Ustekinumab

1 INDICATIONS AND USAGE Ustekinumab-aekn 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-aekn 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-aekn 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-aekn is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease. 1.4 Ulcerative Colitis Ustekinumab-aekn is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.

12.1 Mechanism of Action Ustekinumab products are human IgG1κ 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.

2 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

6 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).

5 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

4 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 )

10 OVERDOSAGE Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800- 222-1222) or a medical toxicologist for additional overdose management recommendations.