ENTYVIO

Vedolizumab is a recombinant humanized

IgG1 monoclonal antibody directed against the human lymphocyte α4β7 integrin, a key mediator of gastrointestinal inflammation implicated in diseases like ulcerative colitis or Crohn's disease. 4 α4β7 integrin facilitates the interaction between lymphocytes and gut endothelial cells through the α4β7 integrin-MAdCAM1 interaction, leading to the mobilization of lymphocytes and thus contributing to gastrointestinal inflammation.

Integrins implicated in cell migration into the intestinal tract included α2β2, α4β1, and α4β7; however, the selective activity of vedolizumab against α4β7 integrin has been thought to contribute to its more favorable safety profile compared to its predecessor natalizumab, the first integrin receptor antagonist approved by the FDA.

Vedolizumab is administered by

Intravenous infusion over a period of 30 minutes; after the first dose, it is given again at two and six weeks and then every 8 weeks thereafter.

Vedolizumab was developed by Takeda and approved by the FDA under the brand name ENTYVIO for the maintenance therapy of moderately to severely active Ulcerative Colitis and Crohn's Disease in April and September 2023, respectively. 6, 7.

Vedolizumab is indicated for adult patients with moderately to severely active Ulcerative Colitis or Crohn's disease. 4,

Non-clinical studies have shown that the pharmacodynamic effects of vedolizumab are reversible upon removal of the antibody: pharmacologic activity of cells inhibited by vedolizumab could be partially restored within 24 hours after removal, with near complete restoration within 4 days.

There are no known drug interactions as vedolizumab is a humanized antibody and does not modulate the production of cytokines, which is known to affect drug metabolism.

The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract.

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is mainly expressed on gut endothelial cells and plays a critical role in homing T-lymphocytes to gut lymph tissue.

The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to chronic inflammation, a hallmark of ulcerative colitis and Crohn's disease.

Inhibition of α4β7 integrin by vedolizumab prevents the adhesion of lymphocytes to its natural ligand, thus decreasing the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue.

In clinical trials with vedolizumab at doses ranging from 0.2-10 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 vedolizumab at doses ranging from 0.2-10 mg/kg and 180-750 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 vedolizumab for four or six weeks compared to placebo control as assessed by histopathology.

In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF.

The intended route of administration is intravenous, therefore there is no absorption data and bioavailability is expected to be 100%.

Following the administration of 300 mg of vedolizumab as a 30-minute intravenous infusion from week 0-2 and 300 mg every eight weeks starting from Week 6, the trough serum concentration of vedolizumab is 26.3 ± 12.9 and 27.4 ± 19.2 mcg/mL for Ulcerative Colitis and Crohn's Disease patients respectively at week 6.

At week 46, the trough serum concentration of vedolizumab is 11.2 ± 7.2 and 13.0 ± 9.1 mcg/mL for Ulcerative Colitis and Crohn's Disease patients respectively.

Serum apparent volume of distribution at steady-state has been found to be moderately greater than the serum volume (approximately 5 L). 4, 5 It is therefore expected to be confined to the systemic circulation, as expected for a high molecular weight protein.

The expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance.

Renal clearance is negligible as vedolizumab is a high molecular weight protein.

Vedolizumab has a long terminal elimination half-life of 25 days. 4, 5.

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 or 0.180-0.266 ml/hr/kg. 4, 5.

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Elevated transaminase levels with or without elevated bilirubin have occurred in patients who have received this drug.

Progressive multifocal leukoencephalopathy (PML) has not been reported with the use of this drug, however, it has occurred in patients who have received different integrin receptor antagonists and is therefore considered a risk for this product.

The use of vedolizumab may increase the risk of developing infections, and one study found that nasopharyngitis occurs more frequently with vedolizumab than with THE placebo for Crohn's disease patients.

Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab-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.

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.

Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Vedolizumab administered during pregnancy could affect immune responses in the in-utero-exposed newborn and infant.

The clinical significance of low levels of vedolizumab in utero-exposed infants is unknown.

The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

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.

is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) .

Patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients.

Important Administration Information Before Initiating ENTYVIO

Consider evaluating patients for tuberculosis (TB) infection.

Update immunizations according to current immunization guidelines.

ENTYVIO should be administered intravenously by a healthcare provider.

ENTYVIO prefilled syringe and ENTYVIO PEN are intended for subcutaneous use.

A patient may self-inject or caregiver may inject after proper training on correct subcutaneous injection technique.

Week 0: 300 mg infused intravenously over approximately 30 minutes.

Week 2: 300 mg infused intravenously 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 and Week 2.

Infusion: 300 mg infused over approximately 30 minutes and then every eight weeks thereafter.

Injection: 108 mg subcutaneously once every two weeks.

ENTYVIO in patients who do not show 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.

See full prescribing information for complete information on reconstitution, dilution, administration, and storage. 2.1 Important Administration Information Before Initiating ENTYVIO Consider evaluating patients for tuberculosis (TB) infection prior to initiating treatment with ENTYVIO.

ENTYVIO should be administered by a healthcare provider prepared to manage hypersensitivity reactions including anaphylaxis, if they occur.

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.

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. 2.2 Recommended Dosage in Adults with Ulcerative Colitis and Crohn’s Disease Week 0: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes.

Week 2: Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes.

Administer ENTYVIO 300 mg by intravenous infusion over approximately 30 minutes and then every eight weeks thereafter.

Administer ENTYVIO 108 mg subcutaneously once every 2 weeks.

Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.

Administer the first subcutaneous dose in place of the next scheduled intravenous infusion and every two weeks thereafter. 2.3 Preparation and Administration Instructions for Intravenous Infusion Reconstitution Instructions Remove the flip-off cap from the single-dose vial and wipe with alcohol swab.

