Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Viscosupplementation for Osteoarthritis Table of Contents Coverage Policy... 1 General Background... 4 Coding/Billing Information... 8 References... 8 Effective Date... 6/15/2017 Next Review Date... 6/15/2018 Coverage Policy Number Related Coverage Resources INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2017 Cigna Coverage Policy Viscosupplementation for Osteoarthritis contains the following products: Preferred Products Monovisc (high molecular weight Orthovisc (high molecular weight Synvisc Synvisc-One Non-Preferred Products Euflexxa (1% sodium hyaluronate) Gel-One (cross-linked hyaluronate) Gelsyn-3 (high molecular weight GenVisc 850 (high molecular weight Hyalgan Hymovis (high molecular weight Supartz FX Cigna covers Monovisc (high molecular weight, Orthovisc (high molecular weight, Synvisc, and Synvisc-One as medically necessary when BOTH of the following criteria are met: Diagnosis of symptomatic osteoarthritis of the knee affecting activities of daily living Inadequate response or not a candidate for BOTH of the following treatment options: o Conservative treatment including physical therapy and/or pharmacotherapy for at least 6 weeks o Intra-articular (IA) corticosteroids Page 1 of 10

2 Cigna covers Euflexxa (1% sodium hyaluronate), Gel-One (cross-linked hyaluronate), Gelsyn- 3 (high molecular weight, GenVisc 850 (high molecular weight, Hyalgan, Hymovis (high molecular weight and Supartz FX (sodium hyaluronate) as medically necessary when BOTH of the following criteria are met: Diagnosis of symptomatic osteoarthritis of the knee affecting activities of daily living Inadequate response or not a candidate for BOTH of the following treatment options: o Conservative treatment including physical therapy and/or pharmacotherapy for at least 6 weeks o Intra-articular (IA) corticosteroids Contraindication per FDA label or documented intolerance to the preferred products (Monovisc [high molecular weight hyaluronan] or Orthovisc [high molecular weight hyaluronan] AND Synvisc [hylan G-F 20] or Synvisc-One [hylan G-F 20]) Cigna covers additional treatment courses of Viscosupplementation for Osteoarthritis as medically necessary when ALL of the following criteria are met: Initial criteria for use of the requested product were met History of clinical beneficial response with previous treatment course (for example, an improvement in an objective measurement of pain and/or functional status [Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, or other validated objective measure]) At least 6 months have lapsed since the completion of the prior treatment course Cigna does not cover viscosupplementation for the treatment of osteoarthritis in locations other than the knee because it is considered experimental, investigational or unproven. When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to Viscosupplementation for Osteoarthritis. Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indication Product Euflexxa (1% sodium hyaluronate) Gel-One (cross-linked hyaluronate) Gelsyn-3 (high molecular weight GenVisc 850 (high molecular weight Hyalgan Hymovis (high molecular weight Monovisc (high molecular weight Indication Treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy and simple analgesics (e.g. acetaminophen). adequately to non-pharmacologic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) or simple analgesics, e.g., acetaminophen. Treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy and simple analgesics (e.g., acetaminophen). Treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy and simple analgesics, e.g., acetaminophen. adequately to conservative nonpharmacologic therapy, and to simple analgesics, e.g., acetaminophen. Treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy or simple analgesics (e.g., acetaminophen). adequately to conservative non-pharmacologic therapy or simple analgesics (e.g., acetaminophen). Page 2 of 10

