Digestive Enzyme Cartridges Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 08|01|2023 POLICY LAST REVIEWED: 03|05|2025 OVERVIEW
This policy describes the reimbursement for digestive enzyme cartridges (e.g. Relizorb). RELiZORB™ (Alcresta Pharmaceuticals) is a single use, point of care digestive enzyme cartridge that can be connected in-line with enteral feeding paths, for use in which individuals do not secrete sufficient levels of pancreatic digestive enzyme, lipase, which breaks down ingested fats for easier digestion and absorption. The RELiZORB system is designed to mimic the normal function of lipase release. The RELiZORB cartridge contains the digestive enzyme lipase. As enteral formula flows through the cartridge, it makes contact with the lipase which hydrolyzes fats from the triglyceride form into fatty acids and monoglycerides to enable easier absorption and utilization by the body.
MEDICAL CRITERIA Medicare Advantage Plans Digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) is considered medically necessary for chronic medical conditions. These conditions include, but are not limited to, individuals with Cystic Fibrosis, Crohn’s Disease or Ulcerative Colitis with complications, and Pancreatic disorders. Refer to Coding section for details.
Commercial Products Initial requests for digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) may be approved if the following criteria are met: 1. Individual has a diagnosis of cystic fibrosis; AND individual has a confirmed history of exocrine pancreatic insufficiency; AND 2. Individual requires enteral tube nutrition for continuous durations of 6 hours or more, and using Relizorb to hydrolyze fats in enteral formula; AND 3. Individual has continued malabsorption of fats (as evidenced by insufficient weight gain or weight loss) from enteral formula, despite optimizing therapy with pancreatic enzyme replacement therapy (PERT) tablets or capsules administered orally or via feeding tube (capsules only). Continuation requests for digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) may be approved if the following criteria are met: 1. Individual has evidence of stable or increased weight from use of Relizorb; AND 2. Individual continues to require enteral tube nutrition for continuous durations of 6 hours or more. PRIOR AUTHORIZATION Prior authorization is not required for Medicare Advantage Plans and is recommended for Commercial Products via the online tool for participating providers. See the Related Policies section.
POLICY STATEMENT Medicare Advantage Plans Digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) is considered medically necessary when the criteria above is met. Refer to Coding section for details.
Medical Coverage Policy | Digestive Enzyme Cartridges

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

Digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) is considered not covered when the criteria above is not met. Refer to Coding section for details.

Commercial Products Digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) is considered medically necessary when the criteria above is met.

Digestive enzymes added to enteral formula via a cartridge device attached to the tubing used for enteral feeding (eg, Relizorb™ immobilized lipase cartridge) is considered not medically necessary when the criteria above is not met.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate Benefit Booklet, Evidence of Coverage, Subscriber agreement for the applicable "Medical Equipment, Medical Supplies and Prosthetic Devices" coverage. BACKGROUND Commercial Products Relizorb is proposed to be useful to people with pancreatic insufficiency and need enteral nutrition (e.g. individuals with cystic fibrosis (CF)). Relizorb is a cartridge, which contains the pancreatic enzyme lipase. The cartridge connects to the enteral tube feeding system and is FDA (Food and Drug Administration) approved for individuals who have difficulty digesting and absorbing fats. Manufacturers declare that the cartridge enzymes convert 90% of the fat in the enteral nutrition to fatty acids and mono-glycerides.

The Absorption and Safety with Sustained use of Relizorb Evaluation (ASSURE) study was a prospective, single- arm, multicenter, 90-day open-label (not intended to compare outcomes between participants who did and did not use Relizorb) study in patients with Cystic Fibrosis. Thirty-six subjects who were given overnight enteral nutrition with the use of Relizorb. The primary end-point was change over time in RBC (red blood cell) membranes (a marker of long-term fatty acid absorption) uptake of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Relizorb was not found to be associated with any unanticipated adverse events. Increased RBC levels of DHA+EPA indicated that fat absorption significantly improved. In the ASSURE study, omega-3 FA erythrocyte levels increased with longer-term RELiZORB use, supporting the role of Relizorb in normalizing deficient DHA and EPA levels and maintaining them over longer periods when RELiZORB was utilized with overnight enteral nutrition feeds. Authors concluded that it is not possible to draw definitive conclusions from the current and previous RELiZORB studies about the influence of Relizorb use on changes in patient anthropometric measurements. While weight, BMI (body mass index) z-scores and percentiles were not significantly different from baseline to 90 days, 61% (20/33) patients in the ASSURE study had improvements in weight z scores and percentiles over the course of the study. Because the current study did not measure body tissue composition, it is unknown whether study participants improved their tissue composition without changing body weight or size. It may turn out that nutritional health may be more accurately measured using biomarkers other than the traditional body weight and body mass index.

Sathe et al (2021) evaluated the effectiveness of in-line immobilized lipase cartridges (ILC) in enterally fed patients with CF. Baseline anthropometric data were obtained and subsequent measurements of height, weight, and body mass index were collected at 6 and 12 months (n=100; age 0-45). Over 12 months of use in patients

2 years of age (n=93), there were significant improvements seen in height and weight z-scores with an improvement trend seen in BMI. The frequency of achieving the 50th percentile increased steadily for weight and BMI from baseline to 12 months but not for height. Authors concluded that better growth is possible over standard of care. The association of ILC use with significant improvements in anthropometric parameters over a 12-month period in people with CF demonstrates the effectiveness of ILC as a rational enzyme therapy during enteral feedings.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

Well-designed clinical trials supporting the efficacy of in-line digestive enzyme cartridges for the treatment of pancreatic insufficiency caused by multiple conditions including, but not limited to: celiac disease, chronic pancreatitis, Crohn’s disease, diabetes mellitus, gastrectomy, pancreatic cancer, pancreatic duct obstruction, small bowel resection, and short bowel syndrome are lacking. In-line cartridges used for emulsion of fat during enteral feeding may demonstrate equivalent or improved clinical outcomes when compared to conventional methods for individuals with CF. There is insufficient evidence to support the effectiveness of digestive enzyme cartridges for the treatment of pancreatic insufficiency caused by other conditions aside from CF.