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.

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.

Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder.

Do not vigorously shake or invert.

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.

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.

Once dissolved, gently invert vial three times.

Immediately, withdraw 5 mL (300 mg) of reconstituted ENTYVIO solution using a syringe with a 21.

Discard any remaining portion of the reconstituted solution in the vial.

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.

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

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.

Table 1.

Storage Instructions for Reconstituted Solution in Vial and Diluted Solution in Infusion Bag Solution Storage Conditions Refrigeration (2°C to 8°C [36°F to 46°F]) Room Temperature (20°C to 25°C [68°F to 77°F]) Reconstituted Solution (in Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, inside vial) 8 hours Use immediately after reconstitution Diluted Solution (in 0.9% Sodium Chloride Injection) 24 hours This time assumes the reconstituted solution is immediately diluted in the 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection, and held in the infusion bag only.

Any time that the reconstituted solution was held in vial should be subtracted from the time the solution may be held in the infusion bag. , This period may include up to 12 hours at room temperature (20°C to 25°C [68°F to 77°F]). 12 hours Diluted Solution (in Lactated Ringer's Injection) 6 hours Use immediately after dilution 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]). 2.4 Preparation and Administration Instructions for Subcutaneous Injection Inspect the solution visually for particulate matter and discoloration prior to administration.

ENTYVIO in prefilled syringe or ENTYVIO

PEN should be a clear to moderately opalescent, colorless to slightly yellow solution.

Do not use ENTYVIO prefilled syringes or ENTYVIO PENs with visible particulate matter or discoloration.

Administer each subcutaneous injection at a different anatomic location (such as thighs, any quadrant of abdomen, or upper arms) than the previous injection.

Administration of

ENTYVIO in the back of upper arm may only be performed by a healthcare professional or caregiver.

Do not inject into moles, scars, bruises, or areas where the skin is tender, erythematous, or indurated.

Missed Subcutaneous Dose If treatment with subcutaneous ENTYVIO is interrupted or if a scheduled dose(s) of subcutaneous ENTYVIO is missed, inject the next subcutaneous dose as soon as possible and then every 2 weeks thereafter.

In the event of incomplete dose administration (i.e., patient attempts administration of dose with ENTYVIO PEN, however it is uncertain if a full dose was administered), instruct the patient to call their pharmacy or healthcare provider.

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 Storage and Handling Refrigerate ENTYVIO unopened vials, prefilled syringes, and prefilled pens at 2°C to 8°C (36° to 46°F).

If needed, the ENTYVIO prefilled syringe or ENTYVIO PEN can be left out of the refrigerator in the original package at room temperature up to 25°C (77°F) for up to 7 days (for example, when traveling).

Do not use ENTYVIO prefilled syringe or ENTYVIO PEN if left out of the refrigerator for more than 7 days.

Do not freeze

ENTYVIO vial, prefilled syringe, or prefilled pen.

Do not use

ENTYVIO vial, prefilled syringe, or prefilled pen if it has been frozen.

Do not shake the ENTYVIO prefilled syringe or ENTYVIO PEN.

Retain in original package to protect from light until the time of use.

ENTYVIO unopened vials, prefilled syringes, and prefilled pens at 2°C to 8°C (36° to 46°F).

If needed, the ENTYVIO prefilled syringe or ENTYVIO PEN can be left out of the refrigerator in the original package at room temperature up to 25°C (77°F) for up to 7 days (for example, when traveling).

Do not use ENTYVIO prefilled syringe or ENTYVIO PEN if left out of the refrigerator for more than 7 days.

Do not freeze

ENTYVIO vial, prefilled syringe, or prefilled pen.

Do not use

ENTYVIO vial, prefilled syringe, or prefilled pen if it has been frozen.

Do not shake the ENTYVIO prefilled syringe or ENTYVIO PEN.

Retain in original package to protect from light until the time of use.

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.

There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy.

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.

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 to 4% and miscarriage is to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and

Embryo/Fetal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions ENTYVIO administered during pregnancy could affect immune responses in the in utero-exposed newborn and infant.

The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown.

The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

The vedolizumab pregnancy exposure registry conducted by OTIS/MotherToBaby study in the United States and Canada collected prospective observational data between and 2022 to assess the risk of major birth defects in live-born infants of women with ulcerative colitis (UC) or Crohn’s disease (CD) treated with vedolizumab during pregnancy.

The study compared pregnant patients with UC or CD exposed to vedolizumab with pregnant patients with UC or CD treated with other biological products.

The registry included 99 women (58 with UC, 41 with CD) treated with vedolizumab during pregnancy, and 76 women (27 with UC, 49 with CD) exposed to other biological products during pregnancy.

The proportion of major birth defects among live-born infants in patients with UC or CD treated with vedolizumab and patients with UC or CD treated with other biological products was 7.4% (7/94) and 5.6% (4/71), respectively.

Overall, there was no evidence of increased risk for major structural birth defects (adjusted RR 1.07, 95% CI: 0.33, 3.52).

The methodological limitations of the registry, including small sample size and the non-randomized design, resulted in a limited ability to estimate the risk of major birth defects and other maternal and infant outcomes.

The conclusions from the pregnancy registry were consistent with the published literature and pharmacovigilance.

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).

Safety and effectiveness of

ENTYVIO in pediatric patients have not been established.

Clinical trials of

ENTYVIO did not include sufficient numbers of patients aged and over (72 patients with Crohn's disease or ulcerative colitis aged and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger adult patients.

However, no overall differences in safety or effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.