Clinical Policy: Hyaluronate Derivatives Form

# Clinical Policy: Hyaluronate Derivatives
Reference Number: CP.PHAR.05  
Effective Date: 10.01.08  
Last Review Date: 11.25  
Line of Business: Commercial, HIM-Medical Benefit*, Medicaid  

**CENTENE Corporation**  

[Coding Implications](Coding Implications)  
[Revision Log](Revision Log)  

See [Important Reminder](Important Reminder) at the end of this policy for important regulatory and legal information.  

## Description  
The following are hyaluronate derivatives requiring prior authorization: sodium hyaluronate (Euflexxa®, Gelsyn-3™, GenVisc®850, Hyalgan®, Supartz FX™, Synojoynt™, Triluron™, TriVisc™, VISCO-3™), hyaluronic acid (Durolane®), cross-linked hyaluronate (Gel-One®), hyaluronan (Hymovis®, Orthovisc®, Monovisc®), and hylan polymers A and B (Synvisc®, Synvisc One®).  

\*For Health Insurance Marketplace (HIM), coverage of hyaluronate derivatives is excluded for the pharmacy benefit and should not be approved using these criteria; these criteria may be used for medical benefit review.  

## FDA Approved Indication(s)  
Hyaluronate derivatives are indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy and to simple analgesics (e.g., acetaminophen).  

## Policy/Criteria  
Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.  

It is the policy of health plans affiliated with Centene Corporation® that hyaluronate derivatives are medically necessary when the following criteria are met:  

### I. Initial Approval Criteria  
#### A. Osteoarthritis of the Knee (must meet all):  
1. Diagnosis of OA of the knee supported by imaging (e.g., X-ray, MRI);  
2. Prescribed by or in consultation with a rheumatologist, orthopedist, physiatrist, or sports medicine physician;  
3. Inadequate response to physical therapy as directed by a physical therapist;  
4. Failure of a ≥4-week trial of one of the following (a or b), as evidenced by claims history, unless all are contraindicated or clinically significant adverse effects are experienced:  
   a. Oral non-steroidal anti-inflammatory drug (NSAID) at continuous therapeutic (prescription strength) dosing;  
   b. Topical NSAID\* if member is ≥75 years old or unable to take oral NSAIDs;  
   \*Prior authorization may be required for topical NSAIDs  
5. Trial of at least one intra-articular glucocorticoid injection\* with a documented positive but inadequate response (see Appendix D for examples) unless contraindicated or history of intolerance;  

# Clinical Policy  
Hyaluronate Derivatives  

\*Prior authorization may be required for intra-articular glucocorticoids  

6. If request is for a product other than Euflexxa, Monovisc, Orthovisc, Synvisc, and Synvisc One: Failure of two of the following (a, b, or c), unless clinically significant adverse effects are experienced or all are contraindicated:^\  
   a. Euflexxa;  
   b. Monovisc or Orthovisc;  
   c. Synvisc or Synvisc One;  
^\*For Illinois HIM requests, the step therapy requirements above do not apply as of 1/1/2026 per IL HB 5395  

7. Member does not have any of the following (a and b):  
   a. Coexistent active inflammatory arthritis other than OA (e.g., rheumatoid arthritis, spondylitis, gouty arthritis) in the targeted knee;  
   b. History of total knee arthroplasty in the targeted knee;  
8. Dose does not exceed one treatment cycle per knee for a 6 month period.  

**Approval duration: 6 months (one treatment cycle per knee) (refer to section V)**  

### B. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial and CP.MN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, HIM-Medical Benefit) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for HIM-Medical Benefit, and CP.MN.16 for Medicaid; or  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for HIM-Medical Benefit, and CP.MN.53 for Medicaid.  

## II. Continued Therapy  
### A. Osteoarthritis of the Knee (must meet all):  
1. Member meets one of the following (a or b):  
   a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria;  
   b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);  
2. Member is responding positively to therapy as evidenced by the following, including but not limited to:  
   a. Decrease in pain symptoms as evidenced by improvement in the Visual Analog Scale for pain;  
   b. Improvement in ambulation or range of motion;  
   c. Improvement in stiffness;  

# Clinical Policy  
Hyaluronate Derivatives  

d. Decrease in rescue pain medication use;  
3. Member has not had total knee arthroplasty in the targeted knee;  
4. If request is for a product other than Euflexxa, Monovisc, Orthovisc, Synvisc, and Synvisc One: Failure of two of the following (a, b, or c), unless clinically significant adverse effects are experienced or all are contraindicated:^\  
   a. Euflexxa;  
   b. Monovisc or Orthovisc;  
   c. Synvisc or Synvisc One;  
^\*For Illinois HIM requests, the step therapy requirements above do not apply as of 1/1/2026 per IL HB 5395  

5. Six or more months have elapsed since the last treatment cycle;  
6. Dose does not exceed one treatment cycle per knee.  

