ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: oInfections [see Warnings and Precautions (5.1)]oMalignancies [see Warnings and Precautions (5.4)]oSerious Hypersensitivity Reactions [see Warnings and Precautions (5.5)]oPosterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]oNoninfectious Pneumonia [see Warnings and Precautions (5.8)]. oInfections [see Warnings and Precautions (5.1)]. oMalignancies [see Warnings and Precautions (5.4)]. oSerious Hypersensitivity Reactions [see Warnings and Precautions (5.5)]. oPosterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]. oNoninfectious Pneumonia [see Warnings and Precautions (5.8)]. Most common adverse reactions are: oPsoriasis and Psoriatic Arthritis (>=3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) oCrohns Disease, induction (>=3%): vomiting. (6.1) oCrohns Disease, maintenance (>=3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) oUlcerative colitis, induction (>=3%): nasopharyngitis (6.1) oUlcerative colitis, maintenance (>=3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oPsoriasis and Psoriatic Arthritis (>=3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) oCrohns Disease, induction (>=3%): vomiting. (6.1) oCrohns Disease, maintenance (>=3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) oUlcerative colitis, induction (>=3%): nasopharyngitis (6.1) oUlcerative colitis, maintenance (>=3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 PsoriasisThe safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 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 summarizes the adverse reactions that occurred at rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY and Ps STUDY [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 and Ps STUDY 2ustekinumabPlacebo45 mg90 mgSubjects treated665664666 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 (1%) (1%) 14 (2%) Dizziness (1%) (1%) 14 (2%) Pharyngolaryngeal pain (1%) (1%) 12 (2%) Pruritus (1%) 10 (2%) (1%) Injection site erythema (<1%) (1%) 13 (2%) Myalgia (1%) (1%) (1%) Depression (<1%) (1%) (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES and 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)]. InfectionsIn 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). MalignanciesIn 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 PsoriasisThe safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY evaluated safety for up to 56 weeks in 44 pediatric subjects to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic ArthritisThe 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. 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. Crohns DiseaseThe safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohns disease (Crohns 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 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 mg/kg as 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 subcutaneous maintenance regimen of either 90 mg ustekinumab every weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 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 Crohns 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 and 7, respectively.Table 6: Common adverse reactions through Week in Trials CD-1 and CD-2 occurring in >=3% of ustekinumab-treated subjects and higher than subjects receiving placeboPlacebo N=466ustekinumab6 mg/kg single intravenous induction doseN=470Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%).Table 7: Common adverse reactions through Week 44 in Trial CD-3 occurring in >=3% of ustekinumab-treated subjects and higher than subjects receiving placeboPlaceboN=133ustekinumab90 mg subcutaneous maintenance dose every weeksN=131NasopharyngitisInjection site erythemaVulvovaginal candidiasis/mycotic infectionBronchitisPruritusUrinary tract infectionSinusitis8%01%3%2%2%2%11%5%5%5%4%4%3%. InfectionsIn subjects with Crohns disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions (5.1)]. MalignanciesWith up to one year of treatment in the Crohns disease clinical trials, 0.2% of ustekinumab-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including AnaphylaxisIn CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One subject experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or related to hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour [see Warnings and Precautions (5.5)]. Ulcerative ColitisThe safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at higher rate than placebo were: oInduction (UC-1): nasopharyngitis (7% vs 4%). oMaintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%). oInduction (UC-1): nasopharyngitis (7% vs 4%). oMaintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%). InfectionsIn subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions (5.1)]. MalignanciesWith up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab- treated subjects (0.48 events per hundred patient-years) and 0.0% of subjects receiving placebo (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of subjects receiving placebo (0.40 events per hundred patient- years).. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products. Approximately to 12.4% of subjects treated with ustekinumab in clinical trials in subjects with plaque psoriasis and psoriatic arthritis developed antibodies to ustekinumab, which were generally low-titer. In clinical trials in subjects with plaque psoriasis, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In trials in subjects with plaque psoriasis, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies.In clinical trials in subjects with Crohns disease and ulcerative colitis, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen.. 6.3 Postmarketing Experience The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to ustekinumab product exposure. Immune system disorders: Hypersensitivity reactions (e.g., anaphylaxis, angioedema, dyspnea, rash, urticaria), including fatal case that presented with chest tightness and dyspnea during infusion of the first dose. Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis). Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES). Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia. Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ustekinumab products are human IgG1 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 shared cell-surface receptor chain, IL-12R1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is hallmark of Crohns 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. 12.2 Pharmacodynamics Plaque PsoriasisIn small exploratory trial, 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 plaque psoriasis. Ulcerative ColitisIn both trial UC-1 (induction) and trial UC-2 (maintenance), positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies (14.5)]. 12.3 Pharmacokinetics AbsorptionIn adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and days, respectively, after 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 single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis. Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady- state serum concentrations of ustekinumab were achieved by Week 28. The mean (+-SD) steady- state trough serum ustekinumab concentrations were 0.69 +- 0.69 mcg/mL for subjects less than or equal to 100 kg receiving 45 mg dose and 0.74 +- 0.78 mcg/mL for subjects greater than 100 kg receiving 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. Following the recommended intravenous induction dose, mean +-SD peak serum ustekinumab concentration was 125.2 +- 33.6 mcg/mL in subjects with Crohns disease, and 129.1 +- 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 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 weeks. Mean +-SD steady-state trough concentration was 2.5 +- 2.1 mcg/mL in subjects with Crohns disease, and 3.3 +- 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every weeks. DistributionPopulation pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 (95% CI: 2.69, 2.78) in subjects with Crohns disease and 3.0 (95% CI: 2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady- state was 4.6 in subjects with Crohns disease and 4.4 in subjects with ulcerative colitis. EliminationThe mean (+-SD) half-life ranged from 14.9 +- 4.6 to 45.6 +- 80.2 days across all trials in subjects with plaque psoriasis following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohns disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohns disease and ulcerative colitis) populations. These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohns disease and ulcerative colitis. MetabolismThe metabolic pathway of ustekinumab products has not been characterized. As human IgG1 monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Specific Populations. WeightWhen given the same dose, subjects with plaque 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 PopulationA population pharmacokinetic analysis (N=106/1937 subjects with plaque 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. Age: Pediatric PopulationFollowing multiple recommended doses of ustekinumab in pediatric subjects years of age and older with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean +-SD steady-state trough serum ustekinumab concentrations were 0.36 +- 0.26 mcg/mL and 0.54 +- 0.43 mcg/mL, respectively, in pediatric subjects to 11 years of age and pediatric subjects 12 years of age and older. Overall, the observed steady state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of ustekinumab. Drug Interaction StudiesThe 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). No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohns disease. [see Drug Interactions (7.2)].Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to TNF blocker in subjects with psoriatic arthritis. In subjects with Crohns disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Adult Subjects with Plaque Psoriasis Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY and Ps STUDY 2) enrolled total of 1996 subjects 18 years of age and older with plaque psoriasis who had 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 trials. Ps STUDY enrolled 766 subjects and Ps STUDY enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects randomized to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks and crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. In both trials, subjects in all treatment groups had median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 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. total of 28% of subjects had history of psoriatic arthritis. In both trials, the endpoints were the proportion of subjects who achieved at least 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physicians Global Assessment (PGA). The PGA is 6-category scale ranging from (cleared) to (severe) that indicates the physicians overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. Clinical ResponseThe results of Ps STUDY and Ps STUDY are presented in Table below. Table 8: Clinical Outcomes at Week 12 in Adult Subjects with Plaque Psoriasis in Ps STUDY and Ps STUDY 2Ps STUDY ustekinumabPs STUDY ustekinumabPlacebo45 mg90 mgPlacebo45 mg90 mgSubjects randomized255255256410409411PASI 75 response8 (3%)171 (67%)170 (66%)15 (4%)273 (67%)311 (76%)PGA of Cleared or Minimal10 (4%)151 (59%)156 (61%)18 (4%)277 (68%)300 (73%)Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab among these subgroups. In subjects who weighed 100 kg or less, response rates were comparable 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 below). Table 9: Clinical Outcomes by Weight at Week 12 in Adult Subjects with Plaque Psoriasis in Ps STUDY and Ps STUDY Subjects were dosed with trial medication at Weeks and 4. Ps STUDY ustekinumabPs STUDY ustekinumabPlacebo45 mg90 mgPlacebo45 mg90 mgSubjects randomized255255256410409411PASI 75 response<=100 kg4%6/16674%124/16865%107/1644%12/29073%218/29778%225/289>100 kg2%2/8954%47/8768%63/923%3/12049%55/11271%86/121PGA of Cleared or Minimal<=100 kg4%7/16664%108/16863%103/1645%14/29074%220/29775%216/289>100 kg3%3/8949%43/8758%53/923%4/12051%57/11269%84/121Subjects in Ps STUDY who were PASI 75 responders at both Weeks 28 and 40 were re- randomized at Week 40 to either continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to ustekinumab 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 Pediatric Subjects with Plaque Psoriasis A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 years of age and older with minimum BSA involvement of 10%, PASI score greater than or equal to 12, and PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy.Subjects were randomized to receive placebo (n 37), the recommended dose of ustekinumab (n 36), or one-half the recommended dose of ustekinumab (n 37) by subcutaneous injection at Weeks and followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive ustekinumab at the recommended dose or one-half the recommended dose. Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics. The endpoints were the proportion of subjects who achieved PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent. Clinical ResponseThe efficacy results at Week 12 for Ps STUDY are presented in Table 10.Table 10: Efficacy Results at Week 12 in Pediatric Subjects 12 Years of Age and Older with Plaque Psoriasis in Ps STUDY Using the weight-based dosage regimen specified in Table and Table 2. Ps STUDY 3Placebon (%)ustekinumab (%)N3736PGAPGA of cleared (0) or minimal (1)2 (5.4%)25 (69.4%)PASIPASI 75 responders4 (10.8%)29 (80.6%)PASI 90 responders2 (5.4%)22 (61.1%). 14.3 Psoriatic Arthritis The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 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. Subjects in these trials had diagnosis of PsA for at least months. Subjects 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 subjects, respectively, had enthesitis and dactylitis at baseline. Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks and followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX (<=25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24. In PsA STUDY and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)- agent was not allowed. In PsA STUDY 2, 58% (n=180) of the subjects 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 ResponseIn both trials, greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the ustekinumab 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with ustekinumab alone or in combination with methotrexate. Responses were similar in subjects regardless of prior TNF exposure.Table 11: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY and PsA STUDY at Week 24a Number of subjects with >= 3% BSA psoriasis skin involvement at baseline PsA STUDY ustekinumabPsA STUDY ustekinumabPlacebo45 mg90 mgPlacebo45 mg90 mgNumber of subjectsrandomized206205204104103105ACR 20 response, (%)47 (23%)87 (42%)101 (50%)21 (20%)45 (44%)46 (44%)ACR 50 response, (%)18 (9%)51 (25%)57 (28%)7 (7%)18 (17%)24 (23%)ACR 70 response, (%)5 (2%)25 (12%)29 (14%)3 (3%)7 (7%)9 (9%)Number of subjects with>= 3% BSAa 146145149808081PASI 75 response, (%)16 (11%)83 (57%)93 (62%)4 (5%)41 (51%)45 (56%)The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1. Figure 1: Percent of subjects achieving ACR 20 response through Week 24The results of the components of the ACR response criteria are shown in Table 12.Table 12: Mean change from baseline in ACR components at Week 24a Number of swollen joints counted (0-66) Number of tender joints counted (0-68) Visual analogue scale; 0= best, 10=worst. Disability Index of the Health Assessment Questionnaire; = best, = worst, measures the patients 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) PsA STUDY ustekinumabPlacebo (N 206)45 mg(N 205)90 mg(N 204)Number of swollen jointsa Baseline 15 12 13 Mean Change at Week 24 -3 -5 -6 Number of tender jointsb Baseline 25 22 23 Mean Change at Week 24 -4 -8 -9 Subjects assessment of painc Baseline 6.1 6.2 6.6 Mean Change at Week 24 -0.5 -2.0 -2.6 Subject global assessmentc Baseline 6.1 6.3 6.4 Mean Change at Week 24 -0.5 -2.0 -2.5 Physician global assessmentc Baseline 5.8 5.7 6.1 Mean Change at Week 24 -1.4 -2.6 -3.1 Disability index (HAQ)d Baseline 1.2 1.2 1.2 Mean Change at Week 24 -0.1 -0.3 -0.4 CRP (mg/dL)e Baseline 1.6 1.7 1.8 Mean Change at Week 24 0.01 -0.5 -0.8 An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared with placebo at Week 24. ustek-img-04.jpg. Physical FunctionUstekinumab-treated subjects showed improvement in physical function compared to subjects receiving placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ- DI responders (>=0.3 improvement in HAQ-DI score) was greater in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24. 14.4 Crohns Disease Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with moderately to severely active Crohns disease (Crohns Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD-2) followed by 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with TNF blocker. Trials CD-1 and CD-2In trials CD-1 and CD-2, 1409 subjects 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 reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week and clinical remission (defined as CDAI score of less than 150) at Week were evaluated. In both trials, subjects were randomized to receive single intravenous administration of ustekinumab at either approximately mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended). In trial CD-1, subjects had failed or were intolerant to prior treatment with TNF blocker: 29% subjects had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had failed or prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 319 in the ustekinumab approximately mg/kg group and 313 in the placebo group. In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received TNF blocker and 31% previously received but had not failed TNF blocker. At baseline, and throughout the trial, approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group.In these induction trials, greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately mg/kg dose) achieved clinical response at Week and clinical remission at Week compared to placebo (see Table 13 for clinical response and remission rates). Clinical response and remission were significant as early as Week in ustekinumab-treated subjects and continued to improve through Week 8.Table 13: Induction of Clinical Response and Remission in CD-1 and CD-2 Clinical remission is defined as CDAI score 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed TNF blocker or were never treated with TNF blocker. Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. 0.001<= < 0.01 p 0.001 CD-1 = 741CD-2 = 627Placebo = 247ustekinumab N 249Treatment differenceand 95% CIPlacebo = 209ustekinumab N 209Treatment differenceand 95% CIClinical Response (100 point), Week 53 (21%) 84 (34%)a 12%(4%, 20%) 60 (29%) 116 (56%)b 27%(18%, 36%) Clinical Remission, Week 18 (7%) 52 (21%)b 14%(8%, 20%) 41 (20%) 84 (40%)b 21%(12%, 29%) Clinical Response (100 point), Week 50 (20%) 94 (38%)b 18%(10%, 25%) 67 (32%) 121 (58%)b 26%(17%, 35%) 70 Point Response,Week 75 (30%) 109 (44%)a 13%(5%, 22%) 81 (39%) 135 (65%)b 26%(17%, 35%) 70 Point Response,Week 67 (27%) 101 (41%)a 13%(5%, 22%) 66 (32%) 106 (51%)b 19%(10%, 28%) Trial CD-3The maintenance trial (CD-3) evaluated 388 subjects who achieved clinical response (>=100-point reduction in CDAI score) at Week with either induction dose of ustekinumab in trials CD-1 or CD-2. Subjects were randomized to receive subcutaneous maintenance regimen of either 90 mg ustekinumab every weeks or placebo for 44 weeks (see Table 14). Table 14: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)Clinical remission is defined as CDAI score 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. subjects 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. subjects who achieved clinical response to ustekinumab at the end of the induction trial. p 0.01 0.01<= < 0.05 Placebo = 131+ 90 mgustekinumabevery weeks = 128+ Treatment difference and95% CIClinical Remission 47 (36%) 68 (53%)a 17% (5%, 29%) Clinical Response 58 (44%) 76 (59%)b 15% (3%, 27%) Clinical Remission in subjects in remission at the start of maintenance therapy 36/79 (46%) 52/78 (67%)a 21% (6%, 36%) At Week 44, 47% of subjects who received ustekinumab were corticosteroid-free and in clinical remission, compared to 30% of subjects in the placebo group. At Week of trial CD-3, 34/56 (61%) ustekinumab-treated subjects who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) subjects were in clinical remission at Week while 16/61 (26%) of these subjects were in remission at Week 44. At Week of trial CD-3, 46/72 (64%) ustekinumab-treated subjects who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week while 31/70 (44%) were in remission at Week 44. In the subset of these subjects who were also naive to TNF blockers, 34/52 (65%) of ustekinumab-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm.Subjects who were not in clinical response weeks after ustekinumab induction were not included in the primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive 90 mg subcutaneous injection of ustekinumab upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the trial.. 14.5 Ulcerative Colitis Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for total of 52 weeks of therapy. Disease assessment was based on the Mayo score, which ranged from to 12 and has four subscores that were each scored from (normal) to (most severe): stool frequency, rectal bleeding, findings on centrally reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of to 12, including Mayo endoscopy subscore >=2. An endoscopy score of was defined by marked erythema, absent vascular pattern, friability, erosions; and score of was defined by spontaneous bleeding, ulceration. At baseline, subjects had median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12). Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone). Trial UC-1In UC-1, 961 subjects were randomized at Week to single intravenous administration of ustekinumab of approximately mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. total of 51% had failed at least one biologic and 17% had failed both TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or immunomodulators but were biologic-naive and an additional 3% had previously received but had not failed biologic. At induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates. The primary endpoint was clinical remission at Week 8. Clinical remission with definition of: Mayo stool frequency subscore of or 1, Mayo rectal bleeding subscore of (no rectal bleeding), and Mayo endoscopy subscore of or (Mayo endoscopy subscore of defined as normal or inactive disease and Mayo subscore of defined as presence of erythema, decreased vascular pattern and no friability) is provided in Table 15. The secondary endpoints were clinical response, endoscopic improvement, and histologic- endoscopic mucosal improvement. Clinical response with definition of (>= points and >= 30% decrease in modified Mayo score, defined as 3-component Mayo score without the Physicians Global Assessment, with either decrease from baseline in the rectal bleeding subscore >=1 or rectal bleeding subscore of or 1), endoscopic improvement with definition of Mayo endoscopy subscore of or 1, and histologic-endoscopic mucosal improvement with definition of combined endoscopic improvement and histologic improvement of the colon tissue [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 14. In UC-1, significantly greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15).Table 15: Proportion of Subjects Meeting Efficacy Endpoints at Week in UC-1+ Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. An additional subjects on placebo and subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics. Clinical remission was defined as Mayo stool frequency subscore of or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of or (modified so that does not include friability). Endoscopic improvement was defined as Mayo endoscopy subscore of or (modified so that does not include friability). Clinical response was defined as decrease from baseline in the modified Mayo score by >=30% and >=2 points, with either decrease from baseline in the rectal bleeding subscore >=1 or rectal bleeding subscore of or 1. Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of or 1) and histologic improvement of the colon tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). Adjusted treatment difference (97.5% CI) p 0.001 EndpointPlaceboN 319 ustekinumab N 322 Treatment difference and97.5% CI N%N%Clinical Remission 227%6219%12%(7%, 18%) Bio-naive 14/151 9% 36/147 24% Prior biologic failure 7/161 4% 24/166 14% Endoscopic Improvement 4013%8025%12%(6%, 19%) Bio-naive 28/151 19% 43/147 29% Prior biologic failure 11/161 7% 34/166 20% Clinical Response+ 9931%18658%27%(18%, 35%) Bio-naive 55/151 36% 94/147 64% Prior biologic failure 42/161 26% 86/166 52% Histologic-Endoscopic Mucosal Improvement 268%5417%9%(3%, 14%) Bio-naive 19/151 13% 30/147 20% Prior biologic failure 6/161 4% 21/166 13% The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week to disease progression and long-term outcomes was not evaluated during UC-1. Rectal Bleeding and Stool Frequency SubscoresDecreases in rectal bleeding and stool frequency subscores were observed as early as Week in ustekinumab-treated subjects. Trial UC-2The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response weeks following the intravenous administration of either induction dose of ustekinumab in UC-1. These subjects were randomized to receive subcutaneous maintenance regimen of either 90 mg ustekinumab every weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks. The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission weeks after induction. Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the recommended dosage (90 mg every weeks) compared to the placebo are shown in Table 16. Table 16: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose) An additional subjects on placebo and subjects on ustekinumab had been exposed to, but had not failed, biologics. The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. Clinical remission was defined as Mayo stool frequency subscore of or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of or (modified so that does not include friability). Clinical response was defined as decrease from baseline in the modified Mayo score by >=30% and >=2 points, with either decrease from baseline in the rectal bleeding subscore >=1 or rectal bleeding subscore of or 1. Endoscopic improvement was defined as Mayo endoscopy subscore of or (modified so that does not include friability). Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44. p =<0.001 p=0.004 EndpointPlaceboN 175+ 90 mgustekinumabevery weeksN 176Treatment difference and95% CIN%N%Clinical Remission 4626%7945%19%(9%, 28%) Bio-naive 30/84 36% 39/79 49% Prior biologic failure 16/88 18% 37/91 41% Maintenance of Clinical Response at Week 44+ 8448%13074%26%(16%, 36%) Bio-naive 49/84 58% 62/79 78% Prior biologic failure 35/88 40% 64/91 70% Endoscopic Improvement 4727%8347%20%(11%, 30%) Bio-naive 29/84 35% 42/79 53% Prior biologic failure 18/88 20% 38/91 42% Corticosteroid-free Clinical Remission 4526%7643%17%(8%, 27%) Bio-naive 30/84 36% 38/79 48% Prior biologic failure 15/88 17% 35/91 38% Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission weeks after induction18/5036%27/4166%31%(12%, 50%) Bio-naive 12/27 44% 14/20 70% Prior biologic failure 6/23 26% 12/18 67% Other Endpoints. Week 16 Responders to Ustekinumab InductionSubjects who were not in clinical response weeks after induction with ustekinumab in UC-1 were not included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive 90 mg subcutaneous injection of ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and received ustekinumab 90 mg subcutaneously every weeks during the UC-2 trial. At Week 44, there were 97/157 (62%) subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission. Histologic-Endoscopic Mucosal Improvement at Week 44The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among subjects on ustekinumab and 40/172 (23%) in subjects on placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2. Endoscopic NormalizationNormalization of endoscopic appearance of the mucosa was defined as Mayo endoscopic subscore of 0. At Week in UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with ustekinumab and 12/319 (4%) of subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects treated with ustekinumab and in 32/175 (18%) of subjects in placebo group.

DOSAGE & ADMINISTRATION SECTION.

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 weeks later, followed by 45 mg administered subcutaneously every 12 weeksgreater than 100 kg 90 mg administered subcutaneously initially and weeks later, followed by 90 mg administered subcutaneously every 12 weeksPediatric Patients Years of Age and Older with Plaque Psoriasis Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg0.75 mg/kg60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):oThe recommended dosage is 45 mg administered subcutaneously initially and weeks later, followed by 45 mg administered subcutaneously every 12 weeks.oFor patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and weeks later, followed by 90 mg administered subcutaneously every 12 weeks.Psoriatic Arthritis Pediatric Years of Age and Older Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg0.75 mg/kg60 kg or more 45 mg greater than 100 kg with co-existent moderate-to-severe plaque psoriasis 90 mg Crohns Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dose (2.3): 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) Crohns Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): subcutaneous 90 mg dose weeks after the initial intravenous dose, then every weeks thereafter. oThe recommended dosage is 45 mg administered subcutaneously initially and weeks later, followed by 45 mg administered subcutaneously every 12 weeks.. oFor patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and weeks later, followed by 90 mg administered subcutaneously every 12 weeks.. 2.1 Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage RegimenoFor patients weighing 100 kg or less, the recommended dosage is 45 mg initially and weeks later, followed by 45 mg every 12 weeks. oFor patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 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)]. oFor patients weighing 100 kg or less, the recommended dosage is 45 mg initially and weeks later, followed by 45 mg every 12 weeks. oFor patients weighing more than 100 kg, the recommended dosage is 90 mg initially and weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage RegimenAdminister OTULFI subcutaneously at Weeks and 4, then every 12 weeks thereafter. The recommended dose of OTULFI for pediatric patients years of age and older with plaque psoriasis based on body weight is shown below (Table 1).Table 1: Recommended Dose of OTULFI for Subcutaneous Injection in Pediatric Patients Years of Age and Older with Plaque PsoriasisFor 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 single-dose vial.Body Weight of Patient at the Time of DosingRecommended Doseless than 60 kg0.75 mg/kg60 kg to 100 kg 45 mg more than 100 kg 90 mg Table 2: Injection volumes of OTULFI 45 mg/0.5 mL single-dose vials for pediatric patients years of age and older with plaque psoriasis and pediatric patients years of age and older with psoriatic arthritis weighing less than 60 kgBody Weight (kg) at the time of dosingDose (mg)Volume of injection (mL)1511.30.121612.00.131712.80.141813.50.151914.30.162015.00.172115.80.172216.50.182317.30.192418.00.202518.80.212619.50.222720.30.222821.00.232921.80.243022.50.253123.30.2632240.273324.80.273425.50.283526.30.2936270.33727.80.313828.50.323929.30.3240300.334130.80.344231.50.354332.30.3644330.374533.80.374634.50.384735.30.3948360.44936.80.415037.50.425138.30.4252390.435339.80.445440.50.455541.30.4656420.465742.80.475843.50.485944.30.49 Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.. 2.2 Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage RegimenoThe recommended dosage is 45 mg initially and weeks later, followed by 45 mg every 12 weeks. oFor patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dosage is 90 mg initially and weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage RegimenAdminister OTULFI subcutaneously at Weeks and 4, then every 12 weeks thereafter. The recommended dose of OTULFI for pediatric patients years of age and older with psoriatic arthritis, based on body weight, is shown below (Table 3).Table 3: Recommended Dose of OTULFI for Subcutaneous Injection in Pediatric Patients Years of Age and Older with Psoriatic Arthritis 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 single-dose vial.Body Weight of Patient at the Time of DosingRecommended Doseless than 60 kg 0.75 mg/kg60 kg or more 45 mg greater than 100 kg with co-existent moderate-to-severeplaque psoriasis 90 mg oThe recommended dosage is 45 mg initially and weeks later, followed by 45 mg every 12 weeks. oFor patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dosage is 90 mg initially and weeks later, followed by 90 mg every 12 weeks. 2.3 Recommended Dosage in Crohns Disease and Ulcerative Colitis Intravenous Induction Adult Dosage RegimenA single intravenous infusion dose of OTULFI using the weight-based dosage regimen specified in Table [see Instructions for dilution of OTULFI 130 mg vial for intravenous infusion (2.5)].Table 4: Initial Intravenous Dosage of OTULFIBody Weight of Patient at the time of dosingDoseNumber of 130 mg/26 mL (5 mg/mL) OTULFI vials55 kg or less 260 mg more than 55 kg to 85 kg 390 mg more than 85 kg 520 mg . Subcutaneous Maintenance Adult Dosage RegimenThe recommended maintenance dosage is subcutaneous 90 mg dose administered weeks after the initial intravenous dose, then every weeks thereafter. 2.4 General Considerations for Administration oOTULFI is intended for use under the guidance and supervision of healthcare provider. OTULFI should only be administered to patients who will be closely monitored and have regular follow-up visits with healthcare provider. The appropriate dose should be determined by healthcare provider using the patients current weight at the time of dosing. In pediatric patients, it is recommended that OTULFI be administered by healthcare provider. If healthcare provider determines that it is appropriate, patient may self-inject or caregiver may inject OTULFI after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use [see Instructions for Use]. oThe needle cover on the prefilled syringe is not made with natural rubber (a derivative of latex). oIt is recommended that each injection be administered at 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, 1 mL syringe with 27 gauge, 1/2 inch needle is recommended.oPrior to administration, visually inspect OTULFI for particulate matter and discoloration. OTULFI is clear to slightly opalescent and colorless to slightly brown-yellow solution. Do not use OTULFI if it is discolored or cloudy, or if other particulate matter is present. OTULFI does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. oOTULFI is intended for use under the guidance and supervision of healthcare provider. OTULFI should only be administered to patients who will be closely monitored and have regular follow-up visits with healthcare provider. The appropriate dose should be determined by healthcare provider using the patients current weight at the time of dosing. In pediatric patients, it is recommended that OTULFI be administered by healthcare provider. If healthcare provider determines that it is appropriate, patient may self-inject or caregiver may inject OTULFI after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Instructions for Use [see Instructions for Use]. oThe needle cover on the prefilled syringe is not made with natural rubber (a derivative of latex). oIt is recommended that each injection be administered at 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, 1 mL syringe with 27 gauge, 1/2 inch needle is recommended.. oPrior to administration, visually inspect OTULFI for particulate matter and discoloration. OTULFI is clear to slightly opalescent and colorless to slightly brown-yellow solution. Do not use OTULFI if it is discolored or cloudy, or if other particulate matter is present. OTULFI does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5 Preparation and Administration of OTULFI 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohns Disease and Ulcerative Colitis) OTULFI solution for intravenous infusion must be diluted, prepared and infused by healthcare professional using aseptic technique. 1.Calculate the dose and the number of OTULFI vials needed based on patient weight (Table 4). Each 26 mL vial of OTULFI contains 130 mg of ustekinumab-aauz. 2.Withdraw, and then discard volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of OTULFI to be added (discard 26 mL sodium chloride for each vial of OTULFI needed, for vials- discard 52 mL, for vials- discard 78 mL, vials- discard 104 mL). Alternatively, 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. 3.Withdraw 26 mL of OTULFI from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix. 4.Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed. 5.Infuse the diluted solution over period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag. 6.Use only polypropylene (PP) or polyvinylchloride (PVC) infusion sets with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). 7.Do not infuse OTULFI concomitantly in the same intravenous line with other agents. 8.OTULFI does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements. 1.Calculate the dose and the number of OTULFI vials needed based on patient weight (Table 4). Each 26 mL vial of OTULFI contains 130 mg of ustekinumab-aauz. 2.Withdraw, and then discard volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of OTULFI to be added (discard 26 mL sodium chloride for each vial of OTULFI needed, for vials- discard 52 mL, for vials- discard 78 mL, vials- discard 104 mL). Alternatively, 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. 3.Withdraw 26 mL of OTULFI from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix. 4.Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed. 5.Infuse the diluted solution over period of at least one hour. Once diluted, the infusion should be completely administered within eight hours of the dilution in the infusion bag. 6.Use only polypropylene (PP) or polyvinylchloride (PVC) infusion sets with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). 7.Do not infuse OTULFI concomitantly in the same intravenous line with other agents. 8.OTULFI does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements. StorageIf necessary, the diluted infusion solution may be kept at room temperature up to 25C (77F) for up to hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution. Protect from light.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics AbsorptionIn adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and days, respectively, after 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 single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis. Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady- state serum concentrations of ustekinumab were achieved by Week 28. The mean (+-SD) steady- state trough serum ustekinumab concentrations were 0.69 +- 0.69 mcg/mL for subjects less than or equal to 100 kg receiving 45 mg dose and 0.74 +- 0.78 mcg/mL for subjects greater than 100 kg receiving 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. Following the recommended intravenous induction dose, mean +-SD peak serum ustekinumab concentration was 125.2 +- 33.6 mcg/mL in subjects with Crohns disease, and 129.1 +- 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 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 weeks. Mean +-SD steady-state trough concentration was 2.5 +- 2.1 mcg/mL in subjects with Crohns disease, and 3.3 +- 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every weeks. DistributionPopulation pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 (95% CI: 2.69, 2.78) in subjects with Crohns disease and 3.0 (95% CI: 2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady- state was 4.6 in subjects with Crohns disease and 4.4 in subjects with ulcerative colitis. EliminationThe mean (+-SD) half-life ranged from 14.9 +- 4.6 to 45.6 +- 80.2 days across all trials in subjects with plaque psoriasis following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohns disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohns disease and ulcerative colitis) populations. These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohns disease and ulcerative colitis. MetabolismThe metabolic pathway of ustekinumab products has not been characterized. As human IgG1 monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Specific Populations. WeightWhen given the same dose, subjects with plaque 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 PopulationA population pharmacokinetic analysis (N=106/1937 subjects with plaque 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. Age: Pediatric PopulationFollowing multiple recommended doses of ustekinumab in pediatric subjects years of age and older with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean +-SD steady-state trough serum ustekinumab concentrations were 0.36 +- 0.26 mcg/mL and 0.54 +- 0.43 mcg/mL, respectively, in pediatric subjects to 11 years of age and pediatric subjects 12 years of age and older. Overall, the observed steady state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of ustekinumab. Drug Interaction StudiesThe 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). No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohns disease. [see Drug Interactions (7.2)].Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to TNF blocker in subjects with psoriatic arthritis. In subjects with Crohns disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEOTULFI (oh tool fee)(ustekinumab-aauz)injection, for subcutaneous useThis Instructions for Use contains information on how to inject OTULFI using prefilled syringe.Read this Instructions for Use before you start using OTULFI. healthcare provider should show you how to prepare and give an injection of OTULFI the right way.If you cannot give the injection: oask healthcare provider to help you, oroask someone who has been trained by healthcare provider to give the injections. Do not try to inject OTULFI until you have been shown how to inject OTULFI by healthcare provider.Important Information You Need to Know Before Injecting OTULFI:oFor subcutaneous use only (inject directly under the skin).oBefore you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by the healthcare provider.oIf the dose is 45 mg, you will receive one 45 mg prefilled syringe. oIf the dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for 90 mg dose, you will need to give two injections, one right after the other.oCheck the expiration date on the prefilled syringe and carton. Do not use OTULFI after the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86oF (30oC) for longer than maximum single period of 30 days, or if the prefilled syringe has been stored above 86oF (30oC). Call your healthcare provider or pharmacist, or call Fresenius Kabi USA, LLC at 1-800-551-7176 for help. oMake sure the syringe is not damaged.oCheck the prefilled syringe for any particles or discoloration. The liquid in the prefilled syringe should look clear and colorless to slightly brown-yellow.oDo not use if it is frozen, discolored, cloudy or has particles. Get new prefilled syringe.oDo not shake the prefilled syringe at any time. Shaking the prefilled syringe may damage the OTULFI medicine. If the prefilled syringe has been shaken, do not use it. Get new prefilled syringe.oTo reduce the risk of accidental needle sticks, each prefilled syringe has needle guard that is automatically activated to cover the needle after you have given the injection. Do not pull back on the plunger at any time.Storing OTULFI prefilled syringesoStore OTULFI prefilled syringes in the refrigerator between 36F to 46F (2C to 8C) oStore OTULFI prefilled syringes in the original carton to protect from light. oDo not freeze OTULFI prefilled syringes.oIf needed, individual OTULFI prefilled syringes may be stored at room temperature up to 86oF (30C) for maximum single period of up to 30 days in the original carton to protect from light. oRecord the date when the prefilled syringe is removed from the refrigerator on the carton in the space provided. oAfter prefilled syringe has been stored at room temperature, do not return it to the refrigerator.oThrow away (discard) the prefilled syringe if it is not used within 30 days at room temperature storage.Keep OTULFI and all medicines out of the reach of children.Gather the supplies you will need to prepare and to give the injection. (See Figure A)You will need: oantiseptic wipes ocotton balls or gauze pads oadhesive bandage othe prescribed dose of OTULFI (See Figure B) oFDA-cleared sharps disposal container. See Step 4: Disposing of the syringes. Figure AFigure BTo prevent early activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use.Step 1: Preparing the injectionoChoose well-lit, clean, flat work surface. oWash your hands well with soap and warm water. oHold the prefilled syringe with the covered needle pointing upward. Step 2: Preparing the injection siteoChoose an injection site around the stomach area (abdomen), buttocks, upper legs (thighs). If caregiver is giving the injection, the outer area of the upper arms may also be used. (See Figure C)oUse different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard. oClean the skin with an antiseptic wipe where you plan to give the injection. oDo not touch this area again before giving the injection. Let the skin dry before injecting. oDo not fan or blow on the clean area. Figure CAreas in gray are recommended injection sites Step 3: Injecting OTULFIoRemove the needle cover when you are ready to inject OTULFI. oDo not touch the plunger or plunger head while removing the needle cover. oHold the body of the prefilled syringe with one hand, and pull the needle cover straight off. (See Figure D) oPut the needle cover in the trash. oYou may also see drop of liquid at the end of the needle. This is normal. oDo not touch the needle or let it touch anything. oDo not use the prefilled syringe if it is dropped without the needle cover in place. Figure oHold the body of the prefilled syringe in one hand between the thumb and index fingers. (See Figure E) Figure EoDo not pull back on the plunger at any time. oUse the other hand to gently pinch the cleaned area of skin. Hold firmly. oUse quick, dart-like motion to insert the needle into the pinched skin at about 45-degree angle. (See Figure F)Figure FoInject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure G) Figure GoWhen the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and then let go of the skin. oSlowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H)Figure HoWhen the needle is pulled out of the skin, there may be little bleeding at the injection site. This is normal. You can press cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with small adhesive bandage, if necessary. If the dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for 90 mg dose, you will need to give second injection right after the first. Repeat Steps to for the second injection using new syringe. Choose different site for the second injection.Step 4: Disposing of the syringesoPut the syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) syringes in your household trash.oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plastic, ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out, oupright and stable during use, oleak-resistant, oand properly labeled to warn of hazardous waste inside the container. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. oDo not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container. oIf you have any questions, talk to your healthcare provider or pharmacist. Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 01/2026 oask healthcare provider to help you, or. oask someone who has been trained by healthcare provider to give the injections. oFor subcutaneous use only (inject directly under the skin).. oBefore you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by the healthcare provider.oIf the dose is 45 mg, you will receive one 45 mg prefilled syringe. oIf the dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for 90 mg dose, you will need to give two injections, one right after the other.. oIf the dose is 45 mg, you will receive one 45 mg prefilled syringe. oIf the dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for 90 mg dose, you will need to give two injections, one right after the other.. oCheck the expiration date on the prefilled syringe and carton. Do not use OTULFI after the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86oF (30oC) for longer than maximum single period of 30 days, or if the prefilled syringe has been stored above 86oF (30oC). Call your healthcare provider or pharmacist, or call Fresenius Kabi USA, LLC at 1-800-551-7176 for help. oMake sure the syringe is not damaged.. oCheck the prefilled syringe for any particles or discoloration. The liquid in the prefilled syringe should look clear and colorless to slightly brown-yellow.. oDo not use if it is frozen, discolored, cloudy or has particles. Get new prefilled syringe.. oDo not shake the prefilled syringe at any time. Shaking the prefilled syringe may damage the OTULFI medicine. If the prefilled syringe has been shaken, do not use it. Get new prefilled syringe.. oTo reduce the risk of accidental needle sticks, each prefilled syringe has needle guard that is automatically activated to cover the needle after you have given the injection. Do not pull back on the plunger at any time.. oStore OTULFI prefilled syringes in the refrigerator between 36F to 46F (2C to 8C) oStore OTULFI prefilled syringes