Vedolizumab

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# Overview
Vedolizumab is a monoclonal antibody that is FDA approved for the treatment of Adult Ulcerative Colitis and Crohns disease.   Common adverse reactions include nasopharyngitis and fatigue.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Ulcerative Colitis or Crohns Disease
The recommended dosage of vedolizumab in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.
Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Vedolizumab in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vedolizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vedolizumab in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Vedolizumab in pediatric patients.

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

# Warnings

### Infusion-Related Reactions and Hypersensitivity Reactions
- In UC Trials I and II and CD Trials I and III, hypersensitivity reactions occurred including a case of anaphylaxis (one out of 1434 patients ).
- Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed.
- The majority were mild to moderate in severity as assessed by the investigator.
- Experience with other biologic medications suggests that hypersensitivity reactions and anaphylaxis to vedolizumab may vary in their time of onset from during infusion or immediately post-infusion to occurring up to several hours post-infusion.
- If anaphylaxis or other serious allergic reactions occur, discontinue administration of vedolizumab immediately and initiate appropriate treatment (e.g., epinephrine and antihistamines).

### Infections
- Patients treated with vedolizumab are at increased risk for developing infections.
- The most commonly reported infections in clinical trials occurring at a rate greater on vedolizumab than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection).
- Serious infections have also been reported in patients treated with vedolizumab, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.
- Vedolizumab is not recommended in patients with active, severe infections until the infections are controlled.
- Consider withholding treatment in patients who develop a severe infection while on treatment with vedolizumab.
- Exercise caution when considering the use of vedolizumab in patients with a history of recurring severe infections.
- Consider screening for tuberculosis (TB) according to the local practice.
- For progressive multifocal leukoencephalopathy (PML),

### Progressive Multifocal Leukoencephalopathy
- Another integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS). PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.
- In vedolizumab clinical trials, patients were actively monitored for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.
- While zero cases of PML were identified among patients with at least 24 months of exposure, a risk of PML cannot be ruled out.
- No claims of comparative safety to other integrin receptor antagonists can be made based on this data.
- Monitor patients on vedolizumab for any new onset, or worsening, of neurological signs and symptoms.
- Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with vedolizumab and refer to a neurologist; if confirmed, discontinue dosing permanently.

### Liver Injury
- There have been reports of elevations of transaminase and/or bilirubin in patients receiving vedolizumab. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. vedolizumab should be discontinued in patients with jaundice or other evidence of significant liver injury.

### Live and Oral Vaccines
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.
- Patients receiving vedolizumab may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks.
- There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab.

# Adverse Reactions

## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to vedolizumab in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.
The safety data described in Table 1 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label vedolizumab 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.
In these trials, 1,434 patients received vedolizumab 300 mg 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 Crohns 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 vedolizumab and 45% of patients treated with placebo (UC Trials I and II: 49% with vedolizumab and 37% with placebo; CD Trials I and III: 55% with vedolizumab and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with vedolizumab compared to 4% of patients treated with placebo (UC Trials I and II: 8% with vedolizumab and 7% with placebo; CD Trials I and III: 12% with vedolizumab and 9%, with placebo).
The most common adverse reactions (reported by 3% of patients treated with vedolizumab 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 1).
Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received vedolizumab 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 Crohns disease trial, are similar to those listed in Table 1.
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following vedolizumab administration in clinical trials. In UC Trials I and II and Crohns Trials I and III, one case of anaphylaxis  was reported by a Crohns 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 vedolizumab and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with vedolizumab (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 vedolizumab) 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 vedolizumab 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 vedolizumab and 0.7 per patient-year in the patients treated with placebo. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. Two percent of patients discontinued vedolizumab 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 vedolizumab and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohns disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohns 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 vedolizumab, 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 vedolizumab and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohns disease patients treated with vedolizumab 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 Crohns disease receiving vedolizumab 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 vedolizumab. 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 vedolizumab. 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 vedolizumab 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 vedolizumab 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 vedolizumab, 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 vedolizumab.
In a placebo-controlled study of healthy volunteers, 61 subjects were given a single vedolizumab 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 vedolizumab did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to vedolizumab 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 vedolizumab, 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 vedolizumab 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. 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 vedolizumab with the incidence of antibodies to other products may be misleading.

## Postmarketing Experience
There is limited information regarding Vedolizumab Postmarketing Experience in the drug label.

# Drug Interactions

### Natalizumab
- Because of the potential for increased risk of PML and other infections, avoid the concomitant use of vedolizumab with natalizumab.

### TNF Blockers
- Because of the potential for increased risk of infections, avoid the concomitant use of vedolizumab with TNF blockers.

### Live Vaccines
- Live vaccines may be administered concurrently with vedolizumab only if the benefits outweigh the risks

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): B
- There are no studies with vedolizumab 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 vedolizumab 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).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vedolizumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Vedolizumab during labor and delivery.

### 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 vedolizumab in pediatric patients have not been established.

### Geriatic Use
- Clinical trials of vedolizumab did not include sufficient numbers of subjects aged 65 and over (46 Crohns and ulcerative colitis patients aged 65 and over were treated with vedolizumab 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.