**Approval duration: 6 months (one treatment cycle per knee) (refer to section V)**  

### B. Other diagnoses/indications (must meet 1 or 2):  
1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b):  
   a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial and CP.MN.255 for Medicaid; or  
   b. For drugs NOT on the formulary (commercial, HIM-Medical Benefit) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for HIM-Medical Benefit, and CP.MN.16 for Medicaid; or  
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial , HIM.PA.154 for HIM-Medical Benefit, and CP.MN.53 for Medicaid.  

## III. Diagnoses/Indications for which coverage is NOT authorized:  
### A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for HIM-Medical Benefit, and CP.MN.53 for Medicaid, or evidence of coverage documents.  

## IV. Appendices/General Information  
### Appendix A: Abbreviation/Acronym Key  
FDA: Food and Drug Administration  
NSAID: non-steroidal anti-inflammatory drug  
OA: osteoarthritis  

### Appendix B: Therapeutic Alternatives  
This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.  

# Clinical Policy  
Hyaluronate Derivatives  

| Drug Name | Dosing Regimen | Dose Limit/Maximum Dose |  
|-----------|---------------|-----------------------|  
| **Oral NSAIDs** | | |  
| diclofenac (Voltaren®) | 50 mg PO TID | 150 mg/day |  
| etodolac (Lodine®) | 400-500 mg PO BID | 1,200 mg/day |  
| fenoprofen (Nalfon®) | 400 mg PO TID to QID | 3,200 mg/day |  
| ibuprofen (Motrin®) | 400-800 mg PO TID to QID | 3,200 mg/day |  
| indomethacin (Indocin®) | 25-50 mg PO BID to TID | 200 mg/day |  
| indomethacin SR (Indocin SR®) | 75 mg PO QD to BID | 150 mg/day |  
| ketoprofen | 25-75 mg PO TID to QID | 300 mg/day |  
| meloxicam (Mobic®) | 7.5-15 mg PO QD | 15 mg/day |  
| naproxen (Naprosyn®) | 250-500 mg PO BID | 1,500 mg/day |  
| naproxen sodium (Anaprox®, Anaprox DS®) | 275-550 mg PO BID | 1,650 mg/day |  
| oxaprozin | 600-1,200 mg PO BID | 1,800 mg/day |  
| piroxicam (Feldene®) | 10-20 mg PO QD | 20 mg/day |  
| salsalate (Disalcid®) | 500-750 mg PO TID, titrated up to 30.00 mg QD | 3,000 mg/day |  
| sulindac | 150 mg-200 mg PO BID | 400 mg/day |  
| tolmetin DS (Tolectin DS®) | 400 mg PO TID, titrated up to 1,800 mg QD | 1,800 mg/day |  
| **Topical NSAIDs** | | |  
| diclofenac 1.5% (Pennsaid®) | 40 drops QID on each painful knee | 320 drops/day |  
| Voltaren® Gel 1% (diclofenac) | 2-4 g applied to affected area QID | 32 g/day |  
| **Intra-articular glucocorticoids** | | |  
| Kenalog® (triamcinolone acetonide) | 40 mg (1 mL) for large joints | 80 mg/treatment |  
| Hexatrione® (triamcinolone hexacetonide) | 10-40 mg for large joints | 40 mg/treatment |  
| methylprednisolone acetate (Depo-Medrol®) | 20-80 mg for large joints | 80 mg/treatment |  
| hydrocortisone acetate | 25-50 mg for large joints | 75 mg/treatment |  
| Zilretta® (triamcinolone acetonide) | 32 mg (5 mL) for large joints | 32 mg/treatment |  

Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic.  

### Appendix C: Contraindications/Boxed Warnings  
- **Contraindication(s):**  
  - ○ Durolane, Euflexxa, Gelsyn-3, GenVisc 850, Hyalgan, Supartz FX, Synojoynt, Triluron, TriVisc, VISCO-3, Gel-One, Hymovis, Orthovisc, Monovisc, Synvisc, Synvisc One:  
    - ■ Known hypersensitivity to hyaluronan preparations  
    - ■ Patients with knee joint infections, infections, or skin disease in the area of the injection site  
  - ○ Hymovis, Monovisc, Orthovisc: do not administer to patients with known hypersensitivity to gram positive bacterial proteins  
  - ○ Monovisc: do not administer to patients with known systemic bleeding disorders  
- **Boxed warning(s):** none reported  

# Clinical Policy  
Hyaluronate Derivatives  

### Appendix D: General Information  
- Examples of documented positive but inadequate response to intra-articular glucocorticoid injections include and are not limited to the following: inadequate pain relief, frequent need of rescue medications such as NSAIDs or opioids, need to decrease or inability to increase activity levels, adequate pain relief but with steroid-induced hyperglycemia.  
- Per the 2014 and 2019 Osteoarthritis Research Society International guidelines, hyaluronate derivatives are not appropriate for multiple joint OA subtypes or joint OA other than the knee.  
  - In DeGroot et al., single hyaluronic acid was compared to saline injection in a small RCT (N=64). At 6 and 12 weeks, there were no significant differences in improvement between the two groups on the American Orthopedic Foot and Ankle Society clinical rating score, the Ankle Osteoarthritis Scale score, or the patient-reported visual analog pain scale. Migliore et al., conducted a review of seven studies for ankle OA that showed mixed results, but were unable to complete a meta-analysis due to use of study design limitations (e.g., inconsistent use of primary endpoints, varying comparators, small sample size) leading to study heterogeneity.  
  - Richette et al. conducted a multicenter, randomized, placebo-controlled trial in hip OA. At 3 months, hyaluronic acid was not more effective than placebo with a treatment difference in pain score of –0.15 (95% CI –11.04, 10.74). Responder rates were 33.3% for hyaluronic acid and 32.6% for placebo (p = 0.94). Additionally, analgesics were taken in by 81% of study days by patients on placebo, and 88% of patients in the hyaluronic acid group.  
- There are no studies that have evaluated the efficacy of hyaluronate derivatives in patients with OA and coexistent other inflammatory conditions such as rheumatoid arthritis.  
- There is no data to suggest efficacy of hyaluronate derivatives in patients who have had total knee arthroplasty in the targeted knee.  

## V. Dosage and Administration  

| Drug Name | Active Ingredient | Dose of Active Ingredient per Injection | Treatment Cycle\* |  
|-----------|-------------------|---------------------------------------|-------------------|  
| Durolane | Hyaluronic acid | 60 mg (3 mL) | 1 injection |  
| Euflexxa | Sodium hyaluronate | 20 mg (2 mL) | 3 injections |  
| Gel-One | Cross-linked sodium hyaluronate | 30 mg (3 mL) | 1 injection |  
| Gelsyn-3 | Sodium hyaluronate | 16.8 mg (2 mL) | 3 injections |  
| GenVisc 850 | Sodium hyaluronate | 25 mg (2.5 mL) | 3-5 injections |  
| Hyalgan | Sodium hyaluronate (Hyalectin®) | 20 mg (2 mL) | 3-5 injections |  

# Clinical Policy  
Hyaluronate Derivatives  

| Drug Name | Active Ingredient | Dose of Active Ingredient per Injection | Treatment Cycle\* |  
|-----------|-------------------|---------------------------------------|-------------------|  
| Hymovis | Sodium hyaluronate (HYADD®4) | 24 mg (3 mL) | 2 injections |  
| Monovisc‡ | Cross-linked sodium hyaluronate | 88 mg (4 mL) | 1 injection |  
| Orthovisc‡ | Sodium hyaluronate | 30 mg (2 mL) | 3-4 injections |  
| Supartz FX | Sodium hyaluronate | 25 mg (2.5 mL) | 3-5 injections |  
| Synojoynt | Sodium hyaluronate | 20 mg (2 mL) | 3 injections |  
| Synvisc | Cross-linked hylan G-F 20 (hylan A and hylan B polymers) | 16 mg (2 mL) | 3 injections |  
| Synvisc One | Cross-linked hylan G-F 20 (hylan A and hylan B polymers) | 48 mg (6 mL) | 1 injection |  
| Triluron | Sodium hyaluronate | 20 mg (2 mL) | 3 injections |  
| TriVisc | Sodium hyaluronate | 25 mg (2.5 mL) | 3 injections |  
| VISCO-3 | Sodium hyaluronate | 25 mg (2.5 mL) | 3 injections |  

\*Treatment cycle: Total number of injections per cycle per knee (if treating both knees, double the number of injections per treatment cycle).  
‡Per product label, one injection of Monovisc is equivalent to 3 injections of Orthovisc.  

