Policy
Under many benefit plans, medically necessary services must be rendered in the least intensive setting that is appropriate for the delivery of the services and supplies. Where applicable, the plan may compare the cost-effectiveness of alternative services, settings or supplies when determining least intensive setting.

• An injectable medication must meet applicable medical necessity criteria for coverage. When coverage criteria are met for the injectable medication, this coverage policy is used to determine the medical necessity of the requested site of care.

Alternative less-intensive site of care facilities include:

• Non-hospital affiliated outpatient infusion (e.g., ambulatory infusion center or physician office).
• Home infusion.

Injectable medication treatment in a hospital outpatient setting or at a hospital-affiliated infusion suite* as medically necessary for an individual with ANY of the following:

• The prescribed medication has a site-of-care restriction for administration per the FDA-approved label
• A documented history of an adverse event warranting a more intense level of care during or following infusion of the prescribed medication, unless the adverse event can be appropriately managed by the use of pre-medication(s) or other preventive actions
• A documented history of a significant comorbidity (e.g., cardiopulmonary disorder) or concerns regarding fluid overload status that precludes treatment at an alternative less-intensive site of care

*Note: A hospital outpatient setting or a hospital-affiliated infusion suite is expected to have immediate access to specific services of a medical center/hospital setting, including having emergency resuscitation equipment and personnel (ACLS protocol), emergency services, and inpatient admission or intensive care, if necessary.

When the above medical necessity criteria for administration of an injectable medication in a hospital outpatient setting or hospital-affiliated infusion suite are not met, an alternative less-intensive site of care should be utilized.

Impacted Drugs 
The Site of Care drug program identifies members who are receiving certain specialty drugs at a higher cost site of service (i.e., hospital outpatient setting) and encourages them to move to an equally appropriate, alternative site of service (infusion center or home). Drugs included in this program include but are not limited to the following:

