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This Product Profiler introduces healthcare professionals to STELARA®, a therapeutic option for the treatment of adult patients 18 years or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
STELARA® is a human IgG1κ monoclonal antibody against the p40 subunit of the interleukin (IL)-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses.1
The safety and efficacy of STELARA® were assessed in 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies, PHOENIX 1 and PHOENIX 2, with a total enrollment of 1996 patients.1–3
Although an increased understanding of the immunopathogenesis of psoriasis has led to the development of agents in patients with psoriasis, a need for additional options exists.4
The efficacy, safety profile, and dosing regimen of STELARA® suggest that it is an important therapeutic option for patients with moderate to severe plaque psoriasis.1
SELECTED SAFETY INFORMATION
STELARA® is an immunosuppressant and may increase the risk of infections, reactivation of latent infections, and malignancies. Serious adverse reactions have been reported in STELARA®-treated patients, including bacterial, fungal, and viral infections, malignancies, and one case of Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
STELARA® should not be given to patients with any clinically important active infection. Patients should be evaluated for tuberculosis prior to initiating treatment with STELARA®. Live vaccines should not be given to patients receiving STELARA®. If RPLS is suspected, discontinue STELARA®.
Footnotes
Please see related and other Important Safety Information on page 15.
Psoriasis is a chronic, immune-mediated inflammatory disease of the skin.5,6 Psoriasis affects males and females equally,6 and onset can occur at any age, although it is most commonly diagnosed between the ages of 15 and 25.7 Diagnosis is made primarily via physical exam and analysis of a skin sample.6
Psoriasis affects many different areas of the body. Key sensitive areas include the scalp, neck, elbows, hands, genitals, knees, and feet.6 The manifestation of plaque psoriasis on the skin appears as red, scaly patches known as plaques.6 Severity is a function of many factors including body surface area (BSA), disease location, thickness, and subjective assessment of impact on the patient’s life.5
Psoriasis can have a profound effect on physical health, comparable to type 2 diabetes and chronic lung disease, as measured by the physical component of the Short-Form Health Survey (SF-36) scale. Figure 1 shows the impact of psoriasis on the physical component of the SF-36 compared with other major diseases.8,9
Comparison of the physical component scores of healthy adults and patients with chronic diseases8
PATHOPHYSIOLOGY
The exact pathophysiology of this disease has not yet been elucidated, although several hypotheses have been proposed. No one antigen has consistently been identified, although the immunopathogenesis underlying this disease is better understood. The cause of psoriasis remains unknown, and there is no cure.5
Over the past several decades, the focus of research has shifted from a model of a disorder of keratinocyte hyperproliferation to a model of psoriasis as a disorder of T-helper (Th) cell-mediated immunity.10
One view of psoriasis pathogenesis is that interferon-gamma (IFN-γ), produced by Th 1 cells, and tumor necrosis factor–alpha (TNF-α), produced by a variety of cell types, have central roles. It is not clear whether the inciting antigen is self-derived, thereby rendering psoriasis an autoimmune disorder, or whether it is of non-self origin.11
Recent evidence suggests that the Th 17 pathway, in addition to the Th 1 pathway, may also play an important role in the development of psoriasis. IL-23 drives the differentiation of Th 17 cells. Th 17 cells, unlike Th 1 cells, secrete a distinct set of proinflammatory cytokines, such as IL-17A, IL-17F, IL-6, TNF-α, and IL-22.10,12
Newer biologic therapies are based on the current understanding of the T-cell–mediated model of psoriasis pathogenesis, in contrast to broad-acting conventional psoriasis treatments. Biologics target specific points in the psoriasis pathogenic pathway.10
TYPES OF PSORIASIS
Psoriasis is classified into several subtypes. Chronic plaque psoriasis (psoriasis vulgaris) is the most common form and comprises 80% of psoriasis cases.13 Other types include guttate, inverse, pustular, and erythrodermic psoriasis.14
CLINICAL PRESENTATION AND DIAGNOSIS
The major manifestation of psoriasis is chronic skin inflammation. The disease is characterized by disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritic.15
Plaque psoriasis appears on the skin as well-defined, sharply demarcated, erythematous plaques varying in size from 1 cm to several centimeters (Figures 2 and 3). Involvement may range from only a few plaques to numerous lesions that can cover almost the entire body. These plaques are irregular and have a round to oval shape. They are located most often on the scalp, trunk, buttocks, and limbs, with a predilection for extensor surfaces such as the elbows and knees. Smaller plaques may coalesce into larger lesions, especially on the legs and trunk.15
Images are used with permission by Centocor Ortho Biotech Inc.
Psoriatic plaques tend to have a dry, thin, silvery-white or micaceous scale and are symmetrically distributed over the body. Histologic findings may include psoriasiform epidermal hyperplasia, parakeratosis with intracorneal neutrophils, hypogranulosis, spongiform pustules, and an infiltrate of neutrophils and lymphocytes in the epidermis and dermis along with an expanded dermal papillary vasculature.15
The diagnosis is most often made by the clinical ap pearance and distribution of lesions, which are graded as mild, moderate, or severe.16
RISK FACTORS
Variations in severity and phenotype of psoriasis are partly attributable to environmental factors such as ultraviolet exposure, alcohol, and physical and psychological stress.17 Studies of twins indicate that the proportion of phenotypic variability attributable to genes is about 80%; however, a lack of complete concordance in identical twins suggests multifactorial inheritance, with genetics and environmental factors playing a role.18
The major genetic determinant is a susceptibility locus (PSORS 1), which accounts for approximately 50% of the heritability of psoriasis.17PSORS 1 has been localized to the region of the major histocompatibility complex (MHC), specifically the human leukocyte antigen (HLA-C) locus on chromosome 6p21.19
A 2009 study identified 2 additional genetic variations within the MHC on chromosome 6p21 that conferred a risk for psoriasis. People who have all 3 genetic variants were estimated to be at a 9-fold increased risk of psoriasis compared with those carrying low-risk genotypes at all 3 loci.20
EVALUATION OF PSORIASIS TREATMENT
The Psoriasis Area and Severity Index (PASI) is a widely used measure of the average erythema, induration, and scaling of psoriasis lesions. In the PASI scale, the body is divided into four regions: the head, trunk, upper extremities, and lower extremities, which account for 10%, 20%, 30%, and 40%, respectively, of the total body surface area (BSA). Each area is assessed separately for erythema, thickness, and scaling, which are each rated on a scale of 0 to 4. The score is then weighted according to the area of involvement. Raw scores on the PASI are numerical and range from 0 (no visible disease) to 72 (complete erythroderma of the severest degree). Clinical trials frequently report efficacy results as PASI 50 or PASI 75, which represent improvements from baseline PASI scores of at least 50% and 75%, respectively.21,22
The Physician’s Global Assessment (PGA) is a 6-category scale ranging from 0 (Cleared) to 5 (Severe) that indicates the physician’s overall assessment of psoriasis, focusing on plaque thickness/induration, erythema, and scaling.1
Clinically, to determine the severity of psoriasis, the physician generally uses subjective qualitative assessment by combining objective evaluation of BSA involvement, disease location, thickness, symptoms, and presence or absence of psoriatic arthritis with the patient’s own assessment of the physical, financial, and emotional impact of the condition on his or her life.15
STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
DOSAGE AND ADMINISTRATION
Dosing
STELARA® is administered by subcutaneous injection.1
For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks
For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks
In patients weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these patients.1
The safety and efficacy of STELARA® have not been evaluated beyond two years.1
General Considerations for Administration
STELARA® is intended for subcutaneous administration under the supervision of a physician.1
Prior to administration, STELARA® should be visually inspected for particulate matter and discoloration. STELARA® is colorless to light yellow and may contain a few small translucent or white particles. STELARA® should not be used if it is discolored or cloudy, or if other particulate matter is present. STELARA® does not contain preservatives; therefore, any unused product remaining in the vial and/or syringe should be discarded.1
The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to latex.1
It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-use vial, a 27-gauge, ½-inch needle is recommended.1
STELARA® should only be administered by a healthcare provider. STELARA® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.1
CONTRAINDICATIONS
There are no contraindications for STELARA®.1
HOW SUPPLIED/STORAGE AND HANDLING
STELARA® does not contain preservatives. STELARA® is available in prefilled syringes containing 45 mg or 90 mg of ustekinumab. Each prefilled syringe is equipped with a needle safety guard.1
