were excluded. In PSUMMIT II, the majority of patients (58%, n=180) had been previously treated with ≥1 anti-TNF-α agents(s) for at least 8 weeks (14 weeks with infliximab) or had discontinued anti-TNF-α for intolerance at any time. Among the patients who had been previously treated with an anti-TNF-α agent, over 70% had discontinued their anti-TNF-α treatment for lack of efficacy or intolerance.
Patients with each subtype of PsA 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 figure).
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).

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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 methotrexate use (see Table 13). Responses observed in the Stelara groups were similar in patients receiving or not receiving concomitant methotrexate. American College of Rheumatology (ACR) responses were maintained through week 52.

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Prior Anti-TNF-α Therapy: PSUMMIT II evaluated 180 patients who were previously treated with ≥1 anti-TNF-α agents for at least 8 weeks (14 weeks with infliximab) or had documented intolerance of anti-TNF-α therapy at any time in the past.
Among patients previously treated with anti-TNF-α agents, a significantly greater proportion of Stelara-treated patients chieved an ACR 20 response at week 24 compared to placebo (see Table 14). American College of Rheumatology (ACR) 20, 50 and 70 responses were generally maintained through week 52.

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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 15). In both studies, improvement in enthesitis score and dactylitis score were maintained at week 52.

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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% improvement in BASDAI scores at week 24 compared with placebo (see Table 16).

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Psoriasis Area and Severity Index (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 17). 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%)].
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 17). In both studies, the proportion of patients achieving both a PASI 75 response and an ACR 20 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%)].

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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 mg and 90 mg groups than in the placebo group (see Table 18).

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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 DIP joints, compared to baseline. A prespecified integrated analysis combining data from 927 subjects in both PSUMMIT I and 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 19). Beyond week 24, Stelara treatment continued to inhibit the progression of structural damage through week 52. The mean change from week 24-52 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 0-24 (see Table 19).

