Zilretta (triamcinolone acetonide ER injection) Clinical Policy Form

PART B DRUG MEDICAL/PHARMACY Effective Date May15, 2025 Policy # ZILRETTA (triamcinolone acetonide ER) Zilretta (triamcinolone acetonide ER) Review Date Applicable to: 02/25/2025 Medicare Advantage Commercial Elevance Health HMO Blue Shield Trio Approver’s Name & Title QI & UM Drug Subcommittee Aspire Health Plan applies medical drug clinical criteria as a reference for medical policy information only. Federal and state laws or requirements, contract language, and Plan benefit may take precedence over the application of these clinical criteria. Please consult the applicable certificate or contract for benefit details. This policy is subject to revision at the discretion of the Plan and is therefore subject to change. Refer to the disclaimer section below for more information. POLICY This policy addresses the coverage of Zilretta (triamcinolone acetonide extended-release injectable suspension) as an intra-articular injection for the management of osteoarthritis pain of the knee.
APPLICABLE HCPCS J3304: Injection, triamcinolone acetonide, preservative-free, extended-release, microsphere formulation, 1 mg (1 billable unit = 1 mg) Available as: Zilretta single-dose kit (containing 32 mg triamcinolone acetonide extended-release injectable powder for suspension with 5 mL of sterile diluent) CLINICAL CRITERIA A. INITIAL CRITERIA Zilretta (triamcinolone acetonide ER injectable suspension) may be authorized when ALL of the following criteria are met, with appropriate documentation: 1. Diagnosis: Confirmed diagnosis of osteoarthritis (OA) of the knee; AND 2. Affected knee(s): Documentation of the affected knee(s) to be treated (left, right, or both) NOTE: Bilateral injections will be authorized only if both knees meet criteria; AND

3. Pain and Functional Impairment: Member reports pain that interferes with functional activities (e.g., ambulation, prolonged standing); AND

4. Failure of Conservative Therapy: Member has experienced therapeutic failure,
   contraindication, or intolerance to at least 3 months of conservative therapy, including:

   a. Non-Pharmacologic Approaches: Physical, psychosocial, or mind-body approach (e.g., land-based or aquatic exercise, physical therapy, tai chi, yoga, weight management, cognitive behavioral therapy, use of a knee brace or cane, etc.); and

   b. Pharmacologic Approaches: Use of topical NSAIDs, oral NSAIDs (with or without oral proton pump inhibitors), COX-2 inhibitors, topical capsaicin, acetaminophen, tramadol, duloxetine, etc.

   AND

5. Attestation / Documentation: a. Member has not previously received Zilretta (triamcinolone acetonide ER) in the requested knee; AND

   b. Member does not have any conditions that preclude intra-articular injections (e.g., active joint infection, unstable joint, etc.); AND

   c. Member has not received intra-articular hyaluronic acid derivatives within the previous 6 months; AND

   d. Member has not received intra-articular short-acting corticosteroid type drugs within the previous 3 months. AND

6. Zilretta must be administered by, or under the supervision of, a:
   a. Rheumatologist b. Orthopedist c. Physical medicine and rehabilitation (physiatrist) d. Physician who has received specific training in the administration and use of viscosupplements.

   B. REAUTHORIZATION / CONTINUATION OF THERAPY CRITERIA

7. Limitation of Use: Zilretta is limited to a single course of therapy per knee. Reauthorization or continuation of treatment is not approved.

8. Rationale: Safety and efficacy of repeat administration has not been studied (Prescribing Information, 2022).

STEP THERAPY

Step Therapy Does NOT Apply if: • The member is currently being treated with the requested medication. • The member has received the requested drug within the last 365 days.

Step Therapy Applies if: • The member is new to therapy (i.e., has not received the requested drug in the last 365 days).

PREFERRED PRODUCT(S) No PA required; No Step Therapy Required for the following PREFERRED products: • Triamcinolone acetonide injection (Kenalog) • Methylprednisolone acetate injection (Depo-Medrol).

A. NON-PREFERRED PRODUCT: Zilretta (triamcinolone acetonide ER injectable suspension)

Zilretta may be authorized when the clinical criteria (section above) are met AND ONE the following:

1. Treatment Failure on Intra-articular Corticosteroids:

   a. The member experienced treatment failure with intra-articular corticosteroids, including immediate-release triamcinolone acetonide injection. Treatment failure is defined as any of the following (not an all-inclusive list):
   i. Inadequate pain relief ii. Frequent need for continued rescue doses of NSAIDs iii. Inability to increase activity levels or need to decrease activity levels iv. Adequate pain relief but experienced steroid- induced hyperglycemia. and b. Prescriber provide a clinical rationale supporting explaining why Zilretta is expected to be effective if the short-acting formulation (e.g., immediate-release triamcinolone) was ineffective. OR

2. Clinical Rationale for Inappropriateness of Short-Acting Corticosteroids:

   Prescriber provide clinical rationale explaining why treatment with a short-acting intra-articular corticosteroid (i.e. intra-articular immediate-release triamcinolone) is inappropriate for the member. NOTE: Convenience alone is not considered a valid clinical rationale.

DOSAGE AND UTHORIZATION TIMEFRAMES

1. Recommended Dose (Osteoarthritis of the Knee) • Dose: ONE injection per knee per lifetime • Maximum Dose: The dose should not exceed 32 mg as a single intra-articular injection into the knee.

2. Authorization Period:
   • Frequency: One dose per knee per lifetime.
   • Billing: 32 billable units (one time only).

3. Limitations • Repeat Administration: The safety and efficacy of repeat administration have not been studied. Therefore, repeat doses are not recommended (Prescribing Information, 2022).

