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——强生单抗药Stelara(Ustekinumab)获FDA和欧盟批准上市
HIGHLIGHTS OF PRESCRIBING INFORMATION
STELARA® is a human interleukin-12 and -23 antagonist indicated for the treatment of adult patients with: moderate to severe plaque psoriasis (Ps) who are candidates for phototherapy or systemic therapy. (1.1) active psoriatic arthritis (PsA), alone or in combination with methotrexate. (1.2) moderately to severely active Crohn's disease (CD) who have failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed a tumor necrosis factor (TNF) blocker or failed or were intolerant to treatment with one or more TNF blockers. (1.3) DOSAGE AND ADMINISTRATION Psoriasis Recommended Adult Subcutaneous Dosage (2.1):
The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks. For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks. Crohn's Disease Recommended Initial Adult Intravenous Dosage (2.3): A single intravenous infusion using weight-based dosing:
A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. DOSAGE FORMS AND STRENGTHS Subcutaneous Injection Injection: 45 mg/0.5 mL or 90 mg/mL in a single-dose prefilled syringe (3) Injection: 45 mg/0.5 mL in a single-dose vial (3) Intravenous Infusion Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial (3) CONTRAINDICATIONS Clinically significant hypersensitivity to ustekinumab or to any of the excipients. (4) WARNINGS AND PRECAUTIONS Infections: Serious infections have occurred. Do not start STELARA® during any clinically important active infection. If a serious infection or clinically significant infection develops, consider discontinuing STELARA® until the infection resolves. (5.1) Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL-12/IL-23. Diagnostic tests for these infections should be considered as dictated by clinical circumstances. (5.2) Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with STELARA®. Initiate treatment of latent TB before administering STELARA®. (5.3) Malignancies: STELARA® may increase risk of malignancy. The safety of STELARA® in patients with a history of or a known malignancy has not been evaluated. (5.4) Hypersensitivity Reactions: Anaphylaxis or other clinically significant hypersensitivity reactions may occur. (5.5) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): One case was reported. If suspected, treat promptly and discontinue STELARA®. (5.6) ADVERSE REACTIONS Most common adverse reactions are: Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) Crohn's Disease, induction (≥3%): vomiting. (6.1) Crohn's Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Psoriasis (Ps) STELARA® is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. 1.2 Psoriatic Arthritis (PsA) STELARA® is indicated for the treatment of adult patients with active psoriatic arthritis. STELARA® can be used alone or in combination with methotrexate (MTX). 1.3 Crohn's Disease (CD) STELARA® is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have: failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) blocker or failed or were intolerant to treatment with one or more TNF blockers. 2 DOSAGE AND ADMINISTRATION 2.1 Psoriasis Subcutaneous Adult Dosage Regimen For patients weighing 100 kg or less, the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)]. 2.2 Psoriatic Arthritis Subcutaneous Adult Dosage Regimen The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. 2.3 Crohn's Disease Intravenous Induction Adult Dosage Regimen A single intravenous infusion dose of STELARA® using the weight-based dosage regimen specified in Table 1 [see Instructions for dilution of STELARA® 130 mg vial for intravenous infusion (2.6)]. Table 1: Initial Intravenous Dosage of STELARA®
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. 2.4 General Considerations for Administration After proper training in subcutaneous injection technique, a patient may self-inject with STELARA® if a physician determines that it is appropriate. Patients should be instructed to follow the directions provided in the Medication Guide [see Medication Guide]. 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. 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-dose vial, a 27 gauge, ½ inch needle is recommended. STELARA® is intended for use under the guidance and supervision of a physician. STELARA® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician. Prior to administration, visually inspect STELARA® for particulate matter and discoloration. STELARA® is clear, colorless to light yellow and may contain a few small translucent or white particles. Do not use STELARA® if it is discolored or cloudy, or if other particulate matter is present. STELARA® does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5 Instructions for Administration of STELARA® Prefilled Syringes Equipped with Needle Safety Guard Refer to the diagram below for the provided instructions. To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.
Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place.
