Subject: Entyvio (vedolizumab) Original Effective Date: 9/4/2014
Guidance Number: MCP-211 Revision Date(s): Review Date(s): 12/16/15; 9/15/2016; 6/22/2017
DISCLAIMER This Medical Guidance is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina medical coverage guidance (MCG) document and provide the directive for all Medicare members.
SUMMARY OF EVIDENCE/POSITION STATEMENTS
This policy addresses the coverage of Entyvio (vedolizumab) for the treatment of for the treatment of adult patients with moderately to severely active UC or adult patients with CD who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
∑ PREFERRED biologic for the treatment of chronic inflammatory conditions: Humira® (adalimumab)
∑ Vedolizumab (Entyvio) is not indicated as first-line therapy. TNF-α inhibitors remain in a treatment position before recommending vedolizamab due to the extensive experience gained from many years of utilizing the TNF-α inhibitors biologics. Entyvio is a second-line biologic option for individuals who are unable to take or who have had an inadequate response to previous treatment. ‹ Although there have been no cases of PML reported to date in any of the patients treated with vedolizumab, without long-term clinical safety data, there remains uncertainty regarding the risk of PML in patients on Entyvio.
∑ There is no evidence from high quality trials or comparative studies supporting the superiority or effectiveness of one biologic medication over another in the treatment of chronic inflammatory conditions. Therefore, when there is no demonstrated difference in safety or efficacy, the most cost-effective medication generally provides the best value for members.
∑ Individual responses and tolerability are unpredictable and may vary between patients. If one biologic agent provides an inadequate response, another biologic may yet be effective.
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∑ For moderate to severe Crohn's disease not responsive to conventional therapy, three tumor necrosis factor (TNF) inhibitors: adalimumab (Humira), certolizumab pegol, and infliximab (Remicade) are recommended. ‹ Infliximab is the only one of the three approved by the FDA for use in children. ‹ The three indicated TNF-inhibitors have not been compared in head-to-head trials. ‹ The American Gastroenterological Association 2013 guidelines noted that certolizumab is the only of the three TNF inhibitors not to demonstrate improvement in remission over placebo and therefore, certolizumab does not carry the FDA indication for inducing and/or maintaining remission.A
∑ FDA approval of vedolizumab (Entyvio) was based on five clinical trials of patients who had not had an adequate response to treatment with corticosteroids, immunomodulators, or tumor necrosis factor blockers.
∑ The safety and effectiveness of Entyvio (vedolizumab) for ulcerative colitis were established in two randomized, double-blind, placebo controlled trials (UC Trials I and II) in approximately 900 adult patients with moderately to severely active UC who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications, according to an FDA press release. Evaluations of patients included measures of stool frequency, rectal bleeding, endoscopic findings, and a physician‘s overall assessment. Results showed in the two studies of about 900 patients with ulcerative colitis that a greater percentage of participants treated with Entyvio compared to a placebo achieved and maintained clinical response, achieved and maintained clinical remission, achieved corticosteroid-free clinical remission, and as seen during endoscopy, had improved appearance of the colon. ‹ The primary endpoints were based on clinical response: reduction in complete Mayo score of >3 points and >30% from baseline with an accompanying decrease in rectal bleeding subscore of >1 point or absolute rectal bleeding subscore of <1 point. Clinical remission: complete Mayo score of <2 points and no individual subscore >1 point. Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability). ‹ In patients with ulcerative colitis, a clinical response occurred in 47.1% of vedolizumab-treated patients after 6 weeks of therapy, compared to 25.5% of those taking placebo. Among responders, continued treatment with vedolizumab every 4 or 8 weeks resulted in clinical remission at 52 weeks in 44.8% and 41.8%, respectively, compared to 15.9% with placebo.4 ‹ 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.
∑ The safety and effectiveness of Entyvio for Crohn‘s disease were established in 3 randomized, double-blind, placebo- controlled clinical trials (CD Trials I, II, and III) involving approximately 1,500 adult patients with moderately to severely active Crohn’s disease who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications. Results showed that in the three studies of these 1,500 patients with CD, a greater proportion of those treated with vedolizumab achieved a clinical response, clinical remission, and a corticosteroid-free clinical remission, compared with those on placebo. ‹ The primary endpoint was Clinical Remission (at Week 6): CDAI <150. • In order to be randomized to treatment in CD Trial III, patients had to have received Entyvio and be in clinical response at week 6. Patients were randomized to receive placebo or Entyvio every 8 weeks or Entyvio every 4 weeks. Efficacy assessments were at week 52. • Treatment with Entyvio did not result in statistically significant improvement over placebo. Results from one of these randomized, controlled trial in patients with Crohn's disease showed clinical remission occurred after 6 weeks of treatment in 14.5% of vedolizumab-treated patients and in 6.8% of those taking placebo. 2 A clinical response occurred in 31.4% of patients treated with vedolizumab and in 25.7% of those randomized to placebo; this difference was not statistically significant. Responders received maintenance therapy with vedolizumab every 4 or 8 weeks, or placebo, for 52 weeks; 36.4% and 39% of patients receiving vedolizumab every 4 and 8 weeks, respectively, were in clinical remission at 52 weeks, compared to 21.6% of those receiving placebo.2 • 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.