The NDC number for the 45 mg prefilled syringe is 57894-060-03
The NDC number for the 90 mg prefilled syringe is 57894-061-03
Storage and Stability
Store STELARA® upright and refrigerated at 2°C to 8°C (36°F to 46°F). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. STELARA® does not contain a preservative; discard any unused portion.1
STELARA® is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, STELARA® is produced in a well-characterized recombinant cell line and is purified using standard bioprocessing technology. The manufacturing process contains steps for the clearance of viruses. STELARA® comprises 1326 amino acids and has an estimated molecular mass that ranges from 148 079 to 149 690 Daltons.1
MECHANISM OF ACTION AND CLINICAL PHARMACOLOGY
Ustekinumab is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12– and IL-23–mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12 β1.1
PHARMACOKINETICS AND DRUG METABOLISM
Absorption
In psoriasis patients, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy patients (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in psoriasis patients. Following multiple subcutaneous doses of STELARA®, the steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg).1
There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.1
Distribution
Following the subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to psoriasis patients, the mean (±SD) apparent volume of distribution during the terminal phase (Vz/F) was 161 ± 65 mL/kg and 179 ± 85 mL/kg, respectively. The mean (±SD) volume of distribution during the terminal phase (Vz) following a single intravenous administration to patients with psoriasis ranged from 56.1 ± 6.5 to 82.1 ± 23.6 mL/kg.1
Metabolism
The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.1
Elimination
The mean (±SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to psoriasis patients ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day per kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.1
Weight
When given the same dose, patients weighing >100 kg had lower median serum ustekinumab concentrations compared with those patients weighing ≤100 kg.1
Hepatic and Renal Impairment
No pharmacokinetic data are available for patients with hepatic or renal impairment.1
Elderly Patients
A population pharmacokinetic analysis (N=106/1937 patients 65 years of age or older) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in patients older than 65 years of age.1
The safety and efficacy of STELARA® were assessed in 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies, PHOENIX 1 and PHOENIX 2, with a total enrollment of 1996 patients.1–3
In both studies, the endpoints were the proportion of patients who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (Cleared or Minimal) on the PGA. The PGA is a 6-category scale ranging from 0 (Cleared) to 5 (Severe) that indicates the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.1
In both studies, patients in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of patients in PHOENIX 1 and 40% of patients in PHOENIX 2. Approximately two-thirds of all patients had received prior phototherapy and 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis. Of that 69%, 56% received prior conventional systemic therapy and 43% received prior biologic therapy. A total of 28% of study patients had a history of psoriatic arthritis.1
PHOENIX 1 AND PHOENIX 2 STUDY DESIGN THROUGH WEEK 28
The PHOENIX 1 and PHOENIX 2 trials included 766 and 1230 patients, respectively. PHOENIX 1 and PHOENIX 2 had the same design through Week 28. In both trials, patients were randomized in equal proportion to placebo, or 45 mg or 90 mg of STELARA®. Patients randomized to STELARA® received 45-mg or 90-mg doses, regardless of weight, at Weeks 0, 4, and 16, and then 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 16.1–3
PHOENIX 1 STUDY DESIGN AFTER WEEK 28
At Week 28, patients who did not have at least a PASI 50 response discontinued the trial. At Week 40, those patients who were PASI 75 responders at both Weeks 28 and 40 were rerandomized to either continued dosing of STELARA® at Week 40 or to withdrawal of therapy (placebo at Week 40).2
Results from PHOENIX 1 demonstrated that after 2 starter doses, STELARA® provided significant improvement in psoriasis, as measured by the PASI and PGA. At Week 12, 67% of patients receiving STELARA® 45 mg and 66% of patients receiving STELARA® 90 mg experienced a PASI 75 response compared with 3% of patients receiving placebo (P<0.0001; see Figure 5). Furthermore, 59% of patients receiving STELARA® 45 mg and 61% of patients receiving STELARA® 90 mg had a PGA score of Cleared (0) or Minimal (1) at Week 12, compared with 4% of patients receiving placebo (P<0.0001; see Figure 5).1,2
