sort of [1%:<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 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 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 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 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 1434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn s disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both of these 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 ENTYVIO was two per 1000 patient-years. In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving 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 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 x ULN was> <2% in patients treated with 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 1434 (0.4%) patients treated with 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. 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 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 ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to 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. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations [see Clinical Pharmacology ( 12.3 )] . None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials. 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 sample handling, timing of sample collection, concomitant medications, presence of vedolizumab, and underlying disease. For these reasons, comparison of the incidence of antibodies to ENTYVIO with the incidence of antibodies to other products may be misleading. Drug Interactions Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab. TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions ( 5.5 )] . USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327). Pregnancy Category B : Risk Summary There are no studies with ENTYVIO in pregnant women. No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the benefits to the mother outweigh the risk to the unborn child. Clinical Considerations Any adverse pregnancy effect from ENTYVIO would likely be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage). Nursing Mothers It is unknown whether vedolizumab is present in human milk. Vedolizumab was detected in the milk of lactating monkeys. Exercise caution when administering vedolizumab to a nursing woman. Pediatric Use Safety and effectiveness of ENTYVIO in pediatric patients have not been established. Geriatric Use Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn s and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Entyvio Injection Description ENTYVIO (vedolizumab), an integrin receptor antagonist, is a humanized IgG 1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human α4β7 integrin. ENTYVIO has an approximate molecular weight of 147 kilodaltons. ENTYVIO is supplied as a sterile, white to off-white, preservative-free, lyophilized cake for intravenous infusion. After reconstitution with 4.8 mL Sterile Water for Injection, USP, the resulting pH is approximately 6.3. Each single-use vial contains 300 mg vedolizumab, 23 mg L-histidine, 21.4 mg L-histidine monohydrochloride, 131.7 mg L-arginine hydrochloride, 500 mg sucrose and 3 mg polysorbate 80. Entyvio Injection - Clinical Pharmacology Mechanism of Action Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn s disease. Pharmacodynamics In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed. In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells. A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to ENTYVIO for four or six weeks compared to placebo control as assessed by histopathology. In a study of 14 healthy subjects, ENTYVIO did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF [see Clinical Pharmacology ( 12.3 )] . Pharmacokinetics Similar pharmacokinetics were observed in ulcerative colitis and Crohn s disease patients administered 300 mg ENTYVIO as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg ENTYVIO every eight weeks starting from Week 6 (Table 2) . * Data from patients in UC Trials I and II and CD Trials I and III with pharmacokinetic data available; data from patients with anti-vedolizumab antibody were excluded. † Steady-state trough serum concentration. Table 2. Mean SD Vedolizumab Concentrations in Patients * with Ulcerative Colitis and Crohn s Disease Patient Population Weeks 0 to 6 Weeks 6 to 52 ENTYVIO Every 8 Weeks Trough Serum Concentration at Week 6 (mcg/mL) Trough Serum Concentration at Week 46 † (mcg/mL) Ulcerative Colitis 26.3 12.9 (N=210) 11.2 7.2 (N=77) Crohn s Disease 27.4 19.2 (N=198) 13.0 9.1 (N=72) The presence of persistent anti-vedolizumab antibody was observed to substantially reduce serum concentrations of vedolizumab, either to undetectable or negligible levels at Weeks 6 and 52 (n=8). Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L. Vedolizumab was not detected in the cerebrospinal fluid (CSF) of 14 healthy subjects at five weeks after a single intravenous administration of 450 mg ENTYVIO (1.5 times the recommended dosage). Special Populations Population pharmacokinetic analysis showed that the severity of disease state, body weight, prior treatment with TNF blocker therapy, age (18 to 78 years), serum albumin, co-administered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and co-administered aminosalicylates did not have a clinically meaningful effect on the pharmacokinetics of ENTYVIO. Pharmacokinetics of vedolizumab in patients with renal or hepatic insufficiency have not been studied. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed. Clinical Studies Clinical Studies in Ulcerative Colitis The safety and efficacy of ENTYVIO were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of six to 12 with endoscopy subscore of two or three. The Mayo score ranges from zero to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration. Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids. Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed. UC Trial I In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage 30 mg/day or equivalent), and immunomodulators (azathioprine or 6 mercaptopurine) were permitted through Week 6. At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6-mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was nine in the ENTYVIO group and eight in the placebo group. In UC Trial I, a greater percentage of patients treated with ENTYVIO compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 3 ). A greater percentage of patients treated with ENTYVIO compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 3 ). In addition, a greater percentage of patients treated with ENTYVIO had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 3 ). * Clinical response: reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of 1 point. † Clinical remission: complete Mayo score of 2 points and no individual subscore >1 point. ‡ Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability). Table 3. Proportion of Patients Meeting Efficacy Endpoints at Week 6 (UC Trial I) Endpoint Placebo N=149 ENTYVIO N=225 p-value Treatment Difference and 95% CI Clinical response * at Week 6 26% 47%> <0.001 22% (12%, 32%) Clinical remission † at Week 6 5% 17% 0.001 12% (5%, 18%) Improvement of endoscopic appearance of the mucosa ‡ at Week 6 25% 41% 0.001 16% (6%, 26%) UC Trial II In order to be randomized to treatment in UC Trial II, patients had to have received ENTYVIO and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received ENTYVIO open-label. In UC Trial II, 373 patients were randomized in a double blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the US but were not permitted beyond Week 6 in the US. At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%) and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was eight in the ENTYVIO every eight week group, the ENTYVIO every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6. In UC Trial II, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 4) . In addition, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 4) . In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 4) . The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration ( 2.3 )] . * Patients must have achieved clinical response at Week 6 to continue into UC Trial II. This group includes patients that were not in clinical remission at Week 6. † The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2 and were randomized to receive placebo from Week 6 through Week 52. ‡ Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability) at Week 52. Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (n=72 for placebo and n=70 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52. Table 4. Proportion of Patients Meeting Efficacy Endpoints at Week 52 * (UC Trial II) Endpoint Placebo † N=126 ENTYVIO Every 8 Weeks N=122 p-value Treatment Difference and 95% CI Clinical remission at Week 52 16% 42%> <0.001 26% (15%, 37%) Clinical response at both Weeks 6 and 52 24% 57%> <0.001 33% (21%, 45%) Improvement of endoscopic appearance of the mucosa ‡ at Week 52 20% 52%> <0.001 32% (20%, 44%) Clinical remission at both Weeks 6 and 52 9% 21% 0.008 12% (3%, 21%) Corticosteroid-free clinical remission 14% 31% 0.012 18% (4%, 31%) Clinical Studies in Crohn s Disease The safety and efficacy of ENTYVIO were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn s disease (CD) (Crohn s Disease Activity Index [CDAI] score of 220 to 450). 1 Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6-mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids. Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed. CD Trial I In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage 30 mg/day or equivalent), and immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) were permitted through Week 6. At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the ENTYVIO group and 319 in the placebo group. In CD Trial I, a statistically significantly higher percentage of patients treated with ENTYVIO achieved clinical remission (defined as CDAI 150) as compared to placebo at Week 6 ( Table 5 ). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6. CD Trial II Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either ENTYVIO 300 mg or placebo at Weeks 0, 2 and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10. At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the ENTYVIO group and 301 in the placebo group. For the primary endpoint (clinical remission at Week 6), treatment with ENTYVIO did not result in statistically significant improvement over placebo ( Table 5 ). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant. * Clinical Remission: CDAI 150 † Adjusted p-value for multiple comparisons of two primary endpoints ‡ The primary analysis population for CD Trial II was patients that had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76% of the overall population) NS: Not significant (Secondary endpoints including assessments at Week 10 were not tested because the CD Trial II primary endpoint was not statistically significant) Table 5. Proportion of Patients in Clinical Remission at Week 6 (CD Trials I and II) Placebo ENTYVIO p-value Treatment Difference and 95% CI CD Trial I: Clinical Remission * at Week 6 7% (10/148) 15% (32/220) 0.041 † 8% (1%, 14%) CD Trial II ‡ : Clinical Remission * at Week 6 12% (19/157) 15% (24/158) NS 3% (-5%, 11%) CD Trial III In order to be randomized to treatment in CD Trial III, patients had to have received ENTYVIO and be in clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received ENTYVIO open-label. In CD Trial III, 461 patients were randomized in a double blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the US but were not permitted beyond Week 6 in the US. At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the ENTYVIO every eight week group, 316 in the ENTYVIO every four week group, and 315 in the placebo group. Patients who had achieved clinical response (≥70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6. In CD Trial III a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission (defined as CDAI score 150) at Week 52. A greater percentage of patients in groups treated with ENTYVIO as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 6) . In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 6 ). The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration ( 2.3) ] . * This group includes patients that were not in clinical remission at Week 6. Patients must have achieved clinical response (defined as ≥70 decrease in CDAI from baseline) at Week 6 to continue into CD Trial III. † The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2, and were randomized to receive placebo from Week 6 through Week 52 ‡ Clinical remission: CDAI 150 Clinical response: ≥100 decrease in CDAI from baseline Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response (defined as ≥70 decrease in CDAI from baseline) at Week 6 (n=82 for placebo and n=82 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52. Table 6. Proportion of Patients Meeting Efficacy Endpoints at Week 52 * (CD Trial III) Placebo † N=153 ENTYVIO Every 8 Weeks N=154 p-value Treatment Difference and 95% CI Clinical remission ‡ at Week 52 22% 39% 0.001 17% (7%, 28%) Clinical response at Week 52 30% 44% 0.013 13% (3%, 24%) Corticosteroid-free clinical remission 16% 32% 0.015 16% (3%, 29%) REFERENCES 1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn s Disease Activity Index, National Cooperative Crohn s Disease Study. Gastroenterology 1976; 70(3): 439-444 How Supplied/Storage and Handling ENTYVIO (vedolizumab) is supplied in sterile 20 mL single-use glass vials, containing 300 mg of vedolizumab as a white to off-white cake. NDC 64764-300-20 300 mg single-dose vial in individual carton Refrigerate unopened vials at 2 to 8 C (36º to 46ºF). Retain in original package to protect from light. Patient Counseling Information See FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction during or following an infusion of ENTYVIO [see Warnings and Precautions ( 5.1 )] . Infections Inform patients that they may be more likely to develop infections when taking ENTYVIO. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions ( 5.2 )] . Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received a different integrin receptor antagonist product. Instruct patients to report if they experience any new onset or worsening of neurological signs and symptoms immediately, as these could be indicative of PML [see Warnings and Precautions ( 5.3 )] . Liver Injury Inform patients that elevated transaminase levels with or without elevated bilirubin has occurred in patients who received ENTYVIO. Instruct patients to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions ( 5.4) ] . Medication Guide ENTYVIO (en ti vee oh) (vedolizumab) What is the most important information I should kn feel free
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