   DRUG INFORMATION

   PHARMACOLOGIC CATEGORY: Corticosteroid, Systemic ROUTE OF ADMINISTRATION: Intra-articular injection FDA-APPROVED INDICATION: Zilretta is indicated for the management of osteoarthritis (OA) pain of the knee. It has not been evaluated for use in OA pain of other joints, such as the shoulder or hip, and is not suitable for small joints (e.g., hand). COMPENDIAL APPROVED (OFF-LABEL) USES: NONE

   CONTRAINDICATIONS:
   • Hypersensitivity to triamcinolone acetonide or any component of the formulation. • Systemic fungal infections.

   CLINICAL SUMMARY / APPENDIX

   Zilretta (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra- articular (IA) injection for treatment of osteoarthritis (OA)-related knee pain. It has not been evaluated for the treatment of OA-related pain in other joints, such as the shoulder or hip. Guideline Recommendations for Intra-Articular Glucocorticoids in OA: • The American College of Rheumatology (ACR) strongly recommends IA glucocorticoid injections for knee OA, while the Osteoarthritis Research Society International (OARSI) conditionally recommends their use. These recommendations are based on evidence demonstrating short-term efficacy in managing knee OA pain. • IA glucocorticoids are available in both short-acting and long-acting formulations. However, there is insufficient evidence to recommend one formulation over another in terms of safety and efficacy. Generic preparations of short-acting triamcinolone acetonide are available, providing a cost-effective option for initial therapy.

Clinical Rationale for a Trial of Short-Acting Triamcinolone: Given the lack of evidence supporting the superiority of long-acting formulations, a trial of short-acting IA triamcinolone acetonide is recommended before considering the extended-release formulation (Zilretta). This approach is supported by the expectation that if a short-acting formulation of the same drug is ineffective, the long-acting formulation is unlikely to provide additional benefit. 2019 ACR/Arthritis Foundation (AF) Guidelines: The 2019 joint guidelines from the ACR and AF strongly support the use of IA glucocorticoid injections for knee and hip OA and conditionally support their use for hand OA for short-term pain management. However, the guidelines note that there is insufficient evidence to recommend long-acting over short-acting formulations or high versus low doses (Kolanski et al., 2019). Lack of Evidence for Extended-Release Formulations: The ACR, AF, and other organizations (e.g., AAOS, OARSI) have concluded that there is insufficient evidence to support a clinical advantage of extended-release (ER) triamcinolone acetonide (Zilretta) over immediate-release (IR) triamcinolone acetonide for knee OA. Additional clinical studies directly comparing the efficacy and safety of equipotent doses of ER versus IR triamcinolone are needed to establish a clear benefit. Non-Pharmacologic Treatment as a Mainstay of Therapy: The ACR, AAOS, and ORSI are aligned that non-pharmacologic treatments are foundational for managing knee OA. These modalities, which include physical therapy, weight management, and exercise, are typically used in combination to maximize effectiveness and should be considered as part of a comprehensive treatment plan. REFERENCES Government Agency Centers for Medicare and Medicaid Services (CMS). Medicare coverage database: National coverage determination (NCD) (search: knee osteoarthritis OR triamcinolone acetonide). Available from CMS. No NCD for TA-ER identified. Prescribing Information Zilretta (triamcinolone acetonide) [prescribing information]. San Diego, CA: Pacira Pharmaceuticals Inc; May 2024. Peer-reviewed Literature, Guidelines, Consensus, 1. American College of Rheumatology (ACR). 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee [published correction appears in Arthritis Care Res (Hoboken). May 2021;73(5):764]. Arthritis Care Res (Hoboken). 2020;72(2):149-162. doi:10.1002/acr.24131. 2. American Academy of Orthopedic Surgeons (AAOS)-Management of Osteoarthritis of the Knee (Non- Arthroplasty): Evidence Based Clinical Practice Guideline. Adopted by the AAOS Board of Directors August, 2021. Available at: AAOS 3. Bannuru RR, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage. 2019:27:1578-158

4. Kolanski 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 and Rheum 2020;72:220-233. Available at: 2019 Osteoarthritis Guideline IMPORTANT REMINDER This Medicare Part B Step Therapy Medical Necessity Guideline is for informational purposes only and does not constitute or replace professional medical advice. Physicians, hospitals, and other providers are responsible for administering and using drugs/biologicals in the most effective and clinically appropriate manner and are solely responsible for all medical care decisions. This guideline is not a substitute for clinical judgment or individualized patient care. Coverage determinations are based on the member's Evidence of Coverage (EOC), which contains specific coverage provisions, limitations, and exclusions. In the event of a conflict between this guideline and the member's EOC, the EOC will govern. Aspire Health Plan (AHP) adheres to applicable Medicare guidelines, including National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), Local Coverage Articles (LCAs), and other relevant Medicare manuals published by the Centers for Medicare & Medicaid Services (CMS). Compliance with these guidelines is required where applicable. For the most current Medicare policies and coverage information, please refer to the CMS website at cms.gov and search the Medicare Coverage Database. All LCDs are the same for each state within a Jurisdiction. The Medicare Administrative Contractor (MAC) for California (Jurisdiction E) is Noridian. Active LCDs for JE Part B can be found on the Noridian Medicare website (noridianmedicare.com). In the event of a discrepancy between this guideline and a Medicare NCD or LCD, the NCD/LCD will govern. This guideline is used by AHP to determine coverage in the absence of applicable CMS Medicare guidelines. The Medicare source materials used to develop this guideline are referenced below. This