Entyvio

Intravenous Administration

• ENTYVIO should be administered by a healthcare provider prepared to manage hypersensitivity reactions including anaphylaxis, if they occur [see Warnings and Precautions (5.1)]. Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete.
• Reconstitute and dilute ENTYVIO lyophilized powder prior to administration as a 30-minute intravenous infusion [see Dosage and Administration (2.3)].

Subcutaneous Injection

• ENTYVIO prefilled syringe and ENTYVIO PEN are intended for subcutaneous use under the guidance and supervision of a healthcare professional.
• Patients may self-inject or caregivers may inject subcutaneous ENTYVIO using either the ENTYVIO prefilled syringe or ENTYVIO PEN after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of ENTYVIO.

• Week 0: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes [see Dosage and Administration (2.3)].
• Week 2: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes.
• Week 6: Patients may remain on ENTYVIO intravenous therapy or switch to subcutaneous injection after receiving two ENTYVIO intravenous doses administered at Week 0 and Week 2.
  • Intravenous Infusion: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes and then every eight weeks thereafter.
  • Subcutaneous Injection: Administer ENTYVIO 108 mg subcutaneously once every 2 weeks.
• Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.

Patients currently receiving and responding to ENTYVIO intravenous therapy after Week 6 may also be switched to subcutaneous injection. Administer the first subcutaneous dose in place of the next scheduled intravenous infusion and every two weeks thereafter.

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, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, at room temperature (20°C to 25°C [68ºF to 77ºF]), 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, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, 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, or Lactated Ringer's Injection, 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.

Administration Instructions

After the infusion is complete, flush with 30 mL of 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection.

Storage and Stability

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, 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, is a total of six hours refrigerated (2°C to 8°C [36°F to 46°F]).

Risk Summary

Available data from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby ENTYVIO Pregnancy Registry, published literature and pharmacovigilance in pregnant women have not reliably identified an ENTYVIO-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data). 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 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.

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).

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.

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 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.

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.

Adults Treated with Intravenous ENTYVIO

The incidence of anti-drug antibodies to intravenous ENTYVIO using a drug-tolerant electrochemiluminescence (ECL) method for patients in UC Trials I and II and CD Trials I and III who had continuous ENTYVIO treatment administered as an intravenous infusion for 52 weeks was 6% (86 out of 1,427 total ENTYVIO-treated patients). Of the 86 patients who tested positive for anti-vedolizumab antibodies, 20 patients were persistently positive (at two or more consecutive study visits) and 56 developed neutralizing antibodies to vedolizumab.

Among the ENTYVIO-treated patients who developed persistent anti-vedolizumab antibodies, 14/20 patients had serum vedolizumab trough concentrations that were markedly reduced or undetectable and 15/20 patients did not achieve clinical remission at Week 52 in UC Trials I and II and CD Trials I and III. Because of the low occurrence of persistent anti-vedolizumab antibodies (1%; 20/1,427), the effect of these antibodies on the safety and effectiveness of ENTYVIO in these studies has not been fully characterized.

Adults Treated with Subcutaneous ENTYVIO

The incidence of anti-drug antibodies to ENTYVIO using a drug-tolerant ECL method for patients in SC UC Trial and SC CD Trial who had continuous treatment for 52 weeks was 3.4% (13 out of 381 total patients treated with subcutaneous ENTYVIO). Of the 13 patients who tested positive for anti-vedolizumab antibodies, 7 patients were persistently positive (at two or more consecutive study visits) and 7 patients developed neutralizing antibodies to vedolizumab. Two of the 7 patients with Crohn’s disease and none of the 6 patients with ulcerative colitis who had positive anti-vedolizumab antibodies achieved clinical remission at Week 52. There is insufficient data to assess the effect of anti-drug antibodies on pharmacokinetics, effectiveness, and safety of ENTYVIO in the SC UC and SC CD trials.

Intravenous Administration

The safety and efficacy of intravenous 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 6 to 12 with endoscopy subscore of two or three. The Mayo score ranges from 0 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 U.S. 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 U.S., 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.

Subcutaneous Administration

CD Trial I - Intravenous

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 intravenous ENTYVIO group and 319 in the placebo group.