3 Product Orthovisc (high molecular weight Supartz FX Synvisc Synvisc-One FDA Recommended Dosing Product Euflexxa (1% sodium hyaluronate) Gel-One (cross-linked hyaluronate) Gelsyn-3 (high molecular weight GenVisc 850 (high molecular weight Hyalgan Hymovis (high molecular weight Monovisc (high molecular weight Orthovisc (high molecular weight Supartz FX Indication adequately to conservative nonpharmacologic therapy and to simple analgesics, e.g., acetaminophen. adequately to conservative non-pharmacologic therapy and simple analgesics, e.g., acetaminophen. adequately to conservative nonpharmacologic therapy and simple analgesics, e.g., acetaminophen. adequately to conservative nonpharmacologic therapy and simple analgesics, e.g., acetaminophen. Dosing A dose of 2 ml is injected intra-articularly into the affected knee at weekly intervals for three weeks, for a total of three injections. Inject the full syringe contents, 2 ml into one knee only. If treatment is being administered to both knees, use a separate syringe for each knee. Single intra-articular injection into the knee joint. Inject the full 3 ml of Gel-One into knee. If treatment is being administered to both knees, use a separate syringe of Gel-One for each knee. Injection of subcutaneous lidocaine or similar local anesthetic may be performed prior to injection of Gel-One. Inject 2 ml (16.8 mg sodium hyaluronate) intra-articularly once a week for a total of 3 injections. If treatment is bilateral, use a separate 2 ml syringe for each knee. Avoid any strenuous activities or prolonged weight-bearing activities for approximately 48 hours after the injection. GenVisc 850 is administered by intra-articular injection. A treatment cycle consists of five injections given at weekly intervals. Some patients may experience benefit with three injections given at weekly intervals. Injection of subcutaneous lidocaine or similar local anesthetic may be recommended prior to injection of GenVisc 850. Administered by intra-articular injection. A treatment cycle consists of 5 injections (2 ml) given at weekly intervals. Some patients may experience benefit with 3 injections given at weekly intervals. This has been noted in studies reported in the literature in which patients treated with 3 injections were followed for 60 days. Inject the full 2 ml in one knee only. If treatment is bilateral, a separate vial should be used for each knee. Hymovis is intended to be injected into the knee joint and is administered as a two intra-articular injection regimen. Inject the full 3 ml in one knee only (do not overfill the joint). If treatment is bilateral, a separate syringe should be used for each knee. Administer the second injection of Hymovis in the same joint in a week after the first injection following the same guidelines. Injected into the knee joint and is administered as a single intra-articular injection of 4 ml. The effectiveness of Monovisc has not been established for more than one course of treatment. Inject the full 4 ml in one knee only. If treatment is bilateral, a separate syringe should be used for each knee. 2 ml injected into the knee joint in a series of intra-articular injections one week apart for a total of three or four injections. Inject the full contents of the syringe into one knee only. If treatment is bilateral, a separate syringe should be used for each knee. If symptoms return, repeat courses of Orthovisc may be administered. Administered by intra-articular injection once a week (1 week apart) for a Page 3 of 10

4 Product Dosing total of 5 injections. Some patients may experience benefit with 3 injections given at weekly intervals. This has been noted in a study in which patients with 3 injections were followed for 90 days. Injection of subcutaneous lidocaine or similar local anesthetic may be recommended prior to injection of Supartz FX. Inject the full 2.5 ml in one knee only. If treatment is bilateral, a separate syringe should be used for each knee. Synvisc Administered by intra-articular injection once a week (one week apart) for a total of 3 injections. Inject the full 2 ml in one knee only. Synvisc-One Administered as a single intra-articular injection. Inject the full 6 ml in one knee only. Drug Availability Product Euflexxa (1% sodium hyaluronate) Gel-One (cross-linked hyaluronate) Gelsyn-3 (high molecular weight GenVisc 850 (high molecular weight Hyalgan Hymovis (high molecular weight Monovisc (high molecular weight Orthovisc (high molecular weight Supartz FX Synvisc Synvisc-One Availability Carton of 3 disposable, pre-filled 2 ml syringes. Each syringe contains sodium hyaluronate 20 mg. Pre-filled, disposable 3 ml syringe. Each syringe contains cross-linked hyaluronate 30 mg. GELSYN-3 is supplied as a sterile solution in a pre-filled