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Pharmacokinetics: Absorption: The median time to reach the maximum serum concentration (Tmax) was 8.5 days after a single 90 mg SC administration in healthy subjects. The median Tmax values of ustekinumab following a single SC administration of either 45 or 90 mg in patients with psoriasis were comparable to that observed in healthy subjects.
The absolute bioavailability of ustekinumab following a single SC administration was estimated to be 57.2% in patients with psoriasis.
Distribution: Median volume of distribution during the terminal phase (Vz) following a single IV administration to patients with psoriasis ranged from 57-83 mL/kg.
Metabolism: The exact metabolic pathway for ustekinumab is unknown.
Elimination: Median systemic clearance (CL) following a single IV administration to patients with psoriasis ranged from 1.99-2.34 mL/day/kg; median half-life (t½) of ustekinumab was approximately 3 weeks in patients with psoriasis, ranging from 15-32 days across all psoriasis studies.
Dose Linearity: The systemic exposure of ustekinumab (Cmax and AUC) increased in an approximately dose-proportional manner after a single IV administration at doses ranging from 0.09-4.5 mg/kg or following a single SC administration at doses ranging from approximately 24-240 mg in patients with psoriasis.
Single Dose versus Multiple Doses: Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple SC dose administrations. Steady-state serum concentrations of ustekinumab were achieved by week 28 after initial SC doses at weeks 0 and 4, followed by doses every 12 weeks. The median steady-state trough concentration ranged from 0.21-0.26 mcg/mL (45 mg) and from 0.47-0.49 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given SC every 12 weeks.
Impact of Weight on Pharmacokinetics: Serum ustekinumab concentrations were affected by patient weight. Within each dose (45 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, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/day 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.
In the population pharmacokinetic analysis, the effect of co-morbidities (past and current history of diabetes, hypertension and hyperlipidemia) on pharmacokinetics of ustekinumab was evaluated. The pharmacokinetics of ustekinumab was impacted by the co-morbidity 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.
In the population pharmacokinetic analysis, 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 methotrexate, cyclosporine or other biological therapeutics for the treatment of psoriasis.
No pharmacokinetic data are available in patients with renal insufficiency and impaired hepatic function.
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.
The pharmacokinetics of ustekinumab was not impacted by the use of tobacco or alcohol.
Toxicology: Preclinical Safety Data: In repeated-dose toxicity studies in 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.
Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalent dose intended to be administered to psoriasis patients and resulted in peak serum concentrations in monkeys that were >100-fold higher than observed in humans.
Carcinogenesis and Mutagenesis: 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.
Reproductive Toxicology: Three (3) developmental toxicity studies were conducted in cynomolgus monkeys. No ustekinumab-related maternal toxicity, abortions, stillbirths, 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 SC 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 SC 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: Treatment of psoriasis and improving quality of life in patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Psoriatic Arthritis (PsA): Treatment for reducing signs and symptoms, improving physical function, inhibiting the progression of structural damage, improving enthesitis, psoriasis and health-related quality of life in adults with active PsA. May be given alone or in combination with methotrexate.
Dosage/Direction for Use
Adults: Plaque Psoriasis: Recommended Dose: 45 mg administered at weeks 0 and 4, then every 12 weeks thereafter. Alternatively, 90 mg may be used in patients with a body weight >100 kg.
Dose Adjustment: For patients who inadequately respond to 45 mg every 12 weeks, consideration may be given to treating with 90 mg every 12 weeks. For patients who inadequately respond to dosing every 12 weeks, a 90-mg dose every 8 weeks may be considered.
Re-Treatment: Re-treatment with a dosing regimen of weeks 0 and 4 after interruption of therapy has been shown to be safe and effective.
Psoriatic Arthritis: Recommended Dose: 45 mg administered at weeks, 0 and 4, then every 12 weeks thereafter. Alternatively, 90 mg may be used in patients with a body weight >100 kg.
Administration: Stelara is administered by SC injection.
General Consideration for Administration: Stelara is intended for use under the guidance and supervision of a physician. A patient may self-inject with Stelara if a physician determines that it is appropriate and with medical follow-up as necessary, after proper training in SC injection technique.
Comprehensive instructions for the administration of Stelara are given in the core patient package insert (CPPI). Patients should be instructed to inject the full amount of Stelara according to the directions provided in the patient information leaflet. 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.
Overdosage
Single doses up to 6 mg/kg IV 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.
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. Antituberculosis 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.
Monitor for the appearance of nonmelanoma skin cancer in all patients, in particular those >60 years, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA.
Hypersensitivity Reactions: If an anaphylactic or other serious allergic reaction occurs, administration of Stelara should be discontinued immediately and appropriate therapy instituted (see Adverse Reactions).
Immunizations: It is recommended that live viral or live bacterial vaccines not be given concurrently with Stelara.
Patients receiving Stelara may receive concurrent inactivated or non-live vaccinations.
Immunosuppression: In psoriasis studies, the safety and efficacy of Stelara in combination with immunosuppressive agents or phototherapy have not been evaluated. In PsA studies, concomitant methotrexate use did not appear to influence the safety and efficacy of Stelara. Caution should be exercised when considering concomitant use of immunosuppressive agents and Stelara or when transitioning from other biologic agents.
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.
Special Populations: Hepatic and Renal Insufficiency: Specific studies have not been conducted in patients with hepatic and renal insufficiency.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Impairment of 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.
Use in Pregnancy: There is no evidence from animal studies of teratogenicity, birth defects or developmental delays at dose levels up to approximately 45-fold higher than the highest equivalent dose intended to be administered to psoriasis patients (see Pharmacology: Toxicology 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.
Use in Lactation: 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.
Use in Children: Specific studies of Stelara in pediatric patients have not been conducted.
Use in the Elderly: No major age-related differences in clearance or volume of distribution were observed in clinical studies. No overall differences in efficacy or safety in patients ≥65 years (N=131) who received Stelara were observed compared with younger patients.
Use In Pregnancy & Lactation
Use in Pregnancy: There is no evidence from animal studies of teratogenicity, birth defects or developmental delays at dose levels up to approximately 45-fold higher than the highest equivalent dose intended to be administered to psoriasis patients (see Pharmacology: Toxicology 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.
Use in Lactation: 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.
Adverse Reactions
Psoriasis Clinical Studies Experience: The safety data described as follows reflect exposure to Stelara in 3 adequate and well-controlled studies of 2,266 patients, including 1,970 exposed for at least 6 months and 1,285 exposed for at least 1 year and 373 for at least 18 months.
The following serious adverse reactions were reported: Serious infections, malignancies.
The most common adverse reactions (>10%) in controlled and uncontrolled portions of the psoriasis clinical studies with Stelara were nasopharyngitis and upper respiratory tract infection. Most were considered to be mild and did not necessitate drug discontinuation.
Table 20 provides a summary of adverse drug reactions from psoriasis clinical studies. The adverse drug 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) and rare (≥1/10,000, <1/1000). (See Table 20.)