## VI. Product Availability  

| Drug Name | Active Ingredient | Availability\*\* |  
|-----------|-------------------|------------------|  
| Durolane | Hyaluronic acid | 3 mL syringe |  
| Euflexxa | Sodium hyaluronate | 2.25 mL syringe |  
| Gel-One | Cross-linked sodium hyaluronate | 3 mL syringe |  
| GenVisc 850 | Sodium hyaluronate | 3 mL syringe |  
| Gelsyn-3 | Sodium hyaluronate | 2.25 mL syringe |  
| Hyalgan | Sodium hyaluronate (Hyalectin®) | 2 mL vial or 2 mL syringe |  
| Hymovis | Sodium hyaluronate (HYADD®4) | 5 mL syringe |  
| Monovisc‡ | Cross-linked sodium hyaluronate | 5 mL syringe |  
| Orthovisc‡ | Sodium hyaluronate | 3 mL syringe |  
| Supartz FX | Sodium hyaluronate | 2.5 mL syringe |  
| Synojoynt | Sodium hyaluronate | 3 mL syringe |  
| Synvisc | Cross-linked hylan G-F 20 (hylan A and hylan B polymers) | 2.25 mL syringe |  
| Synvisc One | Cross-linked hylan G-F 20 (hylan A and hylan B polymers) | 10 mL syringe |  
| TriVisc | Sodium hyaluronate | 3 mL syringe |  
| Triluron | Sodium hyaluronate | 2 mL syringe or 2 mL vial |  
| VISCO-3 | Sodium hyaluronate | 2.5 mL syringe |  

\*\* All syringes/vials are single-use (i.e., one injection/one knee); syringes are pre-filled.  
‡Per product label, one injection of Monovisc is equivalent to 3 injections of Orthovisc.  

# Clinical Policy  
Hyaluronate Derivatives  

## VII. References  
1. Durolane Prescribing Information. Durham, NC: Bioventus LLC; September 2019. Available at: https://www.oakneepainrelief.com/wp-content/uploads/2019/09/DUROLANE-IFU.pdf. Accessed July 10, 2025.  
2. Euflexxa Prescribing Information. Parsippany, NJ: Ferring Pharmaceuticals, Inc. July 2016. Available at: http://www.euflexxa.com/. Accessed July 10, 2025.  
3. Gel-One Prescribing Information. Warsaw, IN: Zimmer; May 2011. Available at: https://zimmer.aspnprograms.com/siteforms/Gel-One%20Pkg%20Insert%20Final.pdf. Accessed July 10, 2025.  
4. Gelsyn-3 Prescribing Information. Durham, NC: Bioventus LLC; December 2017. Available at: https://www.oakneepainrelief.com/wp-content/uploads/2019/09/GELSYN-3-IFU.pdf. Accessed July 10, 2025.  
5. GenVisc 850 Prescribing Information. Doylestown, PA: Orthogen Rx, Inc.; January 2024. Available at: https://orthogenrx.com/wp-content/uploads/2024/09/GNV-IFU.pdf. Accessed July 10, 2025.  
6. Hyalgan Prescribing Information. Parsippany, NJ: Fidia Pharma USA, Inc.; August 2017. Available at: https://hyalgan.com/. Accessed July 10, 2025.  
7. Hymovis Prescribing Information. Parsippany, NJ: Fidia Pharma USA, Inc.; June 2021. Available at: https://hcp.hymovis.com/. Accessed July 10, 2025.  
8. Monovisc Prescribing Information. Bedford, MA: Anika Therapeutics, Inc. July 2023. Available at: https://www.anikaifu.com/wp-content/uploads/2023/12/Monovisc-USA-AML-500-299-E.pdf. Accessed July 10, 2025.  
9. Orthovisc Prescribing Information. Bedford, MA: Anika Therapeutics, Inc.; July 2023. Available at: https://www.anikaifu.com/wp-content/uploads/2021/10/Orthovisc-USA-AML-500-254-D.pdf. Accessed July 10, 2025.  
10. Supartz FX Prescribing Information. Durham, NC: Bioventus, LLC; March 2016.Available at:https://www.oakneepainrelief.com/wp-content/uploads/2025/04/SUPARTZFX_IFU_Mar31_2016.pdf. Accessed July 10, 2025.  
11. Synojoynt Prescribing Information. Naples, FL: Arthrex, Inc.; November 2021. Available at: https://edfu.arthrex.com/ARX/products?keycode=DFU-0373-1. Accessed July 10, 2025.  
12. Synvisc Prescribing Information. Ridgefield, NJ: Genzyme Corporation; January 2025. Available at: https://products.sanofi.us/synvisc/synvisc.pdf. Accessed July 10, 2025.  
13. Synvisc One Prescribing Information. Ridgefield, NJ: Genzyme Corporation; January 2025. Available at: https://products.sanofi.us/synviscone/synviscone.pdf. Accessed July 10, 2025.  
14. Triluron Prescribing Information. Florham Park, NJ: Fidia Pharma; July 2019. Available at: https://triluron.com/wp-content/uploads/2020/06/Leaflet-TRILURON-Medico-USA.pdf. Accessed July 10, 2025.  
15. TriVisc Prescribing Information. Doylestown, PA: OrthogenRx, Inc; December 2017. Available at: https://orthogenrx.com/wp-content/uploads/2022/04/TriVisc-PI.pdf. Accessed July 10, 2025.  
16. VISCO-3 Prescribing Information. Warsaw, IN: Zimmer, Inc.; December 2015. Available at: https://zimmer.aspnprograms.com/resources.aspx. Accessed July 10, 2025.  
17. Clinical Pharmacology [database online]. Philadelphia, PA: Elsevier. Updated periodically. Available at: http://www.clinicalkey.com/pharmacology. Accessed September 2, 2025.  

# Clinical Policy  
Hyaluronate Derivatives  

18. Strand V, Baraf HS, Lavin PT, et al. Effectiveness and safety of a multicenter extension and retreatment trial of Gel-200 in patients with knee osteoarthritis. Cartilage. 2012;3(4):297-304.  
19. Sun SF, Hsu CW, Hwang CW, et al. Hyaluronate improves pain, physical function and balance in the geriatric osteoarthritic knee: A 6-month follow-up study using clinical tests. Osteoarthritis Cartilage. 2006;14:696-701.  
20. American Academy of Orthopaedic Surgeons Management of Osteoarthritis of the Knee (Non-Arthroplasty) Evidence-Based Clinical Practice Guideline. Published August 31, 2021. Available at: https://www.aaos.org/ook3cpg. Accessed September 1, 2025.  
21. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2020 Feb;72(2):220-233.  
22. Bannuru RR, Osani M, Vaysbrot EE, McAlindon TE. Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthritis Cartilage. August 2, 2016. pii: S1063-4584(16)30196-0. doi: 10.1016/j.joca.2016.07.010. [Epub ahead of print]  
23. Rannou F, Pelletier JP, Martel-Pelletier J. Efficacy and safety of topical NSAIDs in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016; 45:S18-S21.  
24. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage. 2019 Nov;27(11):1578-1589.  
25. Nelson AE, Allen KD, Golightly YM, et al. A systematic review of recommendations and guidelines for the management of osteoarthritis: The chronic osteoarthritis management initiative of the U.S. Bone and Joint Initiative. Semin Arthritis Rheum. 2014; 43:701-712.  
26. Kort NP, Bernelmans YFL, Hugo M, et al. Patient selection criteria for outpatient joint arthroplasty. Knee Surg Sports Traumatol Arthrosec. 2017;25:2668-2675.  
27. DeGroot H, Uzunishvili S, Weir R et al. Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg 2012; 94(1):2-8.  
28. Migliore A, Giovannangeli F, Bizzi E et al. Viscosupplementation in the management of ankle osteoarthritis: a review. Arch Orthop Trauma Surg 2011; 131(1):139-47.  
29. Richette P, Ravaud P, Conrozier T, et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum. 2009;60(3):824-30.  
30. Hayashi D, Roemer FW, Guermazi A. Imaging for osteoarthritis. Ann Phys Rehab Med 2016 Jun




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