Patients in PHOENIX 1 and PHOENIX 2 who achieved PASI 75 or a PGA score of 0 or 1 at Week 12 (P<0.0001)1–3*
*Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.1
After 2 doses of STELARA®, 42% and 37% of patients achieved a PASI 90 response with STELARA® 45 mg and 90 mg, respectively, at Week 12 compared with 2% of patients with placebo (P<0.0001).2
CLINICAL RESPONSE AT WEEK 12 IN PHOENIX 2
Results from PHOENIX 2 demonstrated that after 2 starter doses, STELARA® provided significant improvement in psoriasis, as measured by the PASI and PGA. At Week 12, 67% of patients receiving STELARA® 45 mg and 76% of patients receiving STELARA® 90 mg experienced a PASI 75 response compared with 4% of patients receiving placebo (P<0.0001; see Figure 5). Further, 68% of patients receiving STELARA® 45 mg and 73% of patients receiving STELARA® 90 mg had a PGA score of Cleared (0) or Minimal (1) at Week 12, compared with 4% of patients receiving placebo (P<0.0001; see Figure 5).1,3
After 2 doses of STELARA®, 42% and 51% of patients achieved a PASI 90 response with STELARA® 45 mg and 90 mg, respectively, at Week 12 compared with 1% of patients with placebo (P<0.0001).3
CLINICAL RESPONSE WITH MAINTENANCE DOSING EVERY 12 WEEKS AFTER 2 STARTER DOSES IN PHOENIX 1
In 1 clinical trial, efficacy was sustained with maintenance therapy among responders who continued treatment with STELARA®. In PHOENIX 1, responses seen at Weeks 12 and 28 with STELARA® were generally maintained through Week 40 of treatment, at which time long-term responders (patients who had a PASI 75 response at Weeks 28 and 40) were rerandomized to receive either ongoing treatment with STELARA® or placebo.1,2
More patients who were rerandomized to active therapy with STELARA® vs patients rerandomized to placebo maintained response. At Week 52, 89% (144/162) of responders rerandomized to maintenance treatment were PASI 75 responders compared with 63% (100/159) rerandomized to placebo (treatment withdrawal after Week 28 dose).1
EFFICACY BY WEIGHT
In patients who weighed >100 kg (220 lbs), higher PASI 75 response rates were seen with 90 mg dosing. As shown in Figure 6, the majority of patients achieved PASI 75 after only 2 doses of STELARA®.1
STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA®.1
STELARA® should not be given to patients with any clinically important active infection. STELARA® should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA® in patients with a chronic infection or a history of recurrent infection.1
Serious infections requiring hospitalization occurred in the psoriasis development program. These serious infections included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections.1
THEORETICAL RISK FOR VULNERABILITY TO PARTICULAR INFECTIONS
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.1
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.1
PRE-TREATMENT EVALUATION FOR TUBERCULOSIS
Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®.1
Do not administer STELARA® to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy 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.1
MALIGNANCIES
STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical studies. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy.1
The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.1
REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 STELARA®-treated subjects. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment.1
RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported.1
If RPLS is suspected, STELARA® should be discontinued and appropriate treatment administered.1
IMMUNIZATIONS
Prior to initiating therapy with STELARA®, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient.1
Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.1
CONCOMITANT THERAPIES
The safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone.1
RATES OF ADVERSE EVENTS WITH STELARA® IN PSORIASIS CLINICAL TRIALS
The safety data reflect exposure to STELARA® in 2266 patients with psoriasis, including 1970 exposed for at least 6 months, 1285 exposed for at least 1 year, and 373 exposed for at least 18 months.1
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 practice.1
Table 1 summarizes the adverse reactions reported by ≥1% of the patients in PHOENIX 1 and PHOENIX 2. Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection-site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of reversible posterior leukoencephalopathy syndrome (RPLS) occurred during the clinical trials.1
TABLE 1.
