ENTYVIO

6 ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3) ] Liver Injury [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo) are: nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities. ( 6.1 ) Adverse reactions with subcutaneous ENTYVIO are similar to those reported with intravenous ENTYVIO with the exception of injection site reactions reported with subcutaneous ENTYVIO. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. The data described below reflect exposure to intravenous ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years. Intravenous Infusion The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II and CD Trials I and III); data from adult patients receiving open-label intravenous ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included [see Clinical Studies (14.1 , 14.2) ] . In these trials, 1,434 patients received ENTYVIO 300 mg intravenously for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn's disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III). Adverse reactions were reported in 52% of patients treated with intravenous ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with intravenous ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo). The most common adverse reactions (reported by ≥3% of patients treated with intravenous ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities (Table 2) . Table 2. Adverse Reactions in ≥3% of Intravenous ENTYVIO-Treated Adult Patients and ≥1% Higher than in Placebo (UC Trials I and II Data from patients receiving open-label intravenous ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. and CD Trials I and III ) Adverse Reaction ENTYVIO IV Patients who received ENTYVIO for up to 52 weeks. (N=1434) Placebo Patients who received placebo for up to 52 weeks. (N=297) Nasopharyngitis 13% 7% Headache 12% 11% Arthralgia 12% 10% Nausea 9% 8% Pyrexia 9% 7% Upper respiratory tract infection 7% 6% Fatigue 6% 3% Cough 5% 3% Bronchitis 4% 3% Influenza 4% 2% Back pain 4% 3% Rash 3% 2% Pruritus 3% 1% Sinusitis 3% 1% Oropharyngeal pain 3% 1% Pain in extremities 3% 1% Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received intravenous ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10-week Crohn's disease trial, are similar to those listed in Table 2 . Infusion-Related Reactions and Hypersensitivity Reactions Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following intravenous ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1) ] . In UC Trials I and II and CD Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with intravenous ENTYVIO (0.07%)] was reported by a Crohn's disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In UC Trials I and II and CD Trials I and III, 4% of patients treated with intravenous ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRRs in the patients treated with intravenous ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria, and vomiting (each of these adverse reactions occurred in <1% in all patients treated with intravenous ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with intravenous ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%. In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone, and/or acetaminophen) prior to next infusion. Infections In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with intravenous ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions (5.2) ] . The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. Two percent of patients discontinued intravenous ENTYVIO due to infections. In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with intravenous ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn's disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn's disease patients. Over 48 months, there was no increase in the rate of serious infections. In controlled- and open-label long-term extension trials in adults treated with intravenous ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with intravenous ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn's disease patients treated with intravenous ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn's disease receiving intravenous ENTYVIO was two per 1,000 patient-years. In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with intravenous ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States (U.S.), and none of the patients had extrapulmonary manifestations. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving intravenous ENTYVIO [see Warnings and Precautions (5.4) ] . In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five intravenous ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3× ULN was <2% in patients treated with intravenous ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed. Malignancies In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with intravenous ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of the appendix (n=1), and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma). Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer, and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Subcutaneous Injection after Two Intravenous Doses of ENTYVIO ENTYVIO was administered as a subcutaneous injection in adult patients with ulcerative colitis and Crohn’s disease in double-blind, placebo-controlled clinical trials (SC UC Trial and SC CD Trial, respectively). Patients who achieved clinical response following two doses of ENTYVIO administered as an intravenous infusion at Week 0 and Week 2 were randomized 2:1 at Week 6 to ENTYVIO as a subcutaneous injection (N=106) or placebo (N=56) (SC UC Trial) and as a subcutaneous injection (N=275) or placebo (N=134) (SC CD Trial) [see Clinical Studies (14.1 , 14.2) ] . The safety profile for up to 52 weeks of total treatment was similar between patients who were switched to ENTYVIO as a subcutaneous injection in SC UC and SC CD clinical trials and patients in UC and CD clinical trials who received ENTYVIO as an intravenous infusion ( Table 2 ) except for injection site reactions, which were reported with subcutaneous ENTYVIO. Injection site reactions with subcutaneous ENTYVIO were reported in 10% (11/106) of patients in SC UC Trial, including injection site erythema, rash, pruritus, swelling, bruising, and hematoma. Injection site reactions with subcutaneous ENTYVIO were reported in 3% (8/275) of patients in SC CD Trial, including injection site erythema, pruritus, urticaria, pain, rash, and edema. Live and Oral Vaccines There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO. In a placebo-controlled study of healthy volunteers, 61 subjects were given a single intravenous ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with intravenous ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to intravenous ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. 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 drug exposure. Immune system disorders: Anaphylaxis [see Warnings and Precautions (5.1) ]. Gastrointestinal system disorders: Acute pancreatitis. Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, pneumonitis.

7 DRUG INTERACTIONS 7.1 Natalizumab Products Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab products. 7.2 TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. 7.3 CYP450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of certain cytokines (e.g., IL-6, IL-10, TNFα, IFN) during chronic inflammation. Therefore, use of ENTYVIO may normalize the formation of CYP450 enzymes by modulating the underlying disease. Upon initiation or discontinuation of ENTYVIO in patients treated with CYP450 substrates, monitor drug concentrations or other therapeutic parameters, and adjust the dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates.