Reconstitution Instructions

1. Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute ENTYVIO vial containing lyophilized powder with 4.8 mL of Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, at room temperature (20°C to 25°C [68°F to 77°F]), using a syringe with a 21- to 25- gauge needle.
2. Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, to the glass wall of the vial to avoid excessive foaming.
3. Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert.
4. Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.
5. Visually inspect the reconstituted ENTYVIO solution for particulate matter and discoloration prior to dilution. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.
6. Once dissolved, gently invert vial three times.
7. Immediately, withdraw 5 mL (300 mg) of reconstituted ENTYVIO solution using a syringe with a 21- to 25- gauge needle. Discard any remaining portion of the reconstituted solution in the vial.

Dilution Instructions

Add the 5 mL (300 mg) of reconstituted ENTYVIO solution to 250 mL of 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.

Discard any unused portion of the infusion solution.

Storage

Specific storage conditions and timing for the reconstituted solution in vial and diluted solution in the infusion bag are outlined in Table 1.

Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag.

The combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with 0.9% Sodium Chloride Injection, USP, is a total of 12 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours refrigerated (2°C to 8°C [36°F to 46°F]). This combined storage time may include up to eight hours of the reconstituted solution in the vial at 2°C to 8°C.

The combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with Lactated Ringer's Injection, USP, is a total of six hours refrigerated (2°C to 8°C [36°F to 46°F]).

Infusion-Related Reactions and Hypersensitivity Reactions

Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1)]. In UC Trials I and II and Crohn's Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with 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 ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with 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 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 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 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 1,434 (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 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 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 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 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× 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 1,434 (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.

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).

Risk Summary

Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). 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 (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a 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 in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.

Clinical Considerations

Data

Risk Summary

Data from a clinical lactation study show the presence of vedolizumab in human milk. The mean calculated daily infant dosage was 0.02 mg/kg/day orally (see Data). Systemic exposure in a breastfed infant is expected to be low because monoclonal antibodies are largely degraded in the gastrointestinal tract. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition.

Data

A milk-only lactation study was conducted in 9 adult lactating women being treated for active ulcerative colitis or Crohn's disease with intravenous ENTYVIO every 8 weeks after reaching steady state and completing the induction phase (ENTYVIO administration at 0, 2, and 6 weeks). Mean concentrations of ENTYVIO in human milk ranged from 0.03 to 0.26 mcg/mL. The mean calculated daily infant oral dosage was 0.02 mg/kg/day calculated as a product of the average concentration over the 8-week dosing interval and the standardized milk consumption of 150 mL/kg/day.

Specific 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, coadministered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and coadministered 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.

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 4). A greater percentage of patients treated with ENTYVIO compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 4). In addition, a greater percentage of patients treated with ENTYVIO had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 4).

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 U.S. but were not permitted beyond Week 6 in the U.S.

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 5). 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 5). 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 5).

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)].

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 6). 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 6). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant.

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 U.S. but were not permitted beyond Week 6 in the U.S.

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 7). 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 7).

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)].