MEDICAL POLICY SUBJECT: VISCOSUPPLEMENTATION OF THE KNEE FOR OSTEOARTHRITIS

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1 MEDICAL POLICY SUBJECT: VISCOSUPPLEMENTATION OF PAGE: 1 OF: 9 If a product excludes coverage for a service, it is not covered, and medical policy criteria do not apply. If a commercial product, including an Essential Plan product, covers a specific service, medical policy criteria apply to the benefit. If a Medicare product covers a specific service, and there is no national or local Medicare coverage decision for the service, medical policy criteria apply to the benefit. POLICY STATEMENT: I. Based upon our criteria and assessment of the peer-reviewed literature, viscosupplementation with an FDA approved preparation (e.g., Synvisc, Hyalgan, Supartz TM, Euflexxa TM [formerly Nuflexxa], Gel-Syn TM, or Orthovisc ) for osteoarthritis of the knee is considered medically appropriate for patients meeting all of the following criteria: A. patient has failed to respond to conservative, non-pharmacologic therapy (e.g., physical therapy, exercise or activity modification); B. patient has failed to respond to simple analgesics, if appropriate (e.g. acetaminophen); C. patient is intolerant of or has contraindications to non-steroidal anti-inflammatory drugs (NSAIDs), is unable to be maintained on NSAIDs, and/or has failed to respond to NSAIDs; D. patient has failed to respond to, has contraindications to, or refuses steroid injections; and E. pain duration must have been for at least 6 months. II. Based upon our criteria and assessment of the peer-reviewed literature, repeat treatment course(s) of intra-articular hyaluronan injections (e.g., Synvisc, Hyalgan, Supartz TM, Euflexxa TM or Orthovisc ) are considered medically appropriate for patients with continued pain in the knee(s) due to osteoarthritis if relief of pain (demonstrated by reduction in the use or need for analgesics) was obtained from the previous treatment course of intra-articular hyaluronan injections, and at least 6 months have elapsed since the previous course of treatment. III. Based upon our criteria and assessment of the peer-reviewed literature, the use of intra-articular hyaluronan injections into joints other than the knee or any other indication other than osteoarthritis (e.g., post ACL reconstruction, menisectomy, total knee arthroplasty or temporomandibular disorders) have not been medically proven to be effective are considered investigational. IV. Based upon our criteria and assessment of the peer-reviewed literature, an FDA approved single-injection treatment intra-articular hyaluronan or derivative (e.g. Synvisc-One TM, Gel-One, Monovisc TM, Durolane ) for osteoarthritis of the knee is considered a medically appropriate treatment option to the multiple-injection course of treatment. Refer to Corporate Medical Policy # regarding Experimental or Investigational Services. POLICY GUIDELINES: I. Synvisc, Synvisc-One, and Euflexxa are considered preferred products for viscosupplementation. Please refer to the FLRx policies, Medical Preferred Drug Process and Medical Specialty (MSD) Guide. II. 5 weekly injections for Hyalgan, Supartz TM, or GenVisc 850, OR 3 weekly injections for Euflexxa TM, Gelsyn-3 TM, or Synvisc OR 3 to 4 weekly injections for OrthoVisc, OR 2 weekly injections of Hymovisc, per treatment course, may be allowed. III. The Federal Employee Health Benefit Program (FEHBP/FEP) requires that procedures, devices or laboratory tests approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus these procedures, devices or laboratory tests may be assessed only on the basis of their medical necessity. A nonprofit independent licensee of the BlueCross BlueShield Association