in the original carton to protect from light. oDo not freeze OTULFI prefilled syringes.. oIf needed, individual OTULFI prefilled syringes may be stored at room temperature up to 86oF (30C) for maximum single period of up to 30 days in the original carton to protect from light. oRecord the date when the prefilled syringe is removed from the refrigerator on the carton in the space provided. oAfter prefilled syringe has been stored at room temperature, do not return it to the refrigerator.. oThrow away (discard) the prefilled syringe if it is not used within 30 days at room temperature storage.. oantiseptic wipes ocotton balls or gauze pads oadhesive bandage othe prescribed dose of OTULFI (See Figure B) oFDA-cleared sharps disposal container. See Step 4: Disposing of the syringes. oChoose well-lit, clean, flat work surface. oWash your hands well with soap and warm water. oHold the prefilled syringe with the covered needle pointing upward. oChoose an injection site around the stomach area (abdomen), buttocks, upper legs (thighs). If caregiver is giving the injection, the outer area of the upper arms may also be used. (See Figure C). oUse different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard. oClean the skin with an antiseptic wipe where you plan to give the injection. oDo not touch this area again before giving the injection. Let the skin dry before injecting. oDo not fan or blow on the clean area. oRemove the needle cover when you are ready to inject OTULFI. oDo not touch the plunger or plunger head while removing the needle cover. oHold the body of the prefilled syringe with one hand, and pull the needle cover straight off. (See Figure D) oPut the needle cover in the trash. oYou may also see drop of liquid at the end of the needle. This is normal. oDo not touch the needle or let it touch anything. oDo not use the prefilled syringe if it is dropped without the needle cover in place. Figure D. oHold the body of the prefilled syringe in one hand between the thumb and index fingers. (See Figure E) oDo not pull back on the plunger at any time. oUse the other hand to gently pinch the cleaned area of skin. Hold firmly. oUse quick, dart-like motion to insert the needle into the pinched skin at about 45-degree angle. (See Figure F). oInject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure G) oWhen the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and then let go of the skin. oSlowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure H). oWhen the needle is pulled out of the skin, there may be little bleeding at the injection site. This is normal. You can press cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with small adhesive bandage, if necessary. oPut the syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) syringes in your household trash.. oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plastic, ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out, oupright and stable during use, oleak-resistant, oand properly labeled to warn of hazardous waste inside the container. omade of heavy-duty plastic, ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out, oupright and stable during use, oleak-resistant, oand properly labeled to warn of hazardous waste inside the container. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. oDo not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container. oIf you have any questions, talk to your healthcare provider or pharmacist. ustek-img-05.jpg. ustek-img-06.jpg. ustek-img-07.jpg. ustek-img-08.jpg. ustek-img-09.jpg. ustek-img-10.jpg. ustek-img-11.jpg. ustek-img-12.jpg.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 01/2026 MEDICATION GUIDEOTULFI (oh tool fee)(ustekinumab-aauz)injection, for subcutaneous or intravenous useWhat is the most important information should know about OTULFIOTULFI is medicine that affects your immune system. OTULFI can increase your risk of having serious side effects, including:oSerious infections. OTULFI may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections during treatment with ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. oYour healthcare provider should check you for TB before starting OTULFI. oIf your healthcare provider feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with OTULFI and during treatment with OTULFI. oYour healthcare provider should watch you closely for signs and symptoms of TB while you are being treated with OTULFI.You should not start OTULFI if you have any kind of infection unless your healthcare provider says it is okay. Before starting OTULFI, tell your healthcare provider if you:othink you have an infection or have symptoms of an infection such as: fever, sweat, or chillsmuscle achescough shortness of breathblood in phlegm weight losswarm, red, or painful skin or sores on your bodydiarrhea or stomach painburning when you urinate or urinate more often than normalfeel very tiredoare being treated for an infection or have any open cuts. oget lot of infections or have infections that keep coming back. ohave TB, or have been in close contact with someone with TB.After starting OTULFI, call your healthcare provider right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. OTULFI can make you more likely to get infections or make an infection that you have worse.oPeople who have genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take OTULFI may also be more likely to get these infections.oCancers. OTULFI may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your healthcare provider if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with OTULFI, tell your healthcare provider if you develop any new skin growths.What is OTULFIOTULFI is prescription medicine used to treat:oadults and children years of age and older with moderate to severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).oadults and children years of age and older with active psoriatic arthritis.oadults with moderately to severely active Crohns disease.oadults with moderately to severely active ulcerative colitis.It is not known if OTULFI is safe and effective in children with Crohns disease or ulcerative colitis or in children less than years of age with plaque psoriasis or psoriatic arthritis. Who should not use OTULFIDo not use OTULFI if you are allergic to ustekinumab products or any of the ingredients in OTULFI. See the end of this Medication Guide for complete list of ingredients in OTULFI. Before you use or receive OTULFI, tell your healthcare provider about all of your medical conditions, including if you:ohave any of the conditions or symptoms listed in the section What is the most important information should know about OTULFI oever had an allergic reaction to ustekinumab products. Ask your healthcare provider if you are not sure. ohave recently received or are scheduled to receive an immunization (vaccine). People who are being treated with OTULFI should avoid receiving live vaccines. Tell your healthcare provider if anyone in your house needs live vaccine. The viruses used in some types of live vaccines can spread to people with weakened immune system and can cause serious problems. You should avoid receiving the BCG vaccine during the one year before receiving OTULFI or one year after you stop receiving OTULFI. have any new or changing lesions within psoriasis areas or on normal skin.oare receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with OTULFI. OTULFI may also increase your risk of having an allergic reaction to an allergy shot.oreceive or have received phototherapy for your psoriasis.oare pregnant or plan to become pregnant. It is not known if OTULFI can harm your unborn baby. You and your healthcare provider should decide if you will receive OTULFI. oare breastfeeding or plan to breastfeed. OTULFI can pass into your breast milk.oTalk to your healthcare provider about the best way to feed your baby if you receive OTULFI.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How should use OTULFIoUse OTULFI exactly as the healthcare provider tells you to. The healthcare provider will determine the right dose of OTULFI, the amount for each injection, and how often it should be given. Be sure to keep all scheduled follow-up appointments. oAdults with Crohns disease and ulcerative colitis will receive the first dose of OTULFI through vein in the arm (intravenous infusion) in healthcare facility by healthcare provider. It takes at least hour to receive the full dose of medicine. OTULFI will then be received as an injection under the skin (subcutaneous injection) weeks after the first dose of OTULFI, as described below.oAdults and children years of age and older with plaque psoriasis or psoriatic arthritis will receive OTULFI as an injection under the skin as described below.oInjecting OTULFI under the skino OTULFI is intended for use under the guidance and supervision of healthcare provider. oIn children, it is recommended that OTULFI be administered by healthcare provider. If healthcare provider decides that you or caregiver may give the injections of OTULFI at home, you or caregiver should receive training on the right way to prepare and inject OTULFI. oDo not try to inject OTULFI until you have been shown how to inject OTULFI by healthcare provider.oOTULFI can be injected under the skin in the upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).oDo not give an injection in an area of the skin that is tender, bruised, red or hard.oUse different injection site each time you use OTULFI.oIf you inject too much OTULFI, call the healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest emergency room right away.Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject dose of OTULFI, and how to properly throw away (dispose of) used needles, syringes and vials. The syringe, needle and vial must never be re-used. After the rubber stopper is punctured,OTULFI can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of OTULFI.What should avoid while using OTULFIYou should avoid receiving live vaccine during treatment with OTULFI. See Before you use or receive OTULFI, tell your healthcare provider about all of your medical conditions, including if you:What are the possible side effects of OTULFIOTULFI may cause serious side effects, including:oSee What is the most important information should know about OTULFI oSerious allergic reactions. Serious allergic reactions including death can occur with OTULFI. Stop using OTULFI and get medical help right away if you get any of the following symptoms of serious allergic reaction: ofeeling faintoswelling of your face, eyelids, tongue, or throatotrouble breathing ochest discomfortoskin rashoPosterior Reversible Encephalopathy Syndrome (PRES). PRES is rare condition that affects the brain and can cause death. Tell your healthcare provider right away if you get any symptoms of PRES during treatment with OTULFI, including:oheadacheoseizures oconfusionovision problemsoLung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab products, and may be serious. These lung problems may need to be treated in hospital. Tell your healthcare provider right away if you develop shortness of breath or cough that doesnt go away during treatment with OTULFI.The most common side effects of OTULFI include:onasal congestion, sore throat, and runny nose oupper respiratory infections ofever oheadache otiredness oitching onausea and vomiting oinfluenzaoredness at the injection site ovaginal yeast infections ourinary tract infections osinus infection obronchitis odiarrhea ostomach painojoint pain These are not all of the possible side effects of OTULFI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Fresenius Kabi USA, LLC at 1-800-551-7176. How should store OTULFIoStore OTULFI vials and prefilled syringes in refrigerator between 36F to 46F (2C to 8C).oStore OTULFI vials standing up straight (upright).oStore OTULFI in the original carton to protect it from light until time to use it.oDo not freeze OTULFI.oDo not shake OTULFI.oIf needed, individual OTULFI prefilled syringes may also be stored at room temperature up to 86F (30C) for maximum single period of up to 30 days in the original carton to protect from light. oRecord the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided.oAfter prefilled syringe has been stored at room temperature, do not return it to the refrigerator. oThrow away (discard) the prefilled syringe if it is not used within 30 days at room temperature storage. oDo not use OTULFI after the expiration date on the carton or on the prefilled syringe.Keep OTULFI and all medicines out of the reach of children.General information about the safe and effective use of OTULFI.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use OTULFI for condition for which it was not prescribed. Do not give OTULFI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about OTULFI that was written for health professionals.What are the ingredients in OTULFIActive ingredient: ustekinumab-aauz Inactive ingredients: Single-dose prefilled syringe and single-dose vial for subcutaneous use contain histidine, Polysorbate 80, sucrose and hydrochloric acid (to adjust pH). Single-dose vial for intravenous infusion contains edetate disodium, histidine, L-histidine hydrochloride monohydrate, methionine, Polysorbate 80, and sucrose.Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A, US License Number 2146For more information, call 1-833-522-4227 or visit the patient support program website: www.kabicare.com oSerious infections. OTULFI may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections during treatment with ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. oYour healthcare provider should check you for TB before starting OTULFI. oIf your healthcare provider feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with OTULFI and during treatment with OTULFI. oYour healthcare provider should watch you closely for signs and symptoms of TB while you are being treated with OTULFI.. othink you have an infection or have symptoms of an infection such as:. fever, sweat, or chillsmuscle achescough shortness of breathblood in phlegm. fever, sweat, or chills. muscle aches. cough shortness of breath. blood in phlegm. weight losswarm, red, or painful skin or sores on your bodydiarrhea or stomach painburning when you urinate or urinate more often than normalfeel very tired. weight loss. warm, red, or painful skin or sores on your body. diarrhea or stomach pain. burning when you urinate or urinate more often than normal. feel very tired. oare being treated for an infection or have any open cuts. oget lot of infections or have infections that keep coming back. ohave TB, or have been in close contact with someone with TB.. oPeople who have genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take OTULFI may also be more likely to get these infections.. oCancers. OTULFI may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your healthcare provider if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with OTULFI, tell your healthcare provider if you develop any new skin growths.. oadults and children years of age and older with moderate to severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).. oadults and children years of age and older with active psoriatic arthritis.. oadults with moderately to severely active Crohns disease.. oadults with moderately to severely active ulcerative colitis.. ohave any of the conditions or symptoms listed in the section What is the most important information should know about OTULFI oever had an allergic reaction to ustekinumab products. Ask your healthcare provider if you are not sure. ohave recently received or are scheduled to receive an immunization (vaccine). People who are being treated with OTULFI should avoid receiving live vaccines. Tell your healthcare provider if anyone in your house needs live vaccine. The viruses used in some types of live vaccines can spread to people with weakened immune system and can cause serious problems. You should avoid receiving the BCG vaccine during the one year before receiving OTULFI or one year after you stop receiving OTULFI. o have any new or changing lesions within psoriasis areas or on normal skin.. oare receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with OTULFI. OTULFI may also increase your risk of having an allergic reaction to an allergy shot.. oreceive or have received phototherapy for your psoriasis.. oare pregnant or plan to become pregnant. It is not known if OTULFI can harm your unborn baby. You and your healthcare provider should decide if you will receive OTULFI. oare breastfeeding or plan to breastfeed. OTULFI can pass into your breast milk.. oTalk to your healthcare provider about the best way to feed your baby if you receive OTULFI.. oUse OTULFI exactly as the healthcare provider tells you to. The healthcare provider will determine the right dose of OTULFI, the amount for each injection, and how often it should be given. Be sure to keep all scheduled follow-up appointments. oAdults with Crohns disease and ulcerative colitis will receive the first dose of OTULFI through vein in the arm (intravenous infusion) in healthcare facility by healthcare provider. It takes at least hour to receive the full dose of medicine. OTULFI will then be received as an injection under the skin (subcutaneous injection) weeks after the first dose of OTULFI, as described below.. oAdults and children years of age and older with plaque psoriasis or psoriatic arthritis will receive OTULFI as an injection under the skin as described below.. oInjecting OTULFI under the skino OTULFI is intended for use under the guidance and supervision of healthcare provider. oIn children, it is recommended that OTULFI be administered by healthcare provider. If healthcare provider decides that you or caregiver may give the injections of OTULFI at home, you or caregiver should receive training on the right way to prepare and inject OTULFI. oDo not try to inject OTULFI until you have been shown how to inject OTULFI by healthcare provider.oOTULFI can be injected under the skin in the upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).oDo not give an injection in an area of the skin that is tender, bruised, red or hard.oUse different injection site each time you use OTULFI.. OTULFI is intended for use under the guidance and supervision of healthcare provider. oIn children, it is recommended that OTULFI be administered by healthcare provider. If healthcare provider decides that you or caregiver may give the injections of OTULFI at home, you or caregiver should receive training on the right way to prepare and inject OTULFI. oDo not try to inject OTULFI until you have been shown how to inject OTULFI by healthcare provider.. oOTULFI can be injected under the skin in the upper arms, buttocks, upper legs (thighs) or stomach area (abdomen).. oDo not give an injection in an area of the skin that is tender, bruised, red or hard.. oUse different injection site each time you use OTULFI.. oIf you inject too much OTULFI, call the healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest emergency room right away.. oSee What is the most important information should know about OTULFI oSerious allergic reactions. Serious allergic reactions including death can occur with OTULFI. Stop using OTULFI and get medical help right away if you get any of the following symptoms of serious allergic reaction:. ofeeling faintoswelling of your face, eyelids, tongue, or throatotrouble breathing. ofeeling faint. oswelling of your face, eyelids, tongue, or throat. otrouble breathing. ochest discomfortoskin rash. ochest discomfort. oskin rash. oPosterior Reversible Encephalopathy Syndrome (PRES). PRES is rare condition that affects the brain and can cause death. Tell your healthcare provider right away if you get any symptoms of PRES during treatment with OTULFI, including:. oheadache. oseizures. oconfusionovision problems. oconfusion. ovision problems. oLung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab products, and may be serious. These lung problems may need to be treated in hospital. Tell your healthcare provider right away if you develop shortness of breath or cough that doesnt go away during treatment with OTULFI.. onasal congestion, sore throat, and runny nose oupper respiratory infections ofever oheadache otiredness oitching onausea and vomiting oinfluenza. oredness at the injection site ovaginal yeast infections ourinary tract infections osinus infection obronchitis odiarrhea ostomach pain. ojoint pain oStore OTULFI vials and prefilled syringes in refrigerator between 36F to 46F (2C to 8C).. oStore OTULFI vials standing up straight (upright).. oStore OTULFI in the original carton to protect it from light until time to use it.. oDo not freeze OTULFI.. oDo not shake OTULFI.. oIf needed, individual OTULFI prefilled syringes may also be stored at room temperature up to 86F (30C) for maximum single period of up to 30 days in the original carton to protect from light. oRecord the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided.. oAfter prefilled syringe has been stored at room temperature, do not return it to the refrigerator. oThrow away (discard) the prefilled syringe if it is not used within 30 days at room temperature storage. oDo not use OTULFI after the expiration date on the carton or on the prefilled syringe.