glass syringe. Only the contents of the syringe are sterile; exterior of the syringe is not sterile. One syringe and a 21 gauge needle in an individually sealed blister are contained within a carton box. GenVisc 850 is supplied as a sterile, non-pyrogenic solution in 3mL prefilled syringe. Supplied as 2 ml vials or 2 ml pre-filled syringes. Each vial or syringe contains sodium hyaluronate 20 mg. HYMOVIS is supplied in a set of 2 single-use 5 ml syringes, each containing a 3 ml dose of treatment to be injected one week apart. Each syringe is labeled Hymovis for ready identification. The contents of the syringe are sterile and non-pyrogenic. The syringe components contain no latex. Single-use 5 ml syringe containing a 4 ml dose of treatment. Each prefilled 4 ml syringe contains hyaluronan 88 mg (equivalent to 3 Orthovisc injections). Single-use 3 ml syringe containing a 2 ml dose. Each syringe contains hyaluronan 30 mg. Supplied as a 2.5 ml pre-filled syringe. Each syringe contains sodium hyaluronate ( 25 mg. Supplied in a 2.25 ml glass syringe containing one 2 ml dose of hylan G- F 20. Each syringe contains hylan polymers (hylan A + hylan B) 16 mg. Supplied as 10 ml glass syringes containing 3 doses (48 mg) of hylan G-F 20. Each 10 ml syringe of Synvisc-One combines the three 2-mL doses (16 mg each) of a complete Synvisc treatment regimen (48 mg). General Background Disease Overview The Centers for Disease Control and Prevention (CDC) define osteoarthritis as a disease characterized by degeneration of cartilage and its underlying bone within a joint as well as bony overgrowth resulting in symptoms of joint stiffness and pain. The joints most commonly affected include knees, hips, and those in the hands and spine. An estimated 14% of adults aged 25 years and older and 34% of adults aged 65 years and older are affected. (CDC, 2015) There is not a cure for the underlying disease process; therefore, treatment is targeted at relieving the symptoms. Various non-pharmacologic (e.g., weight loss, physical therapy) and pharmacologic (e.g., acetaminophen, non-steroidal anti-inflammatory [NSAIDs], intra-articular injections of corticosteroids, intra-articular hyaluronates) treatment modalities are utilized. Viscosupplements contain hyaluronate. Hyaluronates are also referred to as hyaluronic acid or hyaluronan. Page 4 of 10

5 Pharmacology Intra-articular (IA) injection of hyaluronates restores the viscoelasticity and protection provided by synovial hyaluronic acid, which is decreased with OA. It also decreases joint pain and improves joint mobility. The hyaluronates have different molecular weights; the clinical impact of molecular weight is not defined. The available products are derived from either bacterial cells or avian sources. Product Euflexxa (1% sodium hyaluronate) Gel-One (cross-linked hyaluronate) Gelsyn-3 (high molecular weight GenVisc 850 (high molecular weight Hyalgan Hymovis (high molecular weight Monovisc (high molecular weight Orthovisc (high molecular weight Supartz FX Synvisc Synvisc-One Hyaluronic Acid Source Bacterial cells Avian (chicken combs) Bacterial fermentation Bacterial fermentation Avian (rooster combs) Bacterial fermentation Bacterial cells Bacterial cells Avian (chicken combs) Avian (chicken combs) Avian (chicken combs) Guidelines Guidelines from organizations recognized by the Agency for Healthcare Research and Quality (AHRQ) are conflicting regarding use of viscosupplements for osteoarthritis (OA) of the knee. In general, for treatment of OA in locations beyond the knee, the guidelines do not recommend use of viscosupplements, do not provide recommendations regarding the use, or the recommendations provided are consensus-based. Knee Osteoarthritis The American Academy of Orthopaedic Surgeons recommend strongly against the use of hyaluronates for the treatment of symptomatic OA of the knee based on a lack of efficacy and not due to a potential risk of harm. The AAOS provides a strong recommendation for the use of oral or topical non-steroidal antiinflammatory drugs (NSAIDs) or tramadol. The AAOS does not recommend for or against the use of acetaminophen, opioids, pain patches, or intra-articular corticosteroids. The AAOS provides a strong recommendation for participation in self-management programs, strengthening, low-impact aerobic exercises, and neuromuscular education; as well as physical