2 PAGE: 2 OF: 9 DESCRIPTION: Viscosupplementation is the intra-articular injection of hyaluronan, also known as hyaluronate or hyaluronic acid, as a treatment for pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative, non-pharmacological therapy and simple analgesics. The proposed purpose of viscosupplementation is to restore normal viscoelasticity in the synovial fluid. It may reduce pain for up to 6 to 12 months. There are several FDA approved hyaluronan preparations. The various preparations differ in their molecular weights and are derived from either bacterial cells or avian sources. RATIONALE: Several preparations of intra-articular hyaluronan have been approved by the U.S. Food and Drug administration (FDA) as an alternative to NSAID therapy in the treatment of osteoarthritis of the knee: Synvisc, Hyalgan, Supartz TM, OrthoVisc, and Euflexxa TM (formerly Nuflexxa). Intra-articular hyaluronic acid is indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy, and to simple analgesics, e.g. acetaminophen. The product inserts indicate that Synvisc and Euflexxa TM should be injected intra-articularly into the knee joint once per week for a total of 3 injections over a 2 to 3 week period. GelSyn- 3 TM received FDA approval in May 2014 and consists of 3 weekly injections. In contrast, 5 weekly injections are recommended for the Hyalgan and Supartz TM products, and 3 to 4 weekly injections are recommended for OrthoVisc. The FDA approved Synvisc One on February 26, Gel-One, which received FDA approval in March of 2011, is also designed as a single injection treatment, similar to Synvisc One. Monovisc TM, FDA approved in February 2014, is a single injection of hyaluronic acid. GenVisc 850 received FDA approval in September GenVisc 850 is administered by intra-articular injection. A treatment cycle consists of five injections given at weekly intervals. Hymovisc also received FDA PMA approval in The intra-articular injections are administered 2 times, in two injections, 1 week apart. Durolane, a non-animal hyaluronic Acid/NASHA (Bioventus) received FDA approval in September It is a single injection product used for joint lubrication in the treatment of mild to moderate pain associated with knee OA. The FDA has not approved intra-articular hyaluronan for joints other than the knee. Evidence from randomized controlled trials is sufficient to conclude that viscosupplementation improves health outcomes, providing pain relief and functional improvement in patients who have failed conventional conservative management or who cannot tolerate alternative medical treatment. Evidence of the safety and effectiveness of repeat treatment cycles is limited, however the FDA has removed the precaution regarding repeat cycles from the product labels for Synvisc and Hyalgan. A literature review of safety and efficacy for multiple courses of viscosupplementation indicates no loss in efficacy for repeat courses. In September 2007 the BlueCross BlueShield Technology Evaluation Center (TEC) published a technology assessment for the Agency for Healthcare Research and Quality (AHRQ) on the treatment of primary and secondary osteoarthritis of the knee. The report concluded that results from 42 trials (5,843 patients) generally show positive effects of viscosupplementation on pain and function scores compared to placebo for patients with primary osteoarthritis of the knee. However, clinical evidence includes considerable uncertainty due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported. Trials of hylan G-F-20 generally reported better results than other trials. There was no evidence for differential effects according to subgroups defined by age, sex, primary/disease, body mass index (BMI)/weight, or disease severity. Minor adverse events accompanying intra-articular injections are common, but the relative risk accompanying hyaluronan injections over placebo appears to be small The risk of local adverse events appears to increase with prior courses of treatment. Pseudoseptic reactions associated with hyaluronans appear relatively uncommon but can be severe. The available data are not sufficient to determine if hyaluronan injections are effective in joints other than the knee.