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryAvailable data from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry, published literature and pharmacovigilance in pregnant women have not identified ustekinumab associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data ). There are risks to the mother and the fetus associated with inflammatory bowel disease (IBD) in pregnancy. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD).All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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.. Clinical ConsiderationsDisease-associated Maternal and Embryo/Fetal RiskPublished data suggest that the risk of adverse pregnancy outcomes in women with IBD is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.Fetal/Neonatal Adverse ReactionsTransport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, Ustekinumab products may be present in infants exposed in utero. The potential clinical impact of ustekinumab product exposure in infants exposed in utero should be considered.DataHuman DataAn observational pregnancy registry conducted by (OTIS)/MotherToBaby in the U.S. and Canada (enrollment between 2013 and 2019) assessed the risk of major birth defects, pattern of major and minor anomalies in live-born infants, miscarriage, and adverse infant outcomes in women with ustekinumab exposure. In the registry study, there were 101 participants and 107 pregnancies with exposure to ustekinumab (88 prospective; 19 retrospective). Most participants had primary indication of CD (65.4%) or psoriasis (30.8%). The pregnancy registry did not identify ustekinumab associated risk of major birth defects, pattern of major or minor anomalies, increased risk of miscarriage or adverse infant outcomes. Methodological limitations of the registry include small sample size, lack of an internal comparison group, mix of prospective and retrospective reports, and unmeasured confounders. The conclusions from the pregnancy registry were consistent with the published literature and pharmacovigilance.Animal DataUstekinumab 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 weeks. In 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 MRHD 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 SummaryLimited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have been identified in the published literature or postmarketing experience. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for OTULFI and any potential adverse effects on the breastfed child from OTULFI or from the underlying maternal condition. 8.4 Pediatric Use Plaque PsoriasisThe safety and effectiveness of OTULFI have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients years of age and older who are candidates for phototherapy or systemic therapy. Use of OTULFI in pediatric patients 12 to less than 17 years of age is supported by evidence from multicenter, randomized, 60-week trial (Ps STUDY 3) of ustekinumab that included 12-week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies (14.2)]. Use of OTULFI in pediatric patients to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)]. The safety and effectiveness of OTULFI have not been established in pediatric patients less than years of age with plaque psoriasis. Psoriatic ArthritisThe safety and effectiveness of OTULFI have been established for treatment of psoriatic arthritis in pediatric patients years of age and older. Use of OTULFI in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adult subjects with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects to 11 years old with psoriasis and 110 pediatric subjects 12 years of age and older with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)]. The safety and effectiveness of OTULFI have not been established in pediatric patients less than years old with psoriatic arthritis. Crohns Disease and Ulcerative ColitisThe safety and effectiveness of OTULFI have not been established in pediatric patients with Crohns disease or ulcerative colitis. 8.5 Geriatric Use Of the 6709 subjects exposed to ustekinumab, total of 340 were 65 years of age or older (183 subjects with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohns disease and 34 subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oInfections: Serious infections have occurred. Avoid starting OTULFI during any clinically important active infection. If serious infection or clinically significant infection develops, discontinue OTULFI until the infection resolves. (5.1) oTheoretical 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) oTuberculosis (TB): Evaluate patients for TB prior to initiating treatment with OTULFI. Initiate treatment of latent TB before administering OTULFI. (5.3) oMalignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with history of or known malignancy has not been evaluated. (5.4) oSerious Hypersensitivity Reactions: If severe or other clinically significant hypersensitivity reaction occurs, discontinue OTULFI immediately and initiate appropriate medical treatment. (5.5) oPosterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue OTULFI. (5.6) oImmunizations: Avoid use of live vaccines in patients during treatment with OTULFI. (5.7) oNoninfectious 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 OTULFI and institute appropriate treatment. (5.8) oInfections: Serious infections have occurred. Avoid starting OTULFI during any clinically important active infection. If serious infection or clinically significant infection develops, discontinue OTULFI until the infection resolves. (5.1) oTheoretical 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) oTuberculosis (TB): Evaluate patients for TB prior to initiating treatment with OTULFI. Initiate treatment of latent TB before administering OTULFI. (5.3) oMalignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with history of or known malignancy has not been evaluated. (5.4) oSerious Hypersensitivity Reactions: If severe or other clinically significant hypersensitivity reaction occurs, discontinue OTULFI immediately and initiate appropriate medical treatment. (5.5) oPosterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue OTULFI. (5.6) oImmunizations: Avoid use of live vaccines in patients during treatment with OTULFI. (5.7) oNoninfectious 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 OTULFI 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: oPlaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. oPsoriatic arthritis: cholecystitis. oCrohns disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. oUlcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Avoid initiating treatment with OTULFI 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 OTULFI in patients with chronic infection or history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with OTULFI and discontinue OTULFI for serious or clinically significant infections until the infection resolves or is adequately treated. oPlaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. oPsoriatic arthritis: cholecystitis. oCrohns disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. oUlcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. 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 OTULFI. Avoid administering OTULFI to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering OTULFI. Consider anti-tuberculosis therapy prior to initiation of OTULFI in patients with past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving OTULFI 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 history of malignancy or who have 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 OTULFI for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with medical history of prolonged immunosuppressant therapy and those with 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 severe or clinically significant hypersensitivity reaction occurs, discontinue OTULFI 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 Crohns disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES few days to several months after ustekinumab product initiation. few cases reported latency of year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products. Monitor all patients treated with OTULFI for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue OTULFI. 5.7 Immunizations Prior to initiating therapy with OTULFI, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with OTULFI should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with OTULFI 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 OTULFI because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during course of OTULFI 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. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue OTULFI and institute appropriate treatment [see Postmarketing Experience (6.3)].