activity. A moderate recommendation is provided for weight loss for individuals with a BMI of at least 25. (AAOS, 2013) For initial management of knee OA, the American College of Rheumatology (ACR) does not provide recommendations regarding the use of intra-articular hyaluronate and conditionally recommends the use of acetaminophen, oral NSAIDs, topical NSAIDs, tramadol, and intra-articular corticosteroids. For persons that do not have an adequate clinical response to acetaminophen, the ACR conditionally recommends the use of intra-articular hyaluronate. The ACR also strongly recommends the following non-pharmacologic therapies: Participation in cardiovascular and/or resistance land-based exercise; participation in aquatic exercise; and weight loss (for those individuals overweight). (Hochberg, 2012) A recent position paper from the ACR reaffirmed the 2012 OA guidelines and states that hyaluronic acid injection is indicated for patients who are not candidates for or who do not respond to other treatment options. (Committee on Rheumatologic Care, 2014) The VA/DoD acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) as first-line treatment. For mild to moderate pain, topical capsaicin can be considered first-line or adjunctive. For persistent moderate Page 5 of 10

6 or moderately severe OA, duloxetine or tramadol maybe offered as an alternative or adjunct to oral NSAIDs. For persistent severe OA pain where there are contraindications, inadequate response or intolerable adverse effects with non-opioid therapies and tramadol, non-tramadol opioids may be considered. For symptomatic OA of the knee, intra-articular corticosteroid injection may be considered. There is insufficient evidence to recommend for or against the use of intra-articular hyaluronate/hylan injection in patients with knee OA; it may be considered for patients who have not responded adequately to nonpharmacologic measures and who have an inadequate response, intolerable AEs, or contraindications to other pharmacologic therapies. (VA/DoD Clinical Practice Guideline for Osteoarthritis, 2014) The American Medical Society for Sports Medicine (AMSSM) recommends the use of hyaluronic acid for Kellgren- Lawrence (K-L) grade II-III knee OA in patients more than 60 years based on benefit using OMERACT- OARSI responder rating and for patients under 60 years due to response of treatment in those over 60 years. The AMSSM recommends clinicians collect OMERACT-OARSI responder data to track individual response to viscosupplementation. (AMSSM, 2016) Other Locations with Osteoarthritis o Hand osteoarthritis: The American College of Rheumatology (ACR) conditionally recommends against the use of intra-articular hyaluronate for hand OA (Hochberg, 2012). o Hip osteoarthritis: The American College of Rheumatology (ACR) does not provide a recommendation for the use of intra-articular hyaluronates due to a lack of efficacy or safety data from randomized controlled trials at the time of review in December (Hochberg, 2012) o Shoulder disorders: The American Academy of Orthopaedic Surgeons states that injectable viscosupplementation is an option for glenohumeral joint OA. The strength of this recommendation is limited, which is defined as the quality of the supporting evidence that exists is unconvincing, or that well-conducted studies show little clear advantage to one approach versus another. (AAOS, 2009) Clinical Efficacy Clinical trials evaluating the use of hyaluronate compare the products to saline or placebo and report variable results; some trials demonstrate benefit compared to saline while others have shown limited to no benefit over saline. A meta-analysis of 19 double-blinded trials did not demonstrate a clinically important benefit of viscosupplements over placebo. (Jevsevar, 2015) The majority of the pivotal trials for the available products evaluated efficacy (change in a pain score measure) from baseline to approximately 6 months. Several products (Euflexxa, Hyalgan, Monovisc, Orthovisc, Synvisc, and Synvisc-One) describe safety data in their respective prescribing information with repeat administration. Comparative Data Studies have been conducted comparing either Euflexxa, Hyalgan, Orthovisc, or Supartz to Synvis, the highmolecular weight, hyaluronate derivative. No significant differences were observed between the sodium hyaluronates and Synvisc except in 2 studies, where improvements in pain were significantly better with Synvisc than Hyalgan and Supartz. Euflexxa vs. Synvisc In Kirchner et al, 314 patients with OA were evaluated in a noninferiority study between Euflexxa and Synvisc. Patients with bilateral disease were also included, with treatment administered to the more symptomatic knee. The mean reduction from baseline in WOMAC pain scores with Euflexxa was 29.9 mm and for Synvisc was 28.4 mm; this met prespecified criteria for non-inferiority. (Kirchner, 2006) Hyalgan vs. Synvisc Raman et al compared 5 weekly injections of Hyalgan to 3 weekly injections of Synvisc. At 6 months, VASmeasured pain was significantly lower compared to baseline with Synvisc (34 mm, p < 0.05) but not with Hyalgan (59 mm, p = NS). According to authors, pain reduction was significantly greater with Synvisc as compared to Hyalgan at 6 months (p = 0.02) and at 12 months (p = 0.01). However, this study was not designed as a superiority trial the proper methodology for a superiority trial was never discussed in this trial. (Raman, 2008) Supartz vs. Synvisc Karlsson et al compared Supartz (described as the international brand Artzal in this study) and Synvisc to placebo. Efficacy of Supartz and Synvisc were similar to placebo. Change in weight bearing pain measured by VAS at 26 weeks was similar between placebo and Supartz or Synvisc. Lequesne index and WOMAC scores, Page 6 of 10

7 secondary endpoints in this study, were also similar between placebo and the active treatment injections. Of note, only 3 injections of Supartz were given 2 injections below the manufacturers recommended dosing. (Karlsson, 2002) Different results were obtained in another Synvisc vs. Supartz study. Wobig et al randomized 70 patients to 3 weekly injections of Supartz or Synvisc and evaluated patients at 12 weeks. The reduction in weight-bearing pain was significantly greater with Synvisc (-39 mm) compared to Supartz (-27 mm; p < 0.05). Mean scores for overall treatment response were significantly greater with Synvisc compared to Supartz with both investigator and patient assessments. (Wobig, 1999) Orthovisc vs. Synvisc Six studies evaluated Orthovisc and Synvisc. WOMAC pain scores were used to assess the efficacy of agents in four trials; two other trials assessed pain using different assessment tools. In Juni et al, patients were randomized to receive Orthovisc, Synvisc, or Ostenil a hyaluronate not available in the United States. WOMAC pain scores improved from baseline at 6 months in all groups (unknown statistical significance). Specific data points were only available graphically and were difficult to estimate. Data from Orthovisc and Ostenil were analyzed together and compared with Synvisc. No difference in change was detected between Synvisc and the combined group of Orthovisc and Ostenil (WOMAC pain score difference 0.1 (95% CI ). (Juni, 2007) Kotevoglu et al compared Orthovisc and Synvisc after 3 weekly injections at six months. WOMAC pain scores improved at 6 months compared to baseline for both groups; scores were numerically similar between groups at 6 months. No statistical comparisons were made between groups. (Kotevoglu, 2006) In a 3-week study comparing Orthovisc to Synvisc, WOMAC pain assessments were evaluated as a secondary outcome. Karatay et al sought to measure nitric oxide levels in synovial fluid for both groups. WOMAC pain scores 1 week after the third injection significantly decreased from baseline with Orthovisc ( ) and Synvisc ( ). No significant differences were observed between groups. (Karatay, 2004) Atamaz et al compared Orthovisc and Synvisc to physical therapy. Comparisons made between Orthovisc or Synvisc were completed as a subgroup analyses. According to study investigators, WOMAC pain subscale scores and spontaneous pain measured by VAS were similar between groups; however, no statistical comparisons were reported. WOMAC function, pain on touch, and pain at rest assessments were significantly better with Synvisc compared to Orthovisc (p < 0.05). (Atamaz, 2006) Bayramoglu et al used the Lequesne Functional Index to compare Orthovisc to Synvisc. Patients were evaluated after the final injection at 3 weeks and were also evaluated at 3 months. All patients also received physical therapy with their injections. At 3 months, Lequesne scores were significantly lower