Ustekinumab

INDICATIONS AND USAGE Ustekinumab-aauz is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with: • moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. ( 1.1 ) • active psoriatic arthritis (PsA) . ( 1.2 ) • moderately to severely active Crohn's disease (CD) . ( 1.3 ) • moderately to severely active ulcerative colitis. ( 1.4 ) Pediatric patients 6 years and older with: • moderate to severe plaque psoriasis (PsO) , who are candidates for phototherapy or systemic therapy. ( 1.1 ) • active psoriatic arthritis (PsA) . ( 1.2 ) 1.1 Plaque Psoriasis (PsO) Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. 1.2 Psoriatic Arthritis (PsA) Ustekinumab-aauz is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis. 1.3 Crohn's Disease (CD) Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active Crohn's disease. 1.4 Ulcerative Colitis Ustekinumab-aauz is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

DOSAGE AND ADMINISTRATION Adult Patients with Plaque Psoriasis Subcutaneous Recommended Dosage ( 2.1 ): Weight Range (kilograms) Dosage less than or equal to 100 kg 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks greater than 100 kg 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks Pediatric Patients 6 Years of Age and Older with Plaque Psoriasis Subcutaneous Recommended Dosage ( 2.1 ): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage ( 2.2 ): 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. Psoriatic Arthritis Pediatric 6 years of Age and Older Subcutaneous Recommended Dosage ( 2.2 ): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co- existent moderate-to-severe plaque psoriasis 90 mg Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage ( 2.3 ): A single intravenous infusion using weight-based dosing: Weight Range (kilograms) Recommended Dose up to 55 kg 260 mg (2 vials) greater than 55 kg to 85 kg 390 mg (3 vials) greater than 85 kg 520 mg (4 vials) Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dose ( 2.3 ): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. 2.1 Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients weighing more than 100 kg, the recommended dosage 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 )]. Subcutaneous Pediatric Dosage Regimen Administer Ustekinumab-aekn subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of Ustekinumab-aekn for pediatric patients 6 years of age and older with plaque psoriasis based on body weight is shown below (Table 1). Table 1: Recommended Dose of Ustekinumab-aekn for Subcutaneous Injection in Pediatric Patients 6 Years of Age and Older With Plaque Psoriasis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg more than 100 kg 90 mg For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the vial. Table 2: Injection volumes of Ustekinumab-aekn 45 mg/0.5 mL Vials for Pediatric Patients 6 Years of Age and Older With Plaque Psoriasis and Pediatric Patients 6 Years of Age and Older With Psoriatic Arthritis* Weighing Less Than 60 kg Body Weight (kg) at the time of dosing Dose (mg) Volume of injection (mL) 15 11.3 0.12 16 12 0.13 17 12.8 0.14 18 13.5 0.15 19 14.3 0.16 20 15 0.17 21 15.8 0.17 22 16.5 0.18 23 17.3 0.19 24 18 0.20 25 18.8 0.21 26 19.5 0.22 27 20.3 0.22 28 21 0.23 29 21.8 0.24 30 22.5 0.25 31 23.3 0.26 32 24 0.27 33 24.8 0.27 34 25.5 0.28 35 26.3 0.29 36 27 0.3 37 27.8 0.31 38 28.5 0.32 39 29.3 0.32 40 30 0.33 41 30.8 0.34 42 31.5 0.35 43 32.3 0.36 44 33 0.37 45 33.8 0.37 46 34.5 0.38 47 35.3 0.39 48 36 0.4 49 36.8 0.41 50 37.5 0.42 51 38.3 0.42 52 39 0.43 53 39.8 0.44 54 40.5 0.45 55 41.3 0.46 56 42 0.46 57 42.8 0.47 58 43.5 0.48 59 44.3 0.49 * Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. 2.2 Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage Regimen The recommended dosage 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 dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage Regimen Administer Ustekinumab-aekn subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of Ustekinumab-aekn for pediatric patients 6 years of age and older with psoriatic arthritis, based on body weight, is shown below (Table 3). Table 3: Recommended Dose of Ustekinumab-aekn for Subcutaneous Injection in Pediatric Patients 6 Years of Age and Older With Psoriatic Arthritis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg* 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co-existent moderate-to-severe plaque psoriasis 90 mg * For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the vial. 2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis I ntravenous Induction Adult Dosage Regimen A single intravenous infusion dose of Ustekinumab-aekn using the weight-based dosage regimen specified in Table 4 [see Instructions for dilution of Ustekinumab-aekn 130 mg vial for intravenous infusion ( 2.5 )] . Table 4: Initial Intravenous Dosage of Ustekinumab-aekn Body Weight of Patient at the time of dosing Dose Number of 130 mg/26 mL (5 mg/mL) Ustekinumab-aekn vials 55 kg or less 260 mg 2 more than 55 kg to 85 kg 390 mg 3 more than 85 kg 520 mg 4 Subcutaneous Maintenance Adult Dosage Regimen 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 Ustekinumab-aekn is intended for use under the guidance and supervision of a healthcare provider. Ustekinumab-aekn should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing. In pediatric patients, it is recommended that Ustekinumab-aekn be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject Ustekinumab-aekn after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use [see Instructions for Use]. Not made with natural rubber 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 vial, a 1 mL syringe with a 27-gauge, 1/2 inch needle is recommended. Prior to administration, visually inspect Ustekinumab-aekn for particulate matter and discoloration. Ustekinumab-aekn is a clear and colorless to slightly yellow solution and free of visible particles. Do not use Ustekinumab-aekn if it is discolored or cloudy, or if other particulate matter is present. Ustekinumab-aekn does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5 Preparation and Administration of Ustekinumab-aekn 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colit