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FDA INDICATIONS
∑ Crohn disease: Treatment of moderately to severely active Crohn disease in patients who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor-alpha (TNF-alpha) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
∑ Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response with, lost response to, were intolerant to a tumor necrosis factor alpha (TNF-alpha) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
Available as: Vial: 300mg/20ml for reconstitution. Single dose
FDA Approved: May 20, 2014
Black Box Warnings: None at the time of this writing
CLASSIFICATION: Integrin Receptor Antagonist
RECOMMENDATIONS/COVERAGE CRITERIA
Entyvio (vedolizumab) may be authorized for members who meet ALL of the following criteria [ALL]
1. � Prescriber specialty [ONE]
ß Board-certified gastroenterologist or colorectal surgeon
ß Consult with a Board-certified specialist with experience in prescribing gastroenterologist or colorectal surgeon. Prescriber submit consultation notes.
2. � Diagnosis/Indication [ONE]
ß Documented diagnosis of moderately to severely active ulcerative colitis (UC)
ß Documented diagnosis of moderately to severely active Crohn’s disease (CD)
3. � Age/Gender/Other restrictions [ALL]
ß 18 years or older ‹ Safety and efficacy in patients younger than 18 years have not been established.
ß A negative tuberculin skin test (TST) or CDC-recommended equivalent for latent tuberculosis within the last 12 months
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4. Step/Conservative Therapy/Other condition Requirements [ALL] �
A. � Clinical documentation of inadequate response must be documented for a minimum treatment period of 12 weeks, intolerance, contraindication, or other clinical rationale for inappropriateness of treatment with: [ONE]
¶ For Crohn’s Disease [BOTH]
û Documentation of an inadequate response, contraindication or intolerance to TWO of the following agents: [TWO] o Corticosteroids (e.g., prednisone, prednisolone, methylprednisolone) o 5-Aminosalicylates (e.g., balsalazide, mesalamine, sulfasalazine) o Immunosuppressives [e.g. 6-mercaptopurine (6-MP, Purinethol®), azathioprine (Imuran®), Methotrexate (MTX)]
û Clinical documentation of inadequate response must be documented for a minimum treatment period of 12 weeks, intolerance, contraindication, or other clinical rationale for inappropriateness of treatment with: [ONE] o Humira (adalimumab): PREFERRED AGENT [Refer to MCG-212] o Remicade (infliximab) [Refer to MCG-213]
¶ For Ulcerative Colitis [BOTH]
û Documentation of an inadequate response, contraindication or intolerance to TWO of the following agents: [TWO] o Corticosteroids (e.g., prednisone, prednisolone, methylprednisolone) o 5-Aminosalicylates (e.g., balsalazide, mesalamine, sulfasalazine) o Immunosuppressives [e.g. 6-mercaptopurine (6-MP, Purinethol®), azathioprine (Imuran®), Methotrexate (MTX)]
û Clinical documentation of inadequate response must be documented for a minimum treatment period of 12 weeks, intolerance, contraindication, or other clinical rationale for inappropriateness of treatment with: [ONE] o Humira (adalimumab): PREFERRED AGENT [Refer to MCG-212] o Remicade (infliximab) [Refer to MCG-213]
B. � NO concurrent use with Another Biologic Therapy Entyvio (vedolizumab) should not be administered in combination with another biologic agent for an inflammatory condition (e.g., Actemra® [tocilizumab], Enbrel® [etanercept], Kineret® [anakinra], Orencia® [abatacept], Remicade [infliximab], Rituxan® [rituximab], Simponi™ [golimumab] or Tysabri® [natalizumab])
NOTE: Molina Healthcare will authorize coverage of only one biologic immunomodulator at a time.
