6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: Infections [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.5)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.6)] Most common adverse reactions are: Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) Crohn's Disease, induction (≥3%): vomiting. (6.1) Crohn's Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Subjects with Plaque Psoriasis The safety data reflect exposure to STELARA® in 3117 adult psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Table 4 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)]. Table 4: Adverse Reactions Reported by ≥1% of Subjects through Week 12 in Ps STUDY 1 and Ps STUDY 2 STELARA® Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Diarrhea 12 (2%) 13 (2%) 13 (2%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical studies [see Warnings and Precautions (5.6)]. Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)]. In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and non-controlled portions of psoriasis clinical studies (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical studies were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Adolescent Subjects with Plaque Psoriasis The safety of STELARA® was assessed in a study of 110 subjects 12 to 17 years of age with moderate to severe plaque psoriasis. The safety profile in these subjects through Week 60 was similar to the safety profile from studies in adults with plaque psoriasis. Psoriatic Arthritis The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in adult psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical studies. Crohn's Disease The safety of STELARA® was assessed in 1407 patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter studies. These 1407 patients included 40 patients who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In Studies CD-1 and CD-2 there were 470 patients who received STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Patients who were responders in either Study CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA® every 8 weeks, or placebo for 44 weeks in Study CD-3. Patients in these 3 studies may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.4)]. The overall safety profile of STELARA® was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical studies. Common adverse reactions in Studies CD-1 and CD-2 and in Study CD-3 are listed in Tables 5 and 6, respectively. Table 5: Common adverse reactions through Week 8 in Studies CD-1 and CD-2 occurring in ≥3% of STELARA®-treated patients and higher than placebo Placebo STELARA® 6 mg/kg single intravenous induction dose N=466 N=470 Vomiting 3% 4% Other less common adverse reactions reported in patients in Studies CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). Table 6: Common adverse reactions through Week 44 in Study CD-3 occurring in ≥3% of STELARA®-treated patients and higher than placebo Placebo STELARA® 90 mg subcutaneous maintenance dose every 8 weeks N=133 N=131 Nasopharyngitis 8% 11% Injection site erythema 0 5% Vulvovaginal candidiasis/mycotic infection 1% 5% Bronchitis 3% 5% Pruritus 2% 4% Urinary tract infection 2% 4% Sinusitis 2% 3% Infections In patients with Crohn's disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes were reported in one patient each. Malignancies With up to one year of treatment in the Crohn's disease clinical studies, 0.2% of STELARA®-treated patients (0.36 events per hundred patient-years) and 0.2% of placebo-treated patients (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of STELARA®-treated patients (0.27 events per hundred patient-years) and in none of the placebo-treated patients. Hypersensitivity Reactions Including Anaphylaxis In CD studies, two patients reported hypersensitivity reactions following STELARA® administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of patients receiving subcutaneous STELARA®). In addition, one patient experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous STELARA® dose (0.08% of patients receiving intravenous STELARA®). These patients were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab in the studies described below with the incidence of antibodies to other products may be misleading. Approximately 6–12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn's disease clinical studies, less than 3% of patients treated with STELARA® developed antibodies to ustekinumab. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies. 6.3 Postmarketing Experience The following adverse reactions have been reported during post-approval of STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria) [see Warnings and Precautions (5.5)]. Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia [see Warnings and Precautions (5.9)]. Skin reactions: Pustular psoriasis, erythrodermic psoriasis.