In CD Trial I, a statistically significantly higher percentage of patients treated with intravenous ENTYVIO achieved clinical remission (defined as CDAI ≤150) as compared to placebo at Week 6 (Table 7). 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 - Intravenous

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 intravenous 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 intravenous ENTYVIO did not result in statistically significant improvement over placebo (Table 7). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant.

CD Trial III - Intravenous

In order to be randomized to treatment in CD Trial III, patients had to have received intravenous 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 intravenous 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: intravenous ENTYVIO 300 mg every eight weeks, intravenous 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 intravenous ENTYVIO every eight week group, 316 in the intravenous 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 intravenous 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 intravenous ENTYVIO as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 8). 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 intravenous ENTYVIO as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 8).

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 (2.2)].

Subcutaneous Administration

SC CD Trial - Subcutaneous

The safety and efficacy of subcutaneous ENTYVIO was evaluated in a randomized, double-blind, placebo-controlled trial (SC CD Trial; NCT02611817) in adult patients with moderately to severely active Crohn’s disease defined as CDAI score of 220 to 450. At baseline, the median CDAI score was 316 (range: 198 to 559).

The trial included patients who had experienced an inadequate response to, loss of response to, or intolerance to at least one of the following: corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate), or TNF blockers (including primary non-responders). Patients were permitted to use concomitant stable doses of oral aminosalicylates, oral corticosteroids (prednisone ≤30 mg/day, budesonide ≤9 mg/day, or equivalent steroid), immunomodulators, probiotics, antidiarrheals, and/or antibiotics. Concomitant biologic therapies, rectal treatment with 5-aminosalicylic acid or corticosteroid enemas/suppositories were prohibited.

All patients received open-label intravenous ENTYVIO 300 mg at Week 0 and Week 2. In order to be randomized to treatment in SC CD Trial, patients had to be in clinical response (defined as a ≥70-point decrease in the CDAI score from baseline) at Week 6. A total of 409 patients were randomized at Week 6 in a double-blind fashion (2:1) to ENTYVIO 108 mg administered by subcutaneous injection or placebo every 2 weeks. Efficacy assessments were at Week 52.

Beginning at Week 6, patients who were receiving corticosteroids were required to begin a corticosteroid tapering regimen.

At the time of randomization into the double-blind phase (Week 6), patients were receiving corticosteroids (45%), immunomodulators (32%), and aminosalicylates (45%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy prior to enrollment.

Patients in the double-blind phase had a mean age of 38 years (range 18 to 76 years); 55% were male; 91% identified as White, 6% as Asian, and 3% identified as another racial group.

The primary endpoint was the proportion of patients with clinical remission (CDAI score ≤150) at Week 52 (see Table 9).

Among patients using oral corticosteroids at baseline (Week 0) and achieving clinical response at Week 6, 45% (43/95) treated with subcutaneous ENTYVIO compared to 18% (8/44) treated with placebo discontinued corticosteroids and were in clinical remission at Week 52. This result was not statistically significant under the prespecified multiple testing procedure.

Intravenous Infusion

ENTYVIO® (vedolizumab) for injection for intravenous infusion is supplied in sterile single-dose glass vials, containing 300 mg of vedolizumab as a white to off-white lyophilized cake.

• ENTYVIO: 300 mg single-dose vial in individual carton: NDC 64764-300-20

Subcutaneous Injection

ENTYVIO (vedolizumab) injection for subcutaneous use is available in a prefilled syringe or a prefilled pen as a clear to moderately opalescent and colorless to slightly yellow solution.

The single-dose, disposable ENTYVIO prefilled syringe and single-dose, disposable ENTYVIO prefilled pen (ENTYVIO PEN) are comprised of a 1 mL long glass syringe with a fixed 27 gauge thin wall, ½ inch needle. The syringe has a rubber needle cover encased in a plastic shell and rubber stopper. Not made with natural rubber latex.

• ENTYVIO: 108 mg/0.68 single-dose prefilled syringe in an individual carton: NDC 64764-107-11
• ENTYVIO PEN: 108 mg/0.68 single-dose prefilled pen in an individual carton: NDC 64764-108-21