One case of RPLS occurred during clinical studies [see Warnings and Precautions (5.6)]. Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)]. In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical studies were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Psoriatic Arthritis The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical studies. Crohn's Disease The safety of STELARA® was assessed in 1407 patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter studies. These 1407 patients included 40 patients who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In Studies CD-1 and CD-2 there were 470 patients who received STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Patients who were responders in either Study CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks, or placebo for 44 weeks in Study CD-3. Patients in these 3 studies may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.3)]. The overall safety profile of STELARA® was consistent with the safety profile seen in the psoriasis and psoriatic arthritis clinical studies. Common adverse reactions in Studies CD-1 and CD-2 and in Study CD-3 are listed in Tables 3 and 4, respectively. Table 3: Common adverse reactions through Week 8 in Studies CD-1 and CD-2 occurring in ≥3% of STELARA®-treated patients and higher than placebo
Table 4: Common adverse reactions through Week 44 in Study CD-3 occurring in ≥3% of STELARA®-treated patients and higher than placebo
In patients with Crohn's disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes were reported in one patient each. Malignancies With up to one year of treatment in the Crohn's disease clinical studies, 0.2% of STELARA®-treated patients (0.36 events per hundred patient-years) and 0.2% of placebo-treated patients (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of STELARA®-treated patients (0.27 events per hundred patient-years) and in none of the placebo-treated patients. Hypersensitivity Reactions Including Anaphylaxis In CD studies, two patients reported hypersensitivity reactions following STELARA® administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of patients receiving subcutaneous STELARA®). In addition, one patient experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous STELARA® dose (0.08% of patients receiving intravenous STELARA®). These patients were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. 6.2 Immunogenicity Approximately 6% of patients treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn's disease clinical studies, less than 3% 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 seen. No ustekinumab-related serious hypersensitivity reactions were observed in psoriasis, psoriatic arthritis and Crohn's disease clinical studies. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. The data above reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab 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. 6.3 Postmarketing Experience The following adverse reactions have been reported during post-approval of STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria) [see Warnings and Precautions (5.5)]. Skin reactions: Pustular psoriasis, erythrodermic psoriasis. 7 DRUG INTERACTIONS 7.1 Live Vaccines Avoid use of live vaccines with STELARA® [see Warnings and Precautions (5.7)]. 7.2 Concomitant Therapies In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated [see Warnings and Precautions (5.8)]. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of STELARA®. In Crohn's disease studies, immunomodulators (6-mercaptopurine, azathioprine, methotrexate) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in approximately 40% of patients. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of STELARA®. 7.3 CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed [see Clinical Pharmacology (12.3)]. 7.4 Allergen Immunotherapy STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to STELARA® during pregnancy. Patients should be encouraged to enroll by calling 1-877-311-8972. Risk Summary Limited data on the use of STELARA® in pregnant women are insufficient to inform a drug associated risk [see Data]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the human exposure at the maximum recommended human subcutaneous dose (MRHD). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Limited data on use of STELARA® in pregnant women from observational studies, published case reports, and postmarketing surveillance are insufficient to inform a drug associated risk. Animal Data Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks. In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the human subcutaneous exposure from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age. 8.2 Lactation Risk Summary There are no data on the presence of ustekinumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ustekinumab was present in the milk of lactating monkeys administered ustekinumab. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Maternal IgG is known to be present in human milk. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because ustekinumab is a large molecule and is degraded in the gastrointestinal tract. However, if ustekinumab is transferred into human milk the effects of local exposure in the gastrointestinal tract are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for STELARA® and any potential adverse effects on the breastfed child from STELARA® or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of STELARA® in pediatric patients have not been established. 8.5 Geriatric Use Of the 5884 subjects exposed to STELARA®, a total of 306 were 65 years or older (183 patients with psoriasis, 65 patients with psoriatic arthritis and 58 with Crohn's disease), and 34 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. 10 OVERDOSAGE 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. 11 DESCRIPTION Ustekinumab is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, ustekinumab is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons. STELARA® (ustekinumab) Injection is a sterile, preservative-free, colorless to slightly yellow solution that may contain a few small translucent or white particles with pH of 5.7– 6.3. STELARA® for Subcutaneous Use Available as 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and as 45 mg of ustekinumab in 0.5 mL in a single-dose 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that contains dry natural rubber (a derivative of latex). Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg). Each 1 mL prefilled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg). STELARA® for Intravenous Infusion Available as 130 mg of ustekinumab in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper. Each 26 mL vial delivers 130 mg ustekinumab, EDTA disodium salt dihydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ustekinumab is a human IgG1қ monoclonal antibody that binds with 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-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab, was shown to be protective. 12.2 Pharmacodynamics In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with psoriasis. 12.3 Pharmacokinetics Absorption In subjects with psoriasis, 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 subjects (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 subjects with psoriasis. Following multiple subcutaneous doses of STELARA® in patients with psoriasis, the steady-state serum concentrations of ustekinumab were achieved by Week 28. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. In patients with Crohn's disease, following the recommended intravenous induction dose, mean peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean steady-state trough concentration was 2.51 ± 2.06 mcg/mL for 90 mg ustekinumab administered every 8 weeks. Distribution In a population pharmacokinetic analysis of ustekinumab, the volume of distribution of the central compartment was 2.74 L (95% CI: 2.69, 2.78), and the total volume of distribution at steady-state was 4.62 L in patients with Crohn's disease. Elimination The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following subcutaneous administration. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day (95% CI: 0.185, 0.197) with an estimated median terminal half-life of approximately 19 days in patients with Crohn's disease. 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. Specific Populations Weight When given the same dose, subjects with psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group. Age: Geriatric Population A population pharmacokinetic analysis (N=106/1937 patients with psoriasis greater than or equal to 65 years old) 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 subjects older than 65 years old. Drug Interaction Studies 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). However, the clinical relevance of in vitro data has not been established [see Drug Interactions (7.3)]. No in vivo drug interaction studies have been conducted with STELARA®. Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in patients with psoriatic arthritis. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females. No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy. 13.2 Animal Toxicology and/or Pharmacology In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection. 14 CLINICAL STUDIES 14.1 Psoriasis Two multicenter, randomized, double-blind, placebo-controlled studies (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies. Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects 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. In both studies, the endpoints were the proportion of subjects 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 Physician's Global Assessment (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. In both studies, subjects 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 subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis. Clinical Response The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 5 below. Table 5: Clinical Outcomes Ps STUDY 1 and Ps STUDY 2
In subjects who weighed 100 kg or less, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 6 below). Table 6: Clinical Outcomes by Weight Ps STUDY 1 and Ps STUDY 2
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks. 14.2 Psoriatic Arthritis The safety and efficacy of STELARA® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline. Patients were randomized to receive treatment with STELARA® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24. In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the patients had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time. Clinical Response In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 7). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were similar in patients regardless of prior TNFα exposure. Table 7: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24
The percent of patients achieving ACR 20 responses by visit is shown in Figure 1. Figure 1: Percent of patients achieving ACR 20 response through Week 24 PsA STUDY 1
The results of the components of the ACR response criteria are shown in Table 8.
Number of tender joints counted (0–68) Visual analogue scale; 0= best, 10=worst. Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. CRP: (Normal Range 0.0–1.0 mg/dL) An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24. Physical Function STELARA® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24. 14.3 Crohn's Disease STELARA® was evaluated in three randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction studies (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (CD-3) representing 52 weeks of therapy. Studies CD-1 and CD-2 In studies CD-1 and CD-2, 1409 patients were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both studies, patients were randomized to receive a single intravenous administration of STELARA® at either approximately 6 mg/kg, placebo (see Table 1), or 130 mg (a lower dose than recommended). In Study CD-1, patients had failed or were intolerant to prior treatment with a TNF blocker: 29% patients had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these patients, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the study, approximately 46% of the patients were receiving corticosteroids and 31% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 319 in the STELARA® approximately 6 mg/kg group and 313 in the placebo group. In Study CD-2, patients had failed or were intolerant to prior treatment with corticosteroids (81% of patients), at least one immunomodulator (6-mercaptopurine, azathioprine, methotrexate; 68% of patients), or both (49% of patients). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the study, approximately 39% of the patients were receiving corticosteroids and 35% of the patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate). The median baseline CDAI score was 286 in the STELARA® and 290 in the placebo group. In these induction studies, a greater proportion of patients treated with STELARA® achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 9 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in STELARA®-treated patients and continued to improve through Week 8. Table 9: Induction of Clinical Response and Remission in CD-1* and CD-2
The maintenance study (CD-3), evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 of induction with STELARA® in studies CD-1 or CD-2. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks or placebo for 44 weeks (see Table 10). Table 10: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)
Patients who achieved clinical response to STELARA ® at the end of the induction study. p < 0.01 0.01≤ p < 0.05 Patients in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not account for any other time point during maintenance therapy. At Week 44, 47% of patients who received STELARA® were corticosteroid-free and in clinical remission, compared to 30% of patients in the placebo group. At Week 0 of Study CD-3, 34/56 (61%) STELARA® treated patients who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these patients were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) patients were in clinical remission at Week 0 while 16/61 (26%) of these patients were in remission at Week 44. At Week 0 of Study CD-3, 46/72 (64%) STELARA® treated patients who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these patients were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these patients were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these patients who were also naïve to TNF blockers, 34/52 (65%) of STELARA® treated patients were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm. Patients who were not in clinical response 8 weeks after STELARA® induction were not included in the primary efficacy analyses for Study CD-3; however, these patients were eligible to receive a 90 mg subcutaneous injection of STELARA® upon entry into Study CD-3. Of these patients, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the study. 15 REFERENCES 1 Surveillance, 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. 16 HOW SUPPLIED/STORAGE AND HANDLING STELARA® (ustekinumab) Injection is a sterile, preservative-free, colorless to slightly yellow solution. STELARA® is available in single-dose prefilled syringes containing 45 mg or 90 mg or single-dose vials containing 45 mg of ustekinumab for subcutaneous use. Each prefilled syringe is equipped with a 27 gauge fixed ½ inch needle, a needle safety guard, and a needle cover that contains dry natural rubber. STELARA® is also available in single-dose vials containing 130 mg ustekinumab for intravenous use.