### Gender
There is no FDA guidance on the use of Vedolizumab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Vedolizumab with respect to specific racial populations.

### Renal Impairment
- Pharmacokinetics of vedolizumab in patients with renal insufficiency have not been studied.

### Hepatic Impairment
- Pharmacokinetics of vedolizumab in patients with hepatic insufficiency have not been studied.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vedolizumab in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Vedolizumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Administer vedolizumab as an intravenous infusion over 30 minutes.
- Do not administer as an intravenous push or bolus.
- Vedolizumab lyophilized powder must be reconstituted with Sterile Water for injection and diluted in 250 mL of sterile 0.9% Sodium Chloride injection prior to administration.
- After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride injection.
- Vedolizumab should be administered by a healthcare professional 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.

### Prior to Administration of vedolizumab
- Prior to initiating treatment with vedolizumab, all patients should be brought up to date with all immunizations according to current immunization guidelines.

### Monitoring
- Monitor for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary.

# IV Compatibility

### Reconstitution Instructions
- Reconstitute vedolizumab at room temperature. Vedolizumab should be reconstituted and prepared by a trained medical professional using aseptic technique by the following procedure:
- Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute vedolizumab vial containing lyophilized powder with 4.8 mL of Sterile Water for injection, 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 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 vedolizumab solution for particulate matter and discoloration prior to administration. 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.
- Prior to withdrawing the reconstituted vedolizumab solution from the vial, gently invert vial three times.
- Withdraw 5 mL (300 mg) of reconstituted vedolizumab 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 vedolizumab solution to 250 mL of sterile 0.9% Sodium Chloride 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.
Storage
Do not freeze. Discard any unused portion of the infusion solution.

# Overdosage
There is limited information regarding Vedolizumab overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
Vedolizumab is a humanized monoclonal antibody that specifically binds to the 47 integrin and blocks the interaction of 47 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 41 and E7 integrins and does not antagonize the interaction of 4 integrins with vascular cell adhesion molecule-1 (VCAM-1).
The 47 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 47 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohns disease.

## Structure
Vedolizumab, an integrin receptor antagonist, is a humanized IgG1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human 47 integrin. Vedolizumab has an approximate molecular weight of 147 kilodaltons.

## Pharmacodynamics
In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of 47 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.
In clinical trials with vedolizumab 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 Crohns 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

## Pharmacokinetics
Similar pharmacokinetics were observed in ulcerative colitis and Crohns disease patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg vedolizumab every eight weeks starting from Week 6 (Table 2).
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 vedolizumab (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 vedolizumab.
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 vedolizumab 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 vedolizumab 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 6mercaptopurine) 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 vedolizumab group and eight in the placebo group.
In UC Trial I, a greater percentage of patients treated with vedolizumab compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 3). A greater percentage of patients treated with vedolizumab 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 vedolizumab had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 3).

### UC Trial II
In order to be randomized to treatment in UC Trial II, patients had to have received vedolizumab and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received vedolizumab open-label.
In UC Trial II, 373 patients were randomized in a doubleblind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 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 vedolizumab every eight week group, the vedolizumab 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 vedolizumab 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 vedolizumab 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 vedolizumab as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 4).
The vedolizumab 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.

### Clinical Studies in Crohns Disease
The safety and efficacy of vedolizumab 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 Crohns disease (CD) (Crohns Disease Activity Index  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 vedolizumab 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 vedolizumab group and 319 in the placebo group.
In CD Trial I, a statistically significantly higher percentage of patients treated with vedolizumab 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 vedolizumab 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 vedolizumab group and 301 in the placebo group.
For the primary endpoint (clinical remission at Week 6), treatment with vedolizumab 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

### CD Trial III
In order to be randomized to treatment in CD Trial III, patients had to have received vedolizumab 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 vedolizumab open-label.
In CD Trial III, 461 patients were randomized in a doubleblind fashion (1:1:1) to one of the following regimens beginning at Week 6: vedolizumab 300 mg every eight weeks, vedolizumab 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 vedolizumab every eight week group, 316 in the vedolizumab 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 vedolizumab 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 vedolizumab 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 vedolizumab as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 6).
The vedolizumab 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.

# How Supplied
- Vedolizumab (vedolizumab) is supplied in sterile 20 mL single-use glass vials, containing 300 mg of vedolizumab as a white to off-white cake.

## Storage
- Refrigerate unopened vials at 2 to 8C (36o to 46oF). Retain in original package to protect from light.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Hypersensitivity Reactions
Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction during or following an infusion of vedolizumab.

### Infections
Inform patients that they may be more likely to develop infections when taking vedolizumab. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection.

### 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

### Liver Injury
- Inform patients that elevated transaminase levels with or without elevated bilirubin has occurred in patients who received vedolizumab. Instruct patients to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice

# Precautions with Alcohol
Alcohol-Vedolizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Entyvio

# Look-Alike Drug Names
There is limited information regarding Vedolizumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price