CODING Medicare Advantage Plans The following code is covered when filed with a covered ICD-10 code below: B4105 In-line cartridge containing digestive enzyme(s) for enteral feeding, each

Covered DX for HCPCS Code B4105 for Medicare Advantage Plans

Commercial Products The following code is covered when the medical criteria above is met: B4105 In-line cartridge containing digestive enzyme(s) for enteral feeding, each RELATED POLICIES Coding and Payment Guideline Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations

PUBLISHED Provider Update, May 2025 Provider Update, May 2024 Provider Update, April/June 2023 Provider Update, April 2022 Provider Update, May 2021 REFERENCES

1. Centers for Medicare and Medicaid Services, Local Coverage Determination (LCD), Noridian Healthcare Solutions, LLC, L38955, Enteral Nutrition.
2. Centers for Medicare and Medicaid Services, Local Coverage Determination Article, Noridian Healthcare Solutions, LLC, A58833, Enteral Nutrition.
3. Ferrie S, Graham C, Hoyle M, et. al. Pancreatic Enzyme Supplementation for patients receiving enteral feeds. Nutr Clin Pract 2011;26:349-51.
4. NCT02750501. Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study (ASSURE) ClinicalTrials.gov. U.S. National Library of Medicine. U.S. National Institutes of Health. Available at https://clinicaltrials.gov/ct2/show/NCT02750501?term=relizorb&rank=2.
5. NCT02598128. Safety, Tolerability and Fat Absorption Using Enteral Feeding In-line Enzyme Cartridge (Relizorb). ClinicalTrials.gov. U.S. National Library of Medicine. U.S. National Institutes of Health. Available at https://clinicaltrials.gov/ct2/show/NCT02598128.
6. Pertzye Packet Inserts. Pertzye. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process.
7. Relizorb Package inserts. Relizorb (immobilized lipase) cartridge. Available at: https://www.relizorb.com/docs/pdfs/Relizorb-Instructions-for-Use.pdf.
8. Schwarzenberg SJ, Hempstead SE, McDonald CM, et. al. Enteral Tube Feeding for Individuals With Cystic Fibrosis: Cystic Fibrosis Foundation Evidence-Informed Guidelines. J Cyst Fibros. 2016. Nov;15(6):724- 735.PMID: 27599607.
9. Shileout G, Koerner A, Maffert M, et. al. Administration of Creon pancrelipase pellets via gastrostomy tube is feasible with no loss of gastric resistance or lipase activity. Clin Drug Investig. 2011;31:e1-e7.
10. Abu-El-Haija, M., Uc, A., et al. “Nutritional Considerations in Pediatric Pancreatitis: A Position Paper from the NASPHAN Pancreas Committee and ESPHAN Cystic Fibrosis/Pancreas Working Group. JPGN 2018;67:131-143.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

11. Alcresta Therapeutics. Relizorb. 2022. https://www.relizorb.com/hcp.
12. Cystic Fibrosis Foundation. Pancreatic Enzymes Clinical Care Guidelines. 2019. https://www.cff.org/Care/Clinical-Care-Guidelines/Nutrition-and-GI-Clinical-Care-Guidelines/Pancreatic- Enzymes-Clinical-Care-Guidelines/.
13. Freeman AJ, Maqbool A, Bellin M, et al. Medical management of chronic pancreatitis in children: a position paper by the North American society of pediatric gastroenterology, hepatology and nutrition pancreas committee. J Pediotr Gostroenterol Nutr. 2021;72: 324-340.
14. Freedman S, Orenstein D, Black P, et al. Increased fat absorption from enteral formula through an in-line digestive cartridge in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2017;65(1):97–101.
15. Katkin, J., Baker, R., et al. “Cystic Fibrosis: Assessment and Management of Pancreatic Insufficiency.” (2022). www.uptodate.com.
16. Schwarzenberg SG, Borowitz D, et al. “Challenging Barriers to an Option for Improved Provision of Enteral Nutrition.” Journal of CF 2019;18:447-449
17. Schwarzenberg SG, Dorsey J. “Pancreatic Enzymes Clinical Care Guidelines.” Bethesda, MD: Cystic Fibrosis Foundation; 2013. www.cff.org/Care/Clinical-Care-Guidelines/Nutrition-and-GI-Clinical-Care- Guidelines/Pancreatic-Enzymes-Clinical-Care-Guidelines.
18. Schwarzenberg SJ, Borowitz D; 20 gastroenterologists, 23 CF physicians, 17 CF dietitians and 1 PharmD. Challenging barriers to an option for improved provision of enteral nutrition. J Cyst Fibros. 2019 Jul;18(4):447-449. PMID: 31230797.
19. Stevens J, Wyatt C, et al. “Absorption and safety with sustained use of Relizorb evaluation (ASSURE) study in patients with cystic fibrosis receiving enteral feeding.” JPGN 2018;67:527-532.
20. U. S. Food and Drug Administration (FDA), Class II Medical Devices, “RELiZORB,” July 12, 2017. https://www.accessdata.fda.gov/cdrh_docs/pdf16/k163057.pdf.
21. U. S. Food and Drug Administration (FDA), Class II Medical Devices, “RELiZORB,” K231156. August 30,

22. https://www.accessdata.fda.gov/cdrh_docs/pdf23/K231156.pdf.

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    This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association. CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS