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Entyvio

Generic Name: Vedolizumab
Class: GI Drugs, Miscellaneous
Chemical Name: Anti-(human integrin LPAM-1 (lymphocyte Peyer's patch adhesion molecule 1)) (human-Mus musculus heavy chain) immunoglobulin G1 disulfide with human-Mus musculus κ-chain dimer
Molecular Formula: C6528H10072N1732O2042S42
CAS Number: 943609-66-3

Introduction

Recombinant humanized anti-α4β7-integrin monoclonal antibody; an immunomodulatory agent that selectively inhibits lymphocyte recruitment to the GI tract.1 2 4 5 6 7 8 9 10 12 13 14 15 16

Uses for Entyvio

Ulcerative Colitis

Used to induce and maintain clinical response and clinical remission, improve endoscopic appearance of mucosa, and achieve corticosteroid-free remission in adults with moderately to severely active ulcerative colitis who have had an inadequate response to, have lost response to, or were intolerant to a tumor necrosis factor (TNF) blocking agent or immunosuppressive agent (e.g., azathioprine, mercaptopurine), or who have had an inadequate response to, were intolerant to, or have demonstrated dependence on corticosteroids.1 2 5 6

Crohn's Disease

Used to achieve clinical response, clinical remission, and corticosteroid-free remission in adults with moderately to severely active Crohn's disease who have had an inadequate response to, have lost response to, or were intolerant to a TNF blocking agent or immunosuppressive agent (e.g., azathioprine, mercaptopurine, methotrexate), or who had an inadequate response to, were intolerant to, or have demonstrated dependence on corticosteroids.1 12 14

Entyvio Dosage and Administration

General

  • Monitor patients closely for infusion-related or hypersensitivity reactions during vedolizumab infusions.1 (See Hypersensitivity and Infusion-related Reactions under Cautions.)

  • Concomitant Therapy
  • Aminosalicylates, corticosteroids, and immunosuppressive agents (azathioprine, mercaptopurine) could be continued in clinical studies in patients with ulcerative colitis.1 6

  • Aminosalicylates, corticosteroids, antibiotics, and immunosuppressive agents (azathioprine, mercaptopurine, or methotrexate) could be continued in clinical studies in patients with Crohn’s disease.1 12

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (IV push or bolus).1

Do not mix with or administer through the same administration set with other drugs.1

Flush IV line with 30 mL of 0.9% sodium chloride injection after the infusion is complete.1

Lyophilized powder must be reconstituted at room temperature and diluted prior to administration.1

Reconstitution

Reconstitute vedolizumab lyophilized powder by adding 4.8 mL of sterile water for injection (using a syringe with a 21- to 25-gauge needle) to a 300-mg vial to provide a solution containing 60 mg/mL.1 Direct diluent toward wall of vial to avoid excessive foaming.1

Gently swirl vial for at least 15 seconds to dissolve powder.1 Do not shake vigorously or invert.1 Allow solution to stand for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle.1 Vial can be swirled and inspected for dissolution during this time.1 If not fully dissolved within 20 minutes, allow an additional 10 minutes.1 Do not use vial if drug is not dissolved within 30 minutes.1

Dilution

Gently invert vial 3 times before withdrawing 5 mL (300 mg) of reconstituted solution (using a syringe with a 21- to 25-gauge needle).1 Add the reconstituted solution to an infusion bag containing 250 mL of 0.9% sodium chloride injection and mix gently.1

Use infusion solution as soon as possible after reconstitution and dilution.1 (See Storage under Stability.)

Discard any unused portions of reconstituted or diluted solutions.1

Rate of Administration

Administer by IV infusion over 30 minutes.1

Dosage

Adults

Ulcerative Colitis
IV

300 mg at 0, 2, and 6 weeks and then every 8 weeks thereafter.1

Discontinue if no therapeutic benefit is evident by week 14 of therapy.1

Crohn's Disease
IV

300 mg at 0, 2, and 6 weeks and then every 8 weeks thereafter.1

Discontinue if no therapeutic benefit is evident by week 14 of therapy.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Entyvio

Contraindications

  • Known history of serious or severe hypersensitivity reaction (e.g., dyspnea, bronchospasm, urticaria, flushing, rash, increased heart rate) to the drug or any ingredient in the formulation.1

Warnings/Precautions

Hypersensitivity and Infusion-related Reactions

Infusion-related and hypersensitivity reactions reported.1 5 6 12 14 Generally mild to moderate, but may be severe.1

Infusion-related reactions (e.g., nausea, headache, pruritus, dizziness, fatigue, pyrexia, urticaria, vomiting) generally occur within first 2 hours after an infusion and resolve without treatment or following administration of antihistamine and/or IV hydrocortisone.1

Hypersensitivity reactions may include dyspnea, bronchospasm, urticaria, flushing, rash, and increased BP and heart rate; anaphylaxis also reported.1 Experience with other biologic agents suggests that time of onset may be variable (during, immediately after, or several hours after an infusion).1

Clinicians should be prepared to treat hypersensitivity and infusion-related reactions.1 Ensure appropriate equipment and agents for treating such reactions are available for immediate use, and monitor patient until infusion is completed.1 If anaphylaxis or other serious allergic reactions occur, immediately discontinue the infusion and initiate appropriate treatment (e.g., epinephrine, antihistamines).1

In clinical trials, patients who experienced a mild infusion-related or hypersensitivity reaction to the drug could receive premedication (e.g., antihistamine, hydrocortisone, and/or acetaminophen) prior to subsequent infusions.1

Infectious Complications

Increased risk of infections.1 Most common infections are nasopharyngeal and upper respiratory tract infections.1 5 6 12 14 However, serious infections (e.g., anal abscess, sepsis [sometimes fatal], tuberculosis, Salmonella sepsis, Listeria meningitis, giardiasis, cytomegaloviral colitis) also reported, more commonly in patients with Crohn's disease than in those with ulcerative colitis.1 14

In clinical trials in ulcerative colitis and Crohn's disease, rate of infection was 0.85 or 0.7 per patient-year in patients receiving vedolizumab or placebo, respectively; rate of serious infection was 0.07 or 0.06 per patient-year, respectively.1 Rate of serious infection did not increase over 48 months.1

Delay initiation of vedolizumab until any active severe infection has been controlled.1 If severe infection develops during therapy, consider interrupting vedolizumab therapy.1

Exercise caution when considering use in patients with a history of recurring severe infections.1

Consider screening for active or latent tuberculosis infection.1

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection of the brain caused by the JC virus, reported in patients receiving natalizumab, an anti-α4-integrin monoclonal antibody.1 20 PML generally occurs only in immunocompromised patients and usually progresses to death or severe disability.1 Patients in vedolizumab clinical trials were actively monitored for PML; although no cases reported among patients exposed to the drug for ≥24 months, risk of PML cannot be ruled out and safety of vedolizumab relative to other integrin receptor antagonists not fully established.1

Monitor for any new or worsening neurologic manifestations (see Advice to Patients).1 If PML is suspected, withhold drug and refer patient to a neurologist.1 Permanently discontinue if PML is confirmed.1

Hepatic Effects

Increases in serum ALT and AST concentrations and/or bilirubin concentrations, including several cases of hepatitis, reported following 2–5 doses of the drug; unclear whether reactions were drug induced or autoimmune.1 All patients recovered following drug discontinuance, although some patients also required corticosteroid treatment.1

Discontinue vedolizumab in patients with jaundice or other evidence of clinically important hepatic injury.1

Immunization

Administer all appropriate vaccines as recommended by current immunization guidelines prior to initiation of vedolizumab.1

Patients receiving vedolizumab may receive inactive vaccines (e.g., parenteral influenza virus vaccine inactivated) and may receive live vaccines if potential benefits justify possible risks.1 (See Interactions.)

Malignancies

Malignancies (excluding dysplasia and basal cell carcinoma) reported in 0.4 or 0.3% of patients receiving vedolizumab or placebo, respectively, during clinical trials in ulcerative colitis or Crohn's disease.1 Malignancies also reported during extension phases of the trials; however, data regarding effects of long-term exposure to the drug are limited.1

Immunogenicity

Formation of antibodies, including neutralizing antibodies, to vedolizumab reported.1 Presence of persistently positive anti-vedolizumab antibodies associated with undetectable or negligible serum concentrations of the drug and failure to achieve clinical remission.1

Specific Populations

Pregnancy

Category B.1 Any adverse effect on pregnancy outcomes likely would be greater during second and third trimesters, since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses.1

Pregnancy registry at 877-825-3327.1

Lactation

Distributed into milk in monkeys; not known whether distributed into human milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; however, no overall differences in efficacy and safety observed.1