STELARA® vials and prefilled syringes must be refrigerated at 2°C to 8°C (36°F to 46°F). Store STELARA® vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c77a9664-e3bb-4023-b400-127aa53bca2b 强生重磅抗炎药Stelara获美国FDA批准治疗中重度克罗恩病（CD） 2016年9月28日,美国医药巨头强生（JNJ）免疫管线近日在美国监管方面传来喜讯，美国食品和药物管理局（FDA）已批准单抗药物Stelara（ustekinumab）用于中度至重度银屑病活动性克罗恩病（Crohn's disease，CD）成人患者的治疗，具体为： （1）接受免疫调节剂或糖皮质激素治疗失败或对这2类药物不耐受、但接受TNF阻断剂治疗从未失败过的CD成人患者； （2）对1种或多种TNF阻断剂治疗失败或不耐受的CD成人患者。 Stelara靶向白细胞介素12（IL-12）和白细胞介素23（IL-23），这2种细胞因子被认为在免疫介导性疾病中发挥着重要作用，包括克罗恩病（CD）。此次批准，使Stelara成为美国市场获批治疗克罗恩病（CD）的首个IL-12/23单抗药物。在欧盟方面，欧洲药物管理局（EMA）人用医药产品委员会（CHMP）于上周支持批准Stelara用于对常规疗法或TNFα拮抗剂治疗应答不足、无应答或不耐受的中度至重度活动性克罗恩病（CD）成人患者的治疗。克罗恩病（CD）是一种胃肠道慢性炎症性疾病，美国患者约70万例，欧洲患者约25万例。 IM-UNITI维持研究是综合性III期项目中的第3个关键性研究。为期1年的诱导和维持数据，证明了Stelara在中度至重度活动性克罗恩病患者中诱导并维持临床缓解的潜力。该项综合性III期项目纳入了TNF初治、经治、治疗失败的克罗恩病患者，总体数据支持了Stelara将为需要有效治疗方案的克罗恩病群体提供显著的临床受益， Stelara的获批，是基于在TNF初治、经治、治疗失败的克罗恩病患者群体中开展的3个关键性III期研究（UNITI-1，UNITI-2，IM-INITI）的数据。前2个研究中，分别有34%（UNITI-1）和56%（UNITI-2）的患者在接受一剂静脉输注Stelara治疗后仅仅6周内克罗恩病症状便得到显著缓解；更重要的是，在治疗后早至3周就能观察到明显改善。第3个研究显示，对诱导剂量表现缓解并且继续接受每8周一次皮下注射Stelara维持剂量治疗的大多数患者，在44周结束时（从诱导剂量开始后52周）仍保持缓解。这些数据证明了Stelara在中度至重度活动性克罗恩病患者中诱导并维持临床缓解的显著疗效。 Stelara的起始剂量需要根据患者体重调整，一次性静脉输注（IV）诱导剂量（260mg[体重≤55公斤]；390mg[体重：55-85公斤]；520mg[体重＞85公斤]），来帮助减轻症状；随后进行每8周一次90mg剂量Stelara皮下注射液维持治疗，使症状保持可控。需要注意的是，第一剂是诱导剂量，静脉输注给药，需要在专业医疗人员监督下进行。随后的维持剂量为每8周一次，皮下注射给药，可由专业医疗人员操作或患者经过适当培训后自我注射。 目前，Stelara已获全球多个国家批准用于中度至重度斑块型银屑病及活动性银屑病关节炎的治疗。在临床上，Stelara是一种广泛认可的中重度银屑病临床标准治疗药物。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