3 PAGE: 3 OF: 9 CODES: Number Description Eligibility for reimbursement is based upon the benefits set forth in the member s subscriber contract. CODES MAY NOT BE COVERED UNDER ALL CIRCUMSTANCES. PLEASE READ THE POLICY AND GUIDELINES STATEMENTS CAREFULLY. Codes may not be all inclusive as the AMA and CMS code updates may occur more frequently than policy updates. CPT: No specific codes; however or may be billed along with the J code. Copyright 2017 American Medical Association, Chicago, IL HCPCS: J7320 Hyaluronan or derivative, GenVisc 850, for intra-articular injection, 1 mg J7321 Hyaluronan or derivative, Hyalgan or Supartz, for intra-articular injection, per dose J7322 Hyaluronan or derivative, Hymovis, for intra-articular injection, 1 mg J7323 Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose J7324 Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose J7325 Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg J7326 Hyaluronan or derivative, Gel-one, for intra-articular injection, per dose J7327 Hyaluronan or derivative, Monovisc, for intra-articular injection, per dose J7328 Hyaluronan or derivative, Gel-Syn for intra-articular injection, 0.1mg ICD9: Osteoarthrosis, localized, primary, lower leg Osteoarthrosis, localized, secondary, lower leg Osteoarthrosis, localized, not specified whether primary or secondary, lower leg Osteoarthrosis, unspecified whether generalized or localized, lower leg ICD10: M17.0-M17.9 Osteoarthritis of knee (code range) REFERENCES: Agency for Healthcare Research and Quality. AHRQ. Technology assessment program. Systematic review for effectiveness of hyaluronic acid in the treatment of severe degenerative joint disease (DJD) of the knee [ accessed 10/5/17. American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee. Updated [ accessed 10/5/17. Ammar TY, et al. Viscosupplementation of treating knee osteoarthrosis: review of the literature. Rev Bras Ortop 2015 Aug 5;50(5): *Bannuru RR, et al. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis- metaanalysis. Osteoarthritis Cartilage 2011 Jun;19(6): Bannuru RR, et al. Relative efficacy of hyaluronic acid in comparison with NSAIDS for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthritis Rheum 2014 Apr;43(5): Bannuru RR, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 2015 Jan;162(1):46-84.

4 PAGE: 4 OF: 9 *Bellamy N, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. The Cochrane Database of Systematic Reviews Berenbaum, F, et al. A randomized, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee arthritis. Ann Rheum Dis 2012 Sep;71(9): BlueCross BlueShield Association. Intra-articular hyaluronan injections for osteoarthritis. Medical Policy Reference Manual. Policy # April 13. *BlueCross BlueShield Association. Special report: intra-articular hyaluronan injections for the treatment of osteoarthritis of the knee Feb. BlueCross BlueShield Association. Technology Evaluation Center. Intra-articular hyaluronic acid for osteoarthritis of the knee Oct;29(6). California Technology Assessment Forum. Hyaluronic acid for treatment of osteoarthritis of the knee: Repeated injections and progression to knee replacement Feb 8 [ accessed 10/5/17. Campos ALS, et al. Viscosupplementation in patients with severe osteoarthritis of the knee: six month follow up of a randomized, double-blind clinical trial. Int Orthop 2017 Aug 30. [Epub ahead of print]. Chang KV, et al. Effectiveness of intra-articular hyaluronic acid for ankle osteoarthritis treatment: a systematic review and meta-analysis. Arch Phys Med Rehabil 2013 May;94(5): Chen WL, et al. Comparison of intra-articular hyaluronic acid injections with transcutaneous electric nerve stimulation for the management of knee osteoarthritis: a randomized controlled trial. Arch Phys Med Rehab 2013 Aug;94(8): Colen S, et al. Hyaluronic acid for the treatment of osteoarthritis in all joints except the knee: what is the current evidence? BioDrugs 2012 Apr 1;26(2): Colen S, et al. Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products. BioDrugs 2013 Aug 1;26(4): Colen S, et al. Intra-articular infiltration therapy for patients with glenohumeral osteoarthritis: a systematic review of the literature. Int J Shoulder Surg 2014 Oct;8(4): *Chevalier X, et al. Single, intra-articular treatment with 6mL of hylan G-G 20 in patients with symptomatic primary osteoarthritis of the knee: A randomized, multi-centre, double-blind, placebo-controlled trial. Ann Rheum Dis 2010 Jan;69(1): *Conrozier T, et al. Clinical response to intra-articular injections of hylan G-F 20 in symptomatic hip osteoarthritis: the OMERACT-OARSI criteria applied to the results of a pilot study. Joint Bone Spine 2006;73: Cooper C, et al. Use of Intraarticular hyaluronic acid in the management of knee osteoarthritis in clinical practice. Arthritis Care Res 2017 Sept;69(9): *Curran MP. Hyaluronic acid (Supartz ): a review of its use in osteoarthritis of the knee. Drugs Aging 2010 Nov 1;27(11): De Campos GC, et al. Adding triamcinolone improves viscosupplementation: A randomized clinical trial. Clin Orthop Relat Res 2012 Oct 26 [Epub ahead of print]. Degroot H 3 rd, 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 Am 2012 Jan 4;94(1):2-8. De Souza RF, et al. Interventions for the management of temporomandibular joint osteoarthritis. Cochrane Database Syst Rev Apr 18;4:CD

5 PAGE: 5 OF: 9 Di Martino A, et al. Early viscosupplementation after anterior cruciate ligament reconstruction: a randomized controlled trial. Am J Sports Med 2016 Oct;44(10): *Espallargues M, et al. Efficacy and safety of viscosupplementation weight hylan G-F 20 for the treatment of knee osteoarthritis. Intern J Technol Assess Health Care 2003;19(1): Evaniew N, et al. Cochrane in COOR : Viscosupplementation for the treatment of osteoarthritis of the knee. Clin Orthop Relat Res 2014 Jul;472(7): *Fernandez Lopez JC, et al. Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. Osteoarthritis Cartilage 2006 Dec;14(12): Filardo G, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: A randomized controlled trial. Am J Sports Med 2015 Jul;43(7): Filardo G, et al. No effects of early viscosupplementation after arthroscopic partial meniscectomy: a randomized controlled trial. Am J Sports Med 2016 Dec;44(12): Fritz GR, et al. The use of sodium hyaluronate in treatment of first carpal metacarpal joint arthritis. Paper #272. Presented at the annual meeting of the American Academy of Orthopedic Surgeons. Feb San Diego. [ accessed 10/5/17. *Fuchs S, et al. Intra-articular hyaluronic acid compared with corticoid injections for the treatment of rhizarthrosis. Ostearthritis Cartilage 2006;14(1):82-8. Goiato MC, et al. Are intra-articular injections of hyaluronic acid effective for the treatment of temporomanidular disorders? A systematic review. Int J oral Maxillofac Surg 2016 Dec;45(12): Guarda-Nardini L, et al. Predictive factors of hyaluronic acid injections short-term effectiveness for TMJ degenerative joint disease. J Oral Rehabil 2011 May;38(5): He WW, et al. Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: a metaanalysis. Int J Surg 2017 March;39: Henrotin Y, et al. Consensus statement on viscosupplementation with hyaluronic acid for the management of osteoarthritis. Semin Arthritis Rheum 2015 Oct;45(2): Hochberg MC, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip and knee. Arthritis Care Res 2012 Apr;64(4): *Huang TL, et al. Intra-articular injections of sodium hyaluronate (Hyalgan ) in osteoarthritis of the knee. A randomized, controlled, double-blind, multicenter trial in the Asian population. BMC Musculoskelet Disord 2011 Oct 6;12(1):221. *Izquierdo R, et al. Treatment of glenohumeral osteoarthritis. J Am Acad Orthop Surg 2010 Jun;18(6): Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2 nd edition. J Am Acad Orthop Surg 2013 Sep;21(9): Jevsevar D, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am 2015 Dec 16;97(24): Johansen M, et al. Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: meta-regression analyses of randomized trials. Semin Arthritis Rheum 2016 Aug;46(1): *Jorgensen A, et al. Intra-articular hyaluronan is without clinical effect in knee arthritis: a multicentre, randomized, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis 2010 Jun;69(6):

6 PAGE: 6 OF: 9 *Karlson J, et al. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. a controlled, randomized, double-blind, parallel-design multicentre study. Rheumatol 2002;41: *Kon E, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy 2011 Nov;27(11): Kroon FP, et al. Intra-articular therapies in the treatment of hand osteoarthritis: a systematic literature review. Drugs Aging 2016 Feb;33(2): Kwon YW, et al. Sodium Hyaluronate for the treatment of chronic shoulder pain associated with glenohumeral osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. J Shoulder Elbow Surg 2013 May;22(5): *Leopold SS, et al. Cortico-steroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. Bone Joint Surg 2003 Jul;85-A(7): Lieberman JR, et al. Is intra-articular hyaluronic acid effective in treating osteoarthritis of the hip joint? J Arthroplasty 2015 Mar;30(3): Machado E, et al. Intra-articular injections with corticosteroids and sodium hyaluronate for treating temporomandibular joint disorders: a systematic review. Dental Press J Orthod 2013 Sep-Oct;18(5): *Maheu E, et al. Comparative efficacy and safety of two different molecular weight (MW) hyaluronans F60027 and Hylan G-F20 in symptomatic osteoarthritis of the knee (KOA). Results of a noninferiority, prospective, randomized, controlled trial. Clin Exp Rheumatol 2011 May-Jun;29(3): *Manfredini D, et al. Hyaluronic acid in the treatment of TMJ disorders: a systematic review of the literature. Cranio 2010 Jul;28(3): McAldindon TE, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014 Mar;22(3): *Migliori A, et al. The symptomatic effects of intra-articular administration of Hylan G-F on osteoarthritis of the hip: clinical data of 6 months follow-up. Clinical Rheumatol 2006 May;25(3): *Migliore A, et al. Viscosupplementation in the management of ankle osteoarthritis: a review. Arch Orthop Trauma Surg 2011 Jan;131(1): Miller LE, et al. Us-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials. Clin Med Insights Arthritis Musculoskelet Disord 2013 Sep 1;6: Monfort J, et al. Comparative efficacy of intra-articular hyaluronic acid and corticoid injections in osteoarthritis of the first carpometacarpal joint: results of a 6-month single-masked randomized study. Joint Bone Spine 2015 Mar;82(2): *Munteanu SE, et al. Effectiveness of intra-articular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first metatarsophalangeal joint osteoarthritis: a randomized placebo-controlled trial. Ann Rheum Dis 2011 Oct;70(10): National Clinical Guideline Centre. Osteoarthritis. Care and Management in adults. No.177. National Institute for Health and Care Excellence (NICE); 2014 Feb. Navarro-Sarabia F, et al. A 40-month multicenter, randomized placebo-controlled study to assess the efficacy and carryover effect of repeated intra-articular injections of hyaluronic acid in knee arthritis: the AMELIA project. Ann Rheum Dis 2011 Nov;70(11):

7 PAGE: 7 OF: 9 O Hanlon CE, et al. Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews. Syst Rev 2016 Nov 4;5(1):186. Pai SK, et al. Are intra-articular injections of hylan G-F 20 efficacious in painful osteoarthritis of the knee? A systematic review & meta-analysis. Int J Clin Pract 2014 Aug;68(8): Palmieri B, et al. Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritis-related pain. Drug Des Devel Ther 2013;7:7-12. *Pavelka K, et al. Efficacy evaluation of highly purified intra-articular hyaluronic acid (Sinovial ) vs hylan G-F20 (Synvisc ) in the treatment of symptomatic knee osteoarthritis. A double-blind, controlled, randomized, parallel-group non-inferiority study. Osteoarthritis Cartilage 2011 Nov;19(11): *Petrella RJ, et al. Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2002 Feb 11;162(3):245-7 and J Fam Pract 2002 May;51(5):411. Piccirilli E, et al. Viscosupplementation with intra-articular hyaluronic acid for hip disorders. A systematic review and meta-analysis. Muscles Ligamnets Tendons J 2016 Dec 21;6(3): Printz JO, et al. Conflict of interest in the assessment of hyaluronic acid injections for osteoarthritis of the knee: an updated systematic review. J Arthroplasty 2013 Sep;28(8 Suppl): *Qvistgaard E, et al. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthritis Cartilage 2006;14(2): *Raynauld JP, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatism 2003 Feb;48(2): *Raynauld JP, et al with Canadian Knee OA Study Group. A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (part 1 of 2);10: Clinical results. Osteoarthritis Cartilage 2002;10: *Reichenbach S, et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum 2007 Dec 15;57(8): Richette P, et al. Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open 2015 May 15;1(1):e Rutjes AW, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med 2012 Aug 7;157(3): *Saito S, et al. Therapeutic effects of hyaluronate injections in patients with chronic painful shoulder: a meta-analysis of randomized controlled trials. Arthritis Care Res 2010 Jul;62(7): *Salk RS, et al. Sodium hyaluronate in the treatment of osteoarthritis of the ankle: a controlled, randomized, double-blind pilot study. J BJS (Amer) 2006 Feb;88A(2): *Samson DS, et al. Treatment of primary and secondary osteoarthritis of the knee. Evid Rep Technol Assess (Full Rep) 2007 Sep;(157):1-157 [ accessed 10/5/17. Strand V, et al. A multicenter, randomized, controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 2012 May;20(5): Strand V, et al. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res 2015 May 7;8:

8 PAGE: 8 OF: 9 Sun SF, et al. Comparison of single intra-articular injection of novel hyaluronan (HYA-JOINT Plus) with Synvisc-One for knee osteoarthritis: a randomized, controlled, double-blind trial of efficacy and safety. J Bone Joint Surg Am 2017 March 15;99(6): Suppan VKL, et al. Randomized controlled trial comparing efficacy of conventional and new single larger dose of intraarticualr viscosupplementation in management of knee osteoarthritis. J Orthop Surg 2017 Sept- Dec;25(3): *Tagliafico A, et al. Ultrasound-guided viscosupplementation of subacromial space in elderly patients with cuff tear arthropathy using a high weight hyaluronic acid: prospective open-label non-randomized trial. Eur Radiol 2011 Jan;21(1): Tigkilidas D, et al. The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritis knee pain. Ann R Coll Surg Engl 2013 Nov;95(8): Tammachote N, et al. Intra-articular, single-shot hylan G-F 20 hyaluronic acid injection compared with corticosteroid in knee osteoarthritis: a double-blind, randomized controlled trial. J Bone Joint Surg Am 2016 June 1;98(11): Thomas T, et al. Inta articular hyaluronic acid in the management of knee osteoarthritis: pharmaco-ecomomic study from the perspective of the national health insurance system. PLoS One 2017 March 22;12(3):e Trellu S, et al. Intra-articular injections in thumb osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Joint Bone Spine 2015 Oct;82(5): Trojian TH, et al. AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med 2016 Jan;50(2): *Van Brakel RW and Eygendaal D. Intra-articular injection of hyaluronic acid is not effective for the treatment of posttraumatic osteoarthritis of the elbow. Arthroscopy 2006 Nov;22(11) Velasco E, et al. Single-arm open-label study of Durolane (NASHA non animal hyaluronic acid) for the treatment of osteoarthritis of the thumb. Rheumatol Res Rev 2017;9: *Waddell DD, et al. An open-label study of a second course of hylan g-f 20 for the treatment of pain associated with knee osteoarthritis. Curr Med Res Opin 2003;19(6): *Wang Y, et al. Effects of Hylan F-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet Disord 2011 Aug 24;12:195. Wang F, et al. Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: a meta-analysis. Exp Ther Med 2015 Feb;9(2): Witteeveen AG, et al. Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle. Cochrane Database Syst Rev 2015 Oct 17;(10):CD *Zhang W, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January Osteoarthritis Cartilage 2010 Apt;18(4): * key article KEY WORDS: Durolane, Euflexxa, Gel-One, Gelsyn, Hyalgan, Hyaluronan, intra-articular injection, Monovisc, Nuflexxa, OrthoVisc, Supartz, Synvisc, Synvisc-One.

9 PAGE: 9 OF: 9 CMS COVERAGE FOR MEDICARE PRODUCT MEMBERS There is currently a Local Coverage Determination (LCD) for drugs and biologics and a subsequent Article that addresses hyaluronans. Please refer to the following LCD websites for Medicare Members: LCD: e=national+government+services%2c+inc.+(13201%2c+a+and+b+and+hhh+mac%2c+j+- +K)&s=All&DocType=Active&bc=AggAAAQAAAAAAA%3d%3d&#0 Article: cscode=j7326&bc=gaaaacaaaaaaaa%3d%3d&