Adverse reactions reported by ≥1% of patients through Week 12 in PHOENIX 1 and PHOENIX 21*
Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in patients receiving STELARA® than in those who received placebo during the placebo-controlled period of PHOENIX 1 and PHOENIX 2.1
INFECTIONS
In the placebo-controlled period of clinical studies of patients with psoriasis (average follow-up of 12.6 weeks for patients treated with placebo and 13.4 weeks for patients treated with STELARA®), 27% of patients treated with STELARA® reported infections (1.39 per patient-year of follow-up) compared with 24% of patients treated with placebo (1.21 per patient-year of follow-up). Serious infections occurred in 0.3% of patients treated with STELARA® (0.01 per patient year of follow-up) and in 0.4% of patients treated with placebo (0.02 per patient-year of follow-up).1
In the controlled and non-controlled portions of psoriasis clinical trials, 61% of patients treated with STELARA® reported infections (1.24 per patient-year of follow-up). Serious infections were reported in 0.9% of patients (0.01 per patient-year of follow-up).1
MALIGNANCIES
In the controlled and non-controlled portions of psoriasis clinical trials, 0.4% of patients treated with STELARA® reported malignancies, excluding non-melanoma skin cancers (0.36 per 100 patient-years of follow-up). Non-melanoma skin cancer was reported in 0.8% of patients treated with STELARA® (0.80 per 100 patient-years of follow-up).1
Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers.1
IMMUNOGENICITY
The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies, resulting in inconclusive results due to assay interference. In PHOENIX 1 and PHOENIX 2, antibody testing was done at time points when ustekinumab may have been present in the serum. Table 2 summarizes the antibody results from PHOENIX 1 and PHOENIX 2.1 In PHOENIX 1, the last ustekinumab injection was between Weeks 28 and 48, and the last test for anti-ustekinumab antibodies was at Week 52. In PHOENIX 2, the last ustekinumab injection was at Week 16, and the last test for anti-ustekinumab antibodies was at Week 24.1
The data reflect the percentage of patients whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading.1
STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA® should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA® in patients with a chronic infection or a history of recurrent infection.
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances.
Pre-Treatment Evaluation of Tuberculosis (TB)
Evaluate patients for TB prior to initiating treatment with STELARA®. STELARA® should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA®. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA®.
Malignancies
STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
One case of RPLS has been reported in a STELARA®-treated patient. If RPLS is suspected, discontinue STELARA® and administer appropriate treatment.
RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.
Immunizations
Prior to initiating therapy with STELARA®, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.
Concomitant Therapies
The safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.
Most Common Adverse Reactions
The most common adverse reactions (≤3% and higher than that with placebo) in clinical trials for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.
With a chronic disease such as psoriasis, patients face the challenge of finding a suitable treatment.6 Treating moderate to severe plaque psoriasis with conventional therapies may present a challenge to clinicians. Treatment should be selected with careful consideration of the benefits and risks of the product. Long-term topical therapy is considered safe and effective, but is limited to mild psoriasis. Patients with moderate or severe plaque psoriasis require more aggressive treatment, such as phototherapy, systemic therapy, or biologic agents.10
Localized Therapies
Local and topical agents for plaque psoriasis include corticosteroids, vitamin D3 analogues, retinoids, coal tar, anthralin, keratolytics, and UVB laser treatments.6
Systemic and/or Phototherapy Treatments
Systemic treatments and/or phototherapy are an integral part of the standards of care for moderate or severe plaque psoriasis and include traditional systemic therapies (acitretin, cyclosporine, and methotrexate), phototherapy (UVB broadband and narrowband), photochemotherapy, and biologics.5
Biologics
Advances in the knowledge of the pathogenesis of psoriasis have allowed for the development of target-specific therapies. Biologic agents have been designed to be introduced at specific steps in the psoriasis pathogenic sequence of events.10
EFFICACY OF STELARA®
In PHOENIX 1 and PHOENIX 2, STELARA® provided significant improvement in psoriasis, as measured by the proportion of patients who achieved a PASI 75 response at Week 12 with STELARA® (66%–76%, P<0.0001) than with placebo (3%–4%).2,3 Patients in PHOENIX 1 were evaluated through Week 52. At Week 40, patients who were PASI 75 responders at both Weeks 28 and 40 were rerandomized either to continue dosing with STELARA® or to placebo. Of those rerandomized to STELARA®, 89% were PASI 75 responders at Week 52 compared with 63% of those rerandomized to placebo at Week 40 (treatment withdrawal after Week 28 dose).1 Based on the available evidence, these results support the notion that STELARA® is an efficacious agent in the treatment of adults with moderate to severe plaque psoriasis.2,3
STELARA® is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines.1 IL-12 and IL-23 may play a role in the immunopathophysiology of psoriasis.
Results from clinical trials with STELARA® show that this product has the potential to be an important therapeutic agent for treating adult patients with moderate to severe plaque psoriasis. The high level of sustained efficacy and safety, as well as the convenience of infrequent dosing with STELARA® (every 12 weeks after 2 starter doses), offers another therapeutic option for moderate to severe plaque psoriasis patients.
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