WARNINGS AND PRECAUTIONS Infections: Serious infections have occurred. Avoid starting Ustekinumab-aekn during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue Ustekinumab-aekn 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. Consider diagnostic tests for these infections as dictated by clinical circumstances. ( 5.2 ) Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with Ustekinumab-aekn. Initiate treatment of latent TB before administering Ustekinumab-aekn. ( 5.3 ) Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. ( 5.4 ) Serious Hypersensitivity Reactions: If a severe or other clinically significant hypersensitivity reaction occurs discontinue Ustekinumab-aekn immediately and initiate appropriate medical treatment. ( 5.5 ) Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly, and discontinue Ustekinumab-aekn. ( 5.6 ) Immunizations: Avoid use of live vaccines in patients during treatment with Ustekinumab-aekn. ( 5.7 ) Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue Ustekinumab-aekn and institute appropriate treatment. ( 5.8 ) 5.1 Infections Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions ( 6.1 , 6.3 )]. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following: Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. Psoriatic arthritis: cholecystitis. Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Avoid initiating treatment with Ustekinumab-aekn in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of Ustekinumab-aekn in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with Ustekinumab-aekn and discontinue Ustekinumab-aekn for serious or clinically significant infections until the infection resolves or is adequately treated. 5.2 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. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances). 5.3 Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with Ustekinumab-aekn. Avoid administering Ustekinumab-aekn to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering Ustekinumab-aekn. Consider anti-tuberculosis therapy prior to initiation of Ustekinumab-aekn in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving Ustekinumab-aekn for signs and symptoms of active tuberculosis during and after treatment. 5.4 Malignancies Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology ( 13 )]. The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non- melanoma skin cancer. Monitor all patients receiving Ustekinumab-aekn for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions ( 6.1 )]. 5.5 Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products in clinical trials and postmarketing. Some serious hypersensitivity reactions have occurred during the first intravenous dose of ustekinumab products [see Adverse Reactions ( 6.1 , 6.3 )]. If a severe or clinically significant hypersensitivity reaction occurs, discontinue Ustekinumab-aekn immediately and initiate appropriate medical treatment [see Contraindications ( 4 )] . 5.6 Posterior Reversible Encephalopathy Syndrome (PRES) Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products. Monitor all patients treated with Ustekinumab-aekn for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue Ustekinumab-aekn. 5.7 Immunizations Prior to initiating therapy with Ustekinumab-aekn, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with Ustekinumab-aekn should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with Ustekinumab-aekn 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 Ustekinumab-aekn because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of Ustekinumab-aekn may not elicit an immune response sufficient to prevent disease. 5.8 Noninfectious Pneumonia Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patien

CONTRAINDICATIONS Ustekinumab-aekn is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in Ustekinumab-aekn [see Warnings and Precautions ( 5.5 )]. Clinically significant hypersensitivity to ustekinumab products or to any of the excipients in Ustekinumab-aekn. ( 4 )

DRUG INTERACTIONS 7.1 Concomitant Therapies In trials in subjects with plaque psoriasis, the safety of ustekinumab products in combination with immunosuppressive agents or phototherapy has not been evaluated. In trials in subjects with psoriatic arthritis, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In trials in subjects with Crohn’s disease (CD-1 and CD-2) and ulcerative colitis (UC-1) , immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of ustekinumab. 7.2 CYP450 Substrates The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of Ustekinumab-aauz in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates. A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology ( 12.3 )] . 7.3 Allergen Immunotherapy Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products 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.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: Infections [see Warnings and Precautions ( 5.1 )] Malignancies [see Warnings and Precautions ( 5.4 )] Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.6 )] Noninfectious Pneumonia [see Warnings and Precautions ( 5.8 )] Most common adverse reactions are: Psoriasis and Psoriatic Arthritis (≥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) Ulcerative colitis, induction (≥3%): nasopharyngitis (6.1) Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Adult Subjects with Plaque Psoriasis The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies ( 14 )]. Table 5: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2 Ustekinumab Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of PRES occurred during clinical trials in adult subjects with plaque psoriasis [see Warnings and Precautions ( 5.6 )]. Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for subjects receiving placebo and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per patient-years of follow-up) compared with 24% of subjects receiving placebo (1.21 per patient-years of follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per patient-years of follow-up) and in 0.4% of subjects receiving placebo (0.02 per patient-years of follow-up) [see Warnings and Precautions ( 5.1 )]. In the controlled and non-controlled portions of clinical trials in subjects with plaque psoriasis (median follow-up of 3.2 years), representing 8998 patient-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per patient-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per patient-years of follow-up). Malignancies In the controlled and non-controlled portions of clinical trials in subjects with plaque psoriasis (median follow-up of 3.2 years, representing 8998 patient-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred patient-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred patient-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials 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 Pediatric Subjects with Plaque Psoriasis The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic Arthritis The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in clinical trials in adult subjects with plaque psoriasis. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (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 trials. Crohn’s Disease The safety of ustekinumab was assessed in 1407 subjects 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 trials. These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration ( 2.3 )]. Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials 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 ( 14.4) ] . The overall safety profile of ustekinumab was consistent with the safety profile seen in the clinical trials in adult subjects with plaque psoriasis and psoriatic arthritis. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7, respectively. Table 6: Common Adverse Reactions Through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of Ustekinumab–Treated Subjects and Higher Than Subjects Receiving Placebo Placebo Ustekinumab 6 mg/kg single intravenous induction dose N=466 N=470 Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4

12.1. Mechanism of Action Ustekinumab products are human IgG1қ monoclonal antibodies that bind 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 products were 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 and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective.