Background

Osteoarthritis (OA) was once thought to be merely a “wear and tear” process, but it involves inflammation of the bone, as “osteo” means bone and “Arthritis” means inflammation. Osteoarthritis is a degenerative joint disease that can impact any joint, but usually affects the hands, knees, hips, lower back, and neck. The causes of OA are multifactorial and include age, obesity, joint injury, genetics, environmental factors, gender, and musculoskeletal abnormalities. Symptoms of OA include joint stiffness, clicking or popping sound during joint movement, joint swelling, joint pain, and joint instability. Diagnosis of knee OA is typically based on medical history, physical examination, and lab tests.

The treatment of knee OA is based on clinical presentation. Mild knee OA treatment includes nonpharmacological management and pharmacological management, such as topical Nonsteroidal anti-inflammatory drugs (NSAID) or capsaicin. For moderate to severe knee OA, nonpharmacological and pharmacological management such as oral NSAIDs or oral duloxetine are used. If persistent or progressive symptoms persist despite these treatments, intra-articular glucocorticoid injections may provide short-term pain relief, with other intra-articular therapies available, such as hyaluronan and platelet-rich plasma.

Zilretta^® is an extended-release formulation of triamcinolone acetonide, a corticosteroid with anti-inflammatory and immunomodulatory effects. The mechanism of action of triamcinolone acetonide involves activating the glucocorticoid receptor, resulting in the stimulation of anti[1]inflammatory transcription factors, such as lipoproteins, and inhibiting the inflammatory transduction pathway by blocking the release of arachidonic acid, thereby preventing the synthesis of prostaglandins and leukotrienes.

Policy

Zilretta is considered MEDICALLY NECESSARY when all the following criteria is met:

1. Patient is 18 year of age or older.
2. Patient had an inadequate response, or has a contraindication, or intolerance to triamcinolone injection.
3. Diagnosis of the knee to be treated is confirmed by radiologic evidence of knee OA (e.g., X-ray, magnetic resonance imaging [MRI], computed tomography [CT] scan, ultrasound).
4. The patient has tried at least TWO of the following three modalities of therapy for OA:
   1. At least one course of physical therapy (PT) for knee osteoarthritis
   2. At least TWO of the following pharmacologic therapies: [verification of therapies required]:
      1. NSAIDs (oral [e.g., naproxen, ibuprofen] or topical [Pennsaid^® solution or Voltaren^® gel], Celebrex^® (celecoxib)) [NOTE: a trial of two or more NSAIDs counts as one pharmacologic therapy]
      2. Acetaminophen
      3. Tramadol
      4. Duloxetine (Cymbalta, generics)
   3. At least TWO injections of Intra-Articular corticosteroids to the affected knee
5. The product is administered by or under the supervision of a physician specializing in rheumatology, orthopedic surgery, or physical medicine and rehabilitation (physiatrist) or a physician who has received specific training in the administration and use of triamcinolone injections.
6. If patient has previously received an injection of Zilretta:
   1. a. They must have had a beneficial response to the injection.
   2. b. Have had no major safety concerns after receiving the first dose.
   3. c. Must be a minimum of 12 weeks after first dose.

References

1. Zilretta [package insert]. Flexion Therapeutics, Inc. Burlington, Massachusetts. Updated January 2020.
2. Management of moderate to severe knee osteoarthritis. UpToDate. Updated January 2018.
3. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthritis. Ann Rheum Dis. 1957 Dec; 16(4): 494-502.
4. Sivapriya R, John C, et al. Corticosteroids: Mechanisms of Action in Health and Disease. Corticosteroids: Mechanisms of Action in Health and Disease - PubMed (nih.gov). Accessed May 2, 2023.
5. Osteoarthritis of the Knee. Osteoarthritis of the Knee | Arthritis Foundation. Accessed May 2, 2023.
6. Michael D, Abhishek A, et al. Clinical manifestations and diagnosis of osteoarthritis. Clinical manifestations and diagnosis of osteoarthritis - UpToDate. Accessed May 2, 2023.
7. American Academy of Orthopaedic Surgeons Management of Osteoarthritis of the Knee (Non-Arthroplasty) Evidence-Based Clinical Practice Guideline (3rd Edition). 08/31/2021. Available at: https://www.aaos.org/oak3cpg. Accessed February 24, 2023.
8. American Academy of Orthopaedic Surgeons. AAOS clinical practice guideline on the treatment of osteoarthritis of the knee. 3rd edition. Rosemont (IL): American Academy of Orthopedic Surgeons; 05/18/2003. 
9. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578-1589. 
10. Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 2015 Jun 3;97(11):877-88.
11. Conaghan PG, Hunter DJ, Cohen SB, et al; FX006-2014-008 Participating Investigators. Effects of a Single Intra-Articular Injection of a Microsphere Formulation of Triamcinolone Acetonide on Knee Osteoarthritis Pain: A Double-Blinded, Randomized, Placebo-Controlled, Multinational Study. J Bone Joint Surg Am. 2018 Apr 18;100(8):666-677.
12. Deveza LA, Bennell K. Management of Knee Osteoarthritis. [UpToDate Web Site]. Updated: 04/05/2022. Available at:https://www.uptodate.com/contents/management-of-knee-osteoarthritis?source=history_widget [via subscription only]. Accessed February 24, 2023.
13. Elsevier’s Clinical Pharmacology Compendium. Zilretta. [ClinicalKey Web site]. 12/16/2021. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed February 24, 2023.
14. 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 (Hoboken). 2020 Feb;72(2):149-162. 
15. Lexi-Drugs Compendium. Triamcinolone acetonide extended release (Zilretta). 02/25/2023​. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/search?q=zilretta&t=name&va= [via subscription only]. Accessed February 24, 2023.
16. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Mar;22(3):363-88.
17. Newberry SJ, FitzGerald J, SooHoo NF, et al. Treatment of Osteoarthritis of the Knee: An Update Review. Rockville (MD): Agency for Healthcare Research and Quality (US). AHRQ Comparative Eff​ectiveness Reviews; 2017 May. Report No.: 17-EHC011-EF.
18. Truven Health Analytics Inc. Micromedex Solutions. Triamcinolone acetonide ER (Zilretta). Updated 02/22/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 24, 2023.
19. US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Triamcinolone acetonide extended release (Zilretta™) Approval letter and Prescribing Information. [FDA website]. Updated 01/2020. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=208845. Accessed February 24, 2023​.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

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

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