References 

1. Aeschlimann FA, Hofer KD, Schneider EC, Schroeder S, Saurenmann RK, et al. Infliximab in pediatric rheumatology patients: a retrospective analysis of infusion reactions and severe adverse events during 2246 infusions over 12 years. J Rheumatol. 2014;41(7):1409-1415.
2. Agency for Healthcare Research and Quality. Enzyme-Replacement Therapies for Lysosomal Storage Diseases. Agency for Healthcare Research and Quality. Effective Health Care Program Technical Brief No. 12. January 2013. Available at: http://www.ncbi.nlm.nih.gov/books/NBK117219/pdf/Bookshelf_NBK117219.pdf. Accessed May 13, 2016.
3. Baker JJ, Leovic TM, O'Connor CA, Pierce CA. Relocating rheumatology patients to a new infusion center at Duke: a case study. Health Care Manag (Frederick). 2003;22(2):159-169.
4. Berthelot JM, Benoist-Gerard S, le Goff B, Muller-Chevalet F, Maugars Y. Outcome and safety of TNFalpha antagonist therapy in 475 consecutive outpatients (with rheumatoid arthritis or spondyloarthropathies) treated by a single physician according to their eligibility for clinical trials. Joint Bone Spine. 2010;77(6):564-569.
5. Braune SA, Wichmann D, von Heinz MC, Nierhaus A, Kluge S, et al. Clinical features of critically ill patients with Shiga toxin-induced hemolytic uremic syndrome. Crit Care Med. 2013;41(7):1702-1710.
6. Buisson A, Seigne AL, D'Huart M C, Bigard MA, Peyrin-Biroulet L. The extra burden of infliximab infusions in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(11):2464-2467.
7. Cayci FS, Cakar N, Hancer VS, Uncu N, Acar B, Gur G. Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation. Pediatr Nephrol. 2012;27(12):2327-2331.
8. Centers for Medicare & Medicaid Services; Self-Administered Drug (SAD) Exclusion List Report. Available at: https://www.cms.gov/medicare-coverage-database/reports/national-and-local-reports.aspx 
9. Choquette D, Faraawi R, Chow A, Rodrigues J, Nantel F, et al. Incidence and management of infusion reactions to infliximab in a prospective real-world community registry. J Rheumatol. 2015;42(7):1105-1111.
10. Christmann M, Hansen M, Bergmann C, Schwabe D, Brand J, Schneider W. Eculizumab as first-line therapy for atypical hemolytic uremic syndrome. Pediatr. 2014;133(6):e1759-e1763.
11. Colombel JF, Loftus EV, Tremaine WJ, Egan LJ, Sandborn WJ, et al. The safety profile of infliximab in patients with Crohn's disease: The Mayo Clinic experience in 500 patients. Gastroenterology. 2004;126(1):19-31.
12. Condino AA, Fidanza S, Hoffenberg EJ. A home infliximab infusion program. J Pediatr Gastroenterol Nutr. 2005;40(1):67-69.
13. Dinh A, Anathasayanan A, Rubin LM. Safe and effective use of eculizumab in the treatment of severe Shiga toxin Escherichia coli-associated hemolytic uremic syndrome. Am J Health-Syst Pharm. 2015;72(2):117-120.
14. Ducharme J, Pelletier C, Zacharias R. The safety of infliximab infusions in the community setting.Can J Gastroenterol. 2010;24(5):307-311.
15. de Eusebio E, Armario-Hita JC, de Miquel VA. Treatment of psoriasis: focus on clinic-based management with infliximab. Am J Clin Derm. 2014;15 Suppl 1(Feb):S5-16.
16. Doran JP, Alraqi S, Callanan I, FitzGerald O, Bresnihan B, Veale DJ. An audit of hospital based outpatient infusions and a pilot program of community-based monoclonal antibody infusions. Ir J Med Sci. 2009;178(4):497-501.
17. Goodhand J, Dawson R, Hefferon M, et al. Inflammatory bowel disease in young people: the case for transitional clinics. Inflamm Bowel Dis. 2010;16(6):947-952.
18. Hazen ACM, Smith FJ, Taylor KMG, Rawcliffe C, Medcalf L, Keady S. Paediatric infliximab therapy: patients' and parents' perspectives on treatment options. Paediatr Perinat Drug Ther. 2008;8(4):177-181.
19. Huynh TK, Ostergaard A, Egsmose C, Madsen OR. Preferences of patients and health professionals for route and frequency of administration of biologic agents in the treatment of rheumatoid arthritis. Patient Prefer Adherence. 2014;8:93-99.
20. Johnson R, Freeman EN. Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab. Am Health Drug Benefits. 2011;4(1):39-46.
21. Kalb RE, Gurske J. Infliximab for the treatment of psoriasis: clinical experience at the State University of New York at Buffalo. J Am Acad Dermatol. 2005;53(4):616-622.
22. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Hillmen P, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117(25):6786-6792.
23. Kelsall J, Rogers P, Galindo G, De Vera MA. Safety of infliximab treatment in patients with rheumatoid arthritis in a real-world clinical setting: description and evaluation of infusion reactions. J Rheumatol. 2012;39(8):1539-1545Kuin S, Stolte SB, Van Den Brink GR, et al. Remicade infusions at home: an alternative setting of infliximab therapy for patients with Crohn's disease. Eur J gastroenterol Hepat. 2016;28(2):222-225.
24. Lequerre T, Vittecoq O, Klemmer N, Goeb V, Loet X, et al. Management of infusion reactions to infliximab in patients with rheumatoid arthritis or spondyloarthritis: Experience from an immunotherapy unit of rheumatology. J Rheumatol. 2006;33(7):1307-1314.
25. Loomes DE, Teshima C, Jacobs P, Fedorak RN. Health care resource use and costs in Crohn's disease before and after infliximab therapy. Can J Gastroenterol. 2011;25(9):497-502.
26. Michielan A, Martinato M, Favarin A, et al. A nurse-led accelerated procedure for infliximab infusion is well tolerated and effective in patients with inflammatory bowel disease. Dig Liver Dis. 2015;47(5):372-377.
27. Moss IB, Moss MB, dos Reis DS, Coelho RM. Immediate infusional reactions to intravenous immunobiological agents for the treatment of autoimmune diseases: experience of 2126 procedures in a non-oncologic infusion centre. Rev Bras Reumatol. Mar-Apr 2014;54(2):102-109.
28. Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013;12(6):554-562.
29. Remicade (infliximab) [product information]. Horsham, PA: Janssen Biotech, Inc.; 2015.
30. REMS@FDA. Approved Risk Evaluation and Mitigation Strategies (REMS). Food and Drug Administration, Department of Health and Human Services. http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm. Accessed October 11, 2016.
31. Scarpa M, Almassy Z, Bodamer O, et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis. 2011;6:72. 
32. Soliris (eculizumab) [product information]. New Haven, CT: Alexion Pharmaceuticals Inc; 2017.
33. Stuby U, Biesenbach G, Pieringer H. Administration of infliximab in general practitioners' offices is safe. Clin Rheumatol. 2007;26(11):1863-1866.
34. Tran H, Chaudhuri A, Concepcion W, Grimm PC. Use of eculizumab and plasma exchange in successful combined liver-kidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediat Nephrol. 2014;29(3):477-480.
35. Tsai HM. Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update. Hematol Oncol Clin North Am. 2013;27(3):565-584.
36. Tursi A, Elisei W, Picchio M, et al. Effectiveness and safety of infliximab and adalimumab for ambulatory Crohn's disease patients in primary gastroenterology centres. Eur J Intern Med. 2014;25(5):485-490.
37. Tursi A, Elisei W, Picchio M, et al. Managing ambulatory ulcerative colitis patients with infliximab: a long term follow-up study in primary gastroenterology centers. Eur J Intern Med. 2014;25(8):757-761.
38. Wasserman MJ, Weber DA, Guthrie JA, Bykerk VP, Lee P, Keystone EC. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol. 2004;31(10):1912-1917.
39. Wee JS, Petrof G, Jackson K, Barker JN, Smith CH. Infliximab for the treatment of psoriasis in the U.K.: 9 years' experience of infusion reactions at a single centre.Br J Dermatol. 2012;167(2):411-416.
40. Wong BJ, Cifaldi MA, Roy S, Skonieczny DC, Stavrakas S. Analysis of drug and administrative costs allowed by U.S. private and public third-party payers for 3 intravenous biologic agents for rheumatoid arthritis. J Manag Care Pharm. 2011;17(4):313-320.
41. Wu M, Sin A, Nishioka F, Park KT. Non-drug costs associated with outpatient infliximab administration in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(7):1514-1517.
42. Yazici Y, McMorris BJ, Darkow T, Rosenblatt LC. Patient and physician perception of the infusion process of the biologic agents abatacept, infliximab, and rituximab for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2009;27(6):907-913.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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