MOLINA INTERNAL STAFF: Verify member’s current medication fill history or prescription drug profile
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5. � Contraindications/Exclusions/Discontinuations Authorization will not be granted if ANY of the following conditions apply [ANY] ¶ Non-FDA approved indications ¶ Severe hypersensitivity to Entyvio (vedolizumab) or any component of the formulation including L-histidine, L-arginine, sucrose, or polysorbate 80 � Exclusions [ANY] � ¶ Combination with another biologic agent for an inflammatory condition (e.g., Actemra [tocilizumab], Enbrel [etanercept], Kineret [anakinra], Orencia [abatacept], Remicade [infliximab], Rituxan [rituximab], Simponi [golimumab] ) ¶ Currently diagnosed with, or history of, progressive multifocal leukoencephalopathy (PML)
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CONTINUATION OF THERAPY Entyvio (vedolizumab) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL]
1. � Initial Coverage Criteria
ß Member currently meets ALL initial coverage criteria
2. Compliance
ß Adherence to therapy at least 85% of the time as verified by Prescriber and member’s medication fill history (review Rx history for compliance), including: û Compliance in taking the medication as prescribed û No intolerable adverse effects or drug toxicity
NOTE: Therapy may be discontinued due to poor adherence upon recommendation of the Molina Medical Director when adherence < 85% has been demonstrated in at least two months during the course of therapy
ß History of non-compliance or non-adherence as verified by member’s medication fill history or prescription drug profile [MOLINA MEDICAL/PHARMACY REVIEWER TO VERIFY]
3. � Labs/Reports/Documentation required [ALL APPLICABLE]
¶ Documentation clinical response and remission of disease maintained with continued use as submitted by the Prescriber, a board-certified gastroenterologist NOTE: Discontinuation of therapy in patients who show no evidence of therapeutic benefit by week 14.a
4. � Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] ß Intolerable adverse effects or drug toxicity ß Persistent and uncorrectable problems with adherence to treatment ß Poor response to treatment as evidenced by physical findings and/or clinical symptoms ß Contraindications/Exclusions to Entyvio (vedolizumab) therapy û Non-FDA approved indications û Hypersensitivity to Entyvio (vedolizumab) or any of its components û Currently diagnosed with, or history of, progressive multifocal leukoencephalopathy (PML)
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ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD
1. � Recommended Dosage [ALL]
¶ For Ulcerative Colitis: 300mg given as a 30 minute intravenous infusion at zero, two and 6 weeks, then every 8 weeks thereafter.
¶ For Crohn’s Disease: 300mg given as a 30 minute intravenous infusion at zero, two and 6 weeks, then every 8 weeks thereafter.
2. � Authorization Limit [ALL]
Initial Authorization
¶ Quantity limit: 900mg for the initial 42 days (6 weeks) [300 mg IV given at zero, two, and six weeks] THEN 300mg IV every 56 days (8 weeks) NOTE: A maximum of 7 infusions in 12 months based on a recommended dose infusion interval of every 8 weeks.
¶ Dispensing limit: Maximum dose and interval that will be approved is 300 mg IV every 8 weeks
¶ Duration of initial authorization: Initial authorization given for four doses (zero, two, six weeks and the first every eight week dose) for 14 weeks. NOTE: Discontinue Entyvio™ (vedolizumab) in patients who do not show evidence of therapeutic benefit by week 14.a
Continuation of Treatment
¶ Duration of reauthorizations (after initial authorization): Prescribing physician must submit a new prior authorization request every 6 months and include member’s medical records documenting positive clinical response for continued authorization after the initial 4 doses.
¶ Dispensing limit: Maximum dose and interval that will be approved is 300 mg IV every 8 weeks
¶ Discontinue Entyvio™ (vedolizumab) in patients who do not show evidence of therapeutic benefit by week 14.a
3. � Route of Administration [ALL]
¶ Vedolizumab (Entyvio) is considered a provider-administered medication. Vedolizumab (Entyvio) is administered by intravenous infusion.
¶ If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy.
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COVERAGE EXCLUSIONS
All other uses of the mentioned drugs that are not an FDA-approved indication or included in ‘Coverage Criteria’ section above are considered experimental/investigational and is not a covered benefit. The following list is not all-inclusive and is subject to change based on research and medical literature:
¶ Non-FDA approved indications ¶ Currently diagnosed with, or history of, progressive multifocal leukoencephalopathy (PML) ¶ Concurrent use of multiple biological response modifiers including, but not limited to: Actemra (tocilizumab), Amevive (alefacept), Enbrel (etanercept), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Remicade (infliximab), Simponi (golimumab) and Stelara (ustekinumab); Tysabri (natalizumab); Xeljanz (tofacitinib) ‹ Combination therapy with two biologic agents is not recommended due to a higher rate of adverse effects with combinations and/or lack of additive efficacy. ‹ There are no studies supporting concomitant therapy with any two of these agents, and since combinations have resulted in increases in serious infections. The FDA has required the prescribing information for these agents to include warnings to avoid combinations of two or these agents or concurrent therapy with other immunosuppressive agents.
SUMMARY
Crohn’s Disease (CD) Crohn’s disease (CD) is a chronic, inflammatory disorder of the gastrointestinal tract of uncertain etiology. It is characterized by patchy, transmural inflammation, which may affect any part of the gastrointestinal tract. Similar to RA, CD is not medically or surgically curable. The clinical and pathological signs of CD are variable, and reflect the distribution and severity of the disease. The course of the disease is often relapsing and remitting, and sometimes complicated by intestinal strictures, fistulas and abscesses. Therapeutic options for the treatment of CD are determined by disease location, severity, and extraintestinal complications.
Biologic agents which have demonstrated effectiveness in the treatment of CD include: • Adalimumab (Humira) • Certolizumab pegol (Cimzia) • Infliximab (Remicade) • Golimumab (Simponi) • Natalizumab (Tysabri) • Vedolizumab (Entyvio)
Ulcerative Colitis (UC) Ulcerative colitis is a chronic, episodic, inflammatory disease of the large intestine and rectum characterized by bloody diarrhea. This disease usually begins in the rectal area and may eventually extend through the entire large intestine. Repeated episodes of inflammation lead to thickening of the wall of the intestine and rectum with scar tissue. Death of colon tissue or sepsis may occur with severe disease. The goals of treatment are to control the acute attacks, prevent recurrent attacks and promote healing of the colon. Hospitalization is often required for severe attacks. Generally, first- line treatments such as corticosteroids, 6- MP and azathioprine are used to treat this condition.
Treatment goals include inducing and maintaining clinical response, inducing and maintaining clinical remission, improving the endoscopic appearance of the mucosa, and achieving corticosteroid-free remission in adult patients with moderately to severely active ulcerative colitis.
Biologic agents which have demonstrated effectiveness in the treatment of UC include: • Adalimumab (Humira)
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• Golimumab (Simponi) • Infliximab (Remicade) • Vedolizumab (Entyvio)
The overall comparative efficacy for these agents in the treatment of UC is uncertain due to lack of high quality evidence in the induction of remission of UC.
Vedolizumab, a humanized monoclonal antibody, works as an antagonist of the α4β7 integrin receptor that ultimately blocks T cell migration within the gastrointestinal tract. Vedolizumab specifically binds to the α4β7 integrin and blocks the interaction of α4β7 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 α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). Vedolizumab binds to and blocks the interaction between integrin alpha-4- beta-7 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the gut which inhibits the migration of specific memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease since it reduces the chronic inflammatory process present in both ulcerative colitis and Crohn’s disease.
DEFINITIONS
N/A �
APPENDIX
N/A �
CODING INFORMATION THE CODES LISTED IN THIS POLICY ARE FOR REFERENCE PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE.
HCPCS Description J3380 Injection, vedolizumab, 1 mg
REFERENCES
Package Insert, FDA, Drug Compendia a. � Entyvio [Prescribing Information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; May 2014. b. � Product Information: ENTYVIO(TM) intravenous injection, vedolizumab intravenous injection. Takeda Pharmaceuticals America (per manufacturer), Deerfield, IL, 2014. c. � AHFS Drug Information® with AHFS®. (www.statref.com), American Society Of Health-System Pharmacists®, Bethesda, MD. Updated periodically. d. � DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically. e. Drug Facts and Comparisons online. (www.drugfacts.com), Wolters Kluwer Health, St. Louis, MO. Updated periodically. f. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2012. URL: http://www.clinicalpharmacology.com.
Clinical Trials, Definitions, Peer-Reviewed Publications �
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1. � Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin [published correction appears in Clin Gastroenterol Hepatol. 2009;7(4):494]. Clin Gastroenterol Hepatol. 2008;6(12):1370-1377. 2. � Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2003 Aug 8;369:711-21. 3. � 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 Had Failed. Gastroenterology. 2014 May 21. 4. � Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013 Aug 22;369(8):699-710. 5. � Feagan B, Sands B, Sankoh S, Milch C, Fox I. Efficacy of vedolizumab in ulcerative colitis by prior treatment failure in GEMINI I, a randomized, placebo-controlled, double-blind, multicenter trial [O-1b abstract]. Inflamm Bowel Dis. 2012;18(Suppl 1): S1-S127.
Government Agencies, Professional Societies, and Other Authoritative Publications A. � Terdiman JP, Gruss C, Heidelbaugh JJ, Sultan S, Falck-Ytter YT, American Gastroenterological Association Institute Guidelines on the use of thiopurines, methotrexate and anti-TNF biologic drugs in inflammatory Crohn's disease. Gastroenterology 2013;1459-1463.
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