compared to baseline for Orthovisc ( ) and Synvisc ( ). No comparative evaluations were made between Orthovisc and Synvisc. (Bayramoglu, 2003) Karatosun et al compared Orthovisc to Synvisc for up to 12 months. Knees were evaluated using a Hospital for Special Surgery (HSS) knee score. Mean improvement from baseline in HSS for Orthovisc was 14.9 and for Synvisc was 19.9 at 12 months. No significant differences in mean improvement of HSS scores were observed between groups at 6 and 12 months. (Karatosun, 2005) Other Therapeutic Interventions: Intra-articular Corticosteroids Intra-articular (IA) corticosteroids (for example, Depo-Medrol, Kenalog) are FDA approved for osteoarthritis. American College of Rheumatology (ACR) guidelines recommend intra-articular (IA) corticosteroids. American Academy of Orthopedic Surgeons (AAOS) does not provide a recommendation for or against IA corticosteroids. A small, controlled, double-blind trial randomized 140 patients with knee osteoarthritis to either intra-articular triamcinolone or saline every 12 weeks for 2 years. While there was no significant difference in pain, there was significantly greater cartilage volume loss with triamcinolone acetate compared to placebo. (McAlindon, 2017) Experimental, Investigational, Unproven Uses Case series, randomized controlled trials and systematic reviews have investigated hyaluronate injections in the following areas: Osteoarthritis of the ankle Page 7 of 10

8 Lateral epicondylitis Osteoarthritis of the foot Osteoarthritis of the hip Tempomandibular joint disorders, including osteoarthritis Coding/Billing Information Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement. Covered when medically necessary: HCPCS Codes J7320 J7321 J7322 J7323 J7324 J7325 J7326 J7327 J7328 Description Hyaluronan or derivative, GenVisc 850, for intra-articular injection, 1 mg Hyaluronan or derivative, Hyalgan or Supartz, for intra-articular injection, per dose Hyaluronan or derivative, Hymovis, for intra-articular injection, 1 mg Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg Hyaluronan or derivative, Gel-One, for intra-articular injection, per dose Hyaluronan or derivative, Monovisc, for intra-articular injection, per dose Hyaluronan or derivative, Gel-One, for intra-articular injection, 0.1 mg References 1. American Academy of Orthopaedic Surgeons (AAOS). The treatment of glenohumeral joint osteoarthritis: guideline and evidence report. December 5, Available at: Accessed May 8, American Academy of Orthopaedic Surgeons (AAOS). Treatment of osteoarthritis of the knee: evidence based guideline, 2 nd edition. May 18, Available at: Accessed May 8, American Medical Society for Sports Medicine (AMSSM). Position Statement: Viscosupplementation Injections for Knee Osteoarthritis: Importance for Individual Patient Outcomes. January Clinical Journal of Sport Medicine. January 2016; 26 (1): Accessed May 15, Atamaz F, Kirazli Y, Akkoc Y. A comparison of two different intra-articular hyaluronan drugs and physical therapy in the management of knee osteoarthritis. Rheumatol Int. Aug 2006; 26 (10): Bayramoglu M, Karatas M, Cetin N, Akman N, Sozay S, Dilek A. Comparison of two different viscosupplements in knee osteoarthritis -- a pilot study. Clin Rheumatol. May 2003; 22 (2): Centers for Disease Control and Prevention. Osteoarthritis. Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion. Last updated October 28, Accessed May 12, Cohen M, Altman R, Hollstrom R, et al. Safety and efficacy of intra-articular sodium hyaluronate (Hyalgan) in a randomized, double-blind study for osteoarthritis of the ankle. Foot Ankle Int Jul;29(7): Committee on Rheumatologic Care. American College of Rheumatology Position Statement: Intra-articular hyaluronic acid injection in osteoarthritis of the knee. February Accessed on May 5, Conrozier T, Vignon E. Is there evidence to support the inclusion of viscosupplementation in the treatment paradign for patients with hip osteoarthritis? Clin Exp Rheumatol Sep-Oct;23(5): DeGroot H 3 rd, 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 Am Jan 4;94(1):2-8. Page 8 of 10