Click on icon to see table/diagram/image

Infections: In the placebo-controlled studies of patients with psoriasis and/or psoriatic arthritis, the rates of infection or serious infection were similar between Stelara-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 Stelara-treated patients and 1.17 per patient-year of follow-up in placebo-treated patients. Serious infections occurred in 0.01 per patient-year of follow-up in Stelara-treated patients (5 serious infections in 616 patient-years of follow-up) and 0.01 per patient-year of follow-up in placebo-treated patients (4 serious infections in 287 patient-years of follow-up) (see Precautions).
In the controlled and noncontrolled portions of psoriasis and psoriatic arthritis, clinical studies representing 9,848 patient-years of exposure in 4,315 patients, the median follow-up was 1.1 year; 3.2 years for psoriasis studies and 1 year for psoriatic arthritis studies. The rate of infection was 0.86 per patient-year of follow-up in Stelara-treated patients. The rate of serious infections was 0.01 per patient-year of follow-up in Stelara-treated patients (107 serious infections in 9,848 patient-years of follow-up) and 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.
Malignancy: In the placebo-controlled period of the psoriasis and psoriatic arthritis clinical studies, the incidence of malignancies excluding nonmelanoma skin cancer was 0.16 per 100 patient-years of follow-up for Stelara-treated patients (1 patient in 615 patient-years of follow-up) compared with 0.35 per 100 patient-years of follow-up for placebo-treated patients (1 patient in 287 patient-years of follow-up).
The incidence of nonmelanoma skin cancer was 0.65 per 100 patient-years of follow-up for Stelara-treated patients (4 patients in 615 patient-years of follow-up) compared with 0.7 per 100 patient-years of follow-up 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 representing 9,848 patient-years of exposure in 4,135 patients, the median follow-up was 1.1 year; 3.2 years for psoriasis studies and 1 year for psoriatic arthritis studies. Malignancies excluding nonmelanoma skin cancers were reported in 55 patients in 9,530 patient-years of follow-up (incidence of 0.56 per 100-patient years of follow-up for Stelara-treated patients). This incidence of malignancies reported in Stelara-treated patients was comparable to the incidence expected in the general population [standardized incidence ratio=0.92 (95% confidence interval: 0.69, 1.2), adjusted for age, gender and race]. The most frequently observed malignancies, other than nonmelanoma skin cancer, were prostate, melanoma, colorectal and breast. The incidence of nonmelanoma skin cancer was 0.5 per 100 patient-years of follow-up for Stelara-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.
Hypersensitivity Reactions: 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.
Immunogenicity: In clinical studies, <8% of patients treated with Stelara developed antibodies to ustekinumab. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was observed. Patients positive for antibodies to ustekinumab tended to have lower efficacy, however, antibody positivity did not preclude a clinical response. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.
Drug Interactions
Specific drug interaction studies have not been conducted with Stelara (see Pharmacology: Pharmacokinetics under Actions).
Live vaccines should not be given concurrently with Stelara (see Precautions).
Caution For Usage
Following administration of Stelara, the syringe should be disposed of with accepted medical practices for used syringes.
Storage
Store in a refrigerator: [2-8°C (36-46°F)]. Protect from light. Do not freeze or shake.
MIMS Class
ATC Classification
L04AC05 - ustekinumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.
Presentation/Packing
Inj (pre-filled syringe) 45 mg/0.5 mL x 1's.
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