Common Adverse Effects

Nasopharyngitis,1 6 12 headache,1 6 arthralgia,1 14 nausea,1 12 14 pyrexia,1 upper respiratory tract infection,1 12 14 fatigue,1 6 12 14 cough,1 6 bronchitis,1 influenza,1 back pain,1 rash,1 pruritus,1 sinusitis,1 oropharyngeal pain,1 pain in extremities.1

Interactions for Entyvio

Vaccines

Inactivated vaccines: For IM hepatitis B vaccine and oral inactivated cholera vaccine (not commercially available in US), see Specific Drugs under Interactions. Effect of vedolizumab on immune responses to other oral or intranasal vaccines not known.1 Manufacturer states patients receiving vedolizumab may receive inactivated vaccines.1

Live vaccines: No data on secondary transmission of infection by live vaccines in patients receiving vedolizumab.1 Manufacturer states patients receiving vedolizumab may receive live vaccines if potential benefits justify possible risks.1

Specific Drugs

Drug

Interaction

Comments

Cholera vaccine, oral inactivated

Single vedolizumab dose given 4 days before initiation of immunization series reduced seroconversion rate and titers of antibody to cholera toxin1 21

May be used concomitantly1

Hepatitis B vaccine

Single vedolizumab dose given 4 days before initiation of IM immunization series did not affect seroconversion rate1 21

May be used concomitantly1

Influenza virus vaccine inactivated

May be used concomitantly1

Natalizumab

Increased risk of PML and other infections1

Avoid concomitant use1

TNF blocking agents

Increased risk of infections1

Avoid concomitant use1

Entyvio Pharmacokinetics

Distribution

Extent

Not known whether vedolizumab distributes into human milk.1

Not detected in CSF at 5 weeks after single IV dose (450 mg).1

Elimination

Half-life

Approximately 25 days at 300-mg dose.1

Clearance dependent on linear and nonlinear pathways; nonlinear clearance decreases with increasing concentrations.1

Special Populations

Pharmacokinetics similar in patients with ulcerative colitis and those with Crohn’s disease.1

Pharmacokinetics not formally studied in patients with renal or hepatic impairment.1

Disease severity, body weight, prior treatment with TNF blocking agents, age (within range of 18–78 years), serum albumin concentration, and concomitant therapy (azathioprine, mercaptopurine, methotrexate, aminosalicylates) did not have a clinically meaningful effect on pharmacokinetics.1

Presence of persistently positive anti-vedolizumab antibodies may reduce serum vedolizumab concentrations to undetectable or negligible levels.1 (See Immunogenicity under Cautions.)

Stability

Storage

Parenteral

Powder for IV Infusion

2–8°C.1 Keep in original package to protect from light.1

Infusion solution: 2–8°C for up to 4 hours; do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Actions

  • Binds specifically to α4β7 integrin, a protein expressed on the surface of a small subset of memory T-lymphocytes that preferentially migrate into the GI tract.1 2 4 5 6 7 8 9 10 12 13 14 15 16 Binding of vedolizumab to α4β7 integrin blocks interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed mainly on vascular endothelial cells in the GI tract, and inhibits migration of memory T-lymphocytes across the endothelium into inflamed GI parenchymal tissue.1 5 8

  • Interaction of α4β7 integrin with MAdCAM-1 implicated as an important contributor to the chronic inflammation of ulcerative colitis and Crohn's disease.1

  • Does not bind to or inhibit the function of α4β1 and αEβ7 integrins; does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).1

  • Appears to exert a more selective effect on the GI tract than does natalizumab, which binds to α4 subunits of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils.7 8 16 20

Advice to Patients

  • Importance of reviewing the manufacturer's patient information (medication guide).1

  • Importance of immediately reporting symptoms consistent with a hypersensitivity reaction (e.g., rash, pruritus, shortness of breath or difficulty breathing, wheezing, dizziness, flushing, palpitations, swelling of lips, tongue, throat, or face) that occur during or following IV infusion of the drug.1

  • Increased risk of infection.1 Importance of informing clinician of any signs or symptoms of infection (e.g., fever, chills, cough, dyspnea, fatigue, red or painful skin or sores, myalgia, rhinorrhea, sore throat, pain on urination).1

  • Potential for PML to occur in patients who receive a different integrin receptor antagonist.1 Importance of immediately informing clinician of any new or worsening neurologic manifestations (e.g., progressive weakness on one side of body or clumsiness of limbs; changes in speech or walking; vision changes; changes in thinking, memory, and orientation leading to confusion and personality changes).1

  • Possibility of increased ALT/AST concentrations, with or without elevated bilirubin concentrations.1 Importance of promptly informing clinician of any symptoms suggestive of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1

  • Importance of reviewing vaccination status with clinician and receiving all age-appropriate vaccines prior to initiation of vedolizumab therapy.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, tuberculosis or other infection) or any history of recurrent infections.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 (See Pregnancy Under Cautions.)

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Vedolizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

300 mg

Entyvio

Takeda

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Takeda Pharmaceuticals, Inc. Entyvio(vedolizumab) prescribing information. Deerfield, IL; 2014 May.

2. Bickston SJ, Behm BW, Tsoulis DJ et al. Vedolizumab for induction and maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2014; 8:CD007571. [PubMed 25105240]

3. Danese S, Fiorino G, Peyrin-Biroulet L et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med. 2014; 160:704-11. [PubMed 24842416]

4. . Induction and maintenance therapy with vedolizumab, a novel biologic therapy for ulcerative colitis. Gastroenterol Hepatol (N Y). 2014; 10:64-6. [PubMed 24799843]

5. Feagan BG, Greenberg GR, Wild G et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 2005; 352:2499-507. [PubMed 15958805]

6. Feagan BG, Rutgeerts P, Sands BE et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369:699-710. [PubMed 23964932]

7. Gilroy L, Allen PB. Is there a role for vedolizumab in the treatment of ulcerative colitis and Crohn's disease?. Clin Exp Gastroenterol. 2014; 7:163-72. [PubMed 23964933]

8. Gledhill T, Bodger K. New and emerging treatments for ulcerative colitis: a focus on vedolizumab. Biologics. 2013; 7:123-30. [PubMed 18829392]

9. McLean LP, Shea-Donohue T, Cross RK. Vedolizumab for the treatment of ulcerative colitis and Crohn's disease. Immunotherapy. 2012; 4:883-98. [PubMed 23964933]

10. . Vedolizumab (Entyvio) for inflammatory bowel disease. Med Lett Drugs Ther. 2014; 56:86-8. [PubMed 25211302]

11. Reenaers C, Louis E, Belaiche J. Current directions of biologic therapies in inflammatory bowel disease. Therap Adv Gastroenterol. 2010; 3:99-106. [PubMed 21180594]

12. Sandborn WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013; 369:711-21. [PubMed 23964933]

13. . A SPECIAL MEETING REVIEW EDITION: Highlights in Crohn's Disease and Ulcerative Colitis: Digestive Disease Week 2012 May 19-22, 2012 • San Diego, CaliforniaSpecial Reporting on:• Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active UC: PURSUIT-SC• The Future of IBD Therapy: Individualized and Optimized Therapy and Novel Mechanisms• Infliximab Concentration and Clinical Outcome in Patients with UC• Vedolizumab Induction Therapy for UC: Results of GEMINI I, A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase III Trial• Novel Infliximab and Antibody-to-lnfliximab Assays Are Predictive of Disease Activity in Patients with CD• Accelerated Step-Care Therapy with Early Azathioprine Versus Conventional Step-Care Therapy in CD• PIANO: A 1,000-Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators and Biologic TherapyPLUS Meeting Abstract Summaries With Expert Commentary by: William J. Sandborn, MDChief of the Division of Gastroenterology Director of the UCSD IBD Center UC San Diego Health System La Jolla, California. Gastroenterol Hepatol (N Y). 2012; 8(8 Suppl 5):1-24. [PubMed 24847182]

14. Sands BE, Feagan BG, Rutgeerts P et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014; 147:618-627.e3. [PubMed 24859203]

15. Seo GS, Chae SC. Biological therapy for ulcerative colitis: An update. World J Gastroenterol. 2014; 20:13234-13238. [PubMed 25309060]

16. Soler D, Chapman T, Yang LL et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009; 330:864-75. [PubMed 19509315]

17. Parikh A, Fox I, Leach T et al. Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013; 19:1691-9. [PubMed 23591599]

18. Parikh A, Leach T, Wyant T et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis. 2012; 18:1470-9. [PubMed 22147460]

19. Feagan BG, Greenberg GR, Wild G et al. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008; 6:1370-7. [PubMed 18829392]

20. Biogen Idec Inc. Tysabri (natalizumab) injection prescribing information. Cambridge, MA; 2013 Dec.

21. Wyant T, Leach T, Sankoh S et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut. 2015; 64:77-83. [PubMed 24763133]

22. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125476Orig1s000: Summary review. From FDA website. Accessed 2015 Jan 22.

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