9 11. de Souza RF, Lovato da Silva CH, Nasser M, Fedorowicz Z, Al-Muharraqi MA. Interventions for the management of temporomandibular joint osteoarthritis. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD DOI: / CD pub Euflexxa (1% sodium hyaluronate) Product Information. Ferring Pharmaceuticals Inc., Parsippany, NJ: June Fernandez-Lopez J, Ruano-Ravina A. Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. OsteoArthritis and Cartilage (2006) 14, Gel-One (cross-linked hyaluronate) Prescribing Information. Zimmer, Warsaw, IN: May Gelsyn-3 (high molecular weight Product Information. Bioventus LLC, Durham, NC: GenVisc 850 (high molecular weight Prescribing Information. OrthogenRx, Inc., Doylestown, PA. 17. Hochberg MC, Altman RD, April KT 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; 64 (4): Hyalgan Prescribing Information. Fidia Pharma USA Inc., Parsippany, NJ: May Hymovis (high molecular weight Instructions for Use. Fidia Pharma USA Inc., Parsippany, NJ: October Jevsevar D, Donnelly P, Brown GA, Cummins DS. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am Dec; 97 (24): Juni P, Reichenbach S, Trelle S, et al. Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: a randomized controlled trial. Arthritis Rheum. Nov 2007; 56 (11): Karatay S, Kiziltunc A, Yildirim K, Karanfil RC, Senel K. Effects of different hyaluronic acid products on synovial fluid levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in knee osteoarthritis. Ann Clin Lab Sci. Summer 2004;34(3): Karatosun V, Unver B, Gocen Z, Sen A. Comparison of two hyaluronan drugs in patients with advanced osteoarthritis of the knee. A prospective, randomized, double-blind study with long term follow-up. Clin Exp Rheumatol. Mar-Apr 2005; 23 (2): Karlsson J, Sjogren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford). Nov 2002; 41 (11): Kirchner M, Marshall D. A double-blind randomized controlled trial comparing alternate forms of high molecular weight hyaluronan for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. Feb 2006; 14 (2): Kotevoglu N, Iyibozkurt PC, Hiz O, Toktas H, Kuran B. A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatol Int. Feb 2006; 26 (4): Krogh T, Bartels E, Ellingsen T. Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials. Am J Sports Med Jun;41(6): Machado E, Bonotto D, Cunali PA. Intra-articular injections with corticosteroids and sodium hyaluronate for treating temporomandibular joint disorders: a systematic review. Dental Press J Orthod 2013; 18 (5): Manfredini D, Piccotti F, Guarda-Nardini L. Hyaluronic acid in the treatment of TMJ disorders: a systematic review of the literature. Cranio 2010; 28 (3): McAlindon, T.E., LaValley, M.P., Harvery, W.F. et al. Effect of Intra-articular Triamcinolone vs. Saline on Knee Cartilage Volume and Pain in Patients with Knee Osteoarthritis. JAMA. 2017;317(19): doi: /jama Monovisc (high molecular weight Information for Prescribers. Anika Therapeutics, Inc., Bedford, MA: December Munteanu S, Zammit G, Menz H, et al. Effectiveness of intra-artiicular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first metatarsophalangeal joing osteoarthritis: a randomized, placebo-controlled trial. Ann Rheum Dis Oct;70(10): Orthovisc (high molecular weight Prescribing Information. Anika Therapeutics, Inc., Woburn, MA: September Qvistgaard E, Christensen R, Torp-Pedersen S, et al. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. OsteoArthritis and Cartilage (2006) 14, Page 9 of 10

10 35. Raman R, Dutta A, Day N, Sharma HK, Shaw CJ, Johnson GV. Efficacy of Hylan G-F 20 and Sodium Hyaluronate in the treatment of osteoarthritis of the knee -- a prospective randomized clinical trial. Knee. Aug 2008; 15 (4): Richette P, Ravaud P, Conrozier T, et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis; a multicenter, randomized, placebo-controlled trial. Arthritis Rheum Mar;60(3): Supartz FX Prescribing Information. Bioventus LLC, Durham, NC: April Synvisc Prescribing Information. Genzyme Biosurgery, Ridgefield, NJ: September Synvisc-One Information for Prescribers. Genzyme Biosurgery, Ridgefield, NJ: September VA/DoD Clinical Practice Guideline for the Non-Surgical Management of Hip & Knee Osteoarthritis (2014). Retrieved from National Guideline Clearinghouse at Accessed May 8, van Brakel R, Eygendaal D, Intra-articular injection of hyaluronic acid is not effective for the treatment of post-traumatic osteoarthritis of the elbow. Arthroscopy Nov;22(11): Wobig M, Bach G, Beks P, et al. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clin Ther. Sep 1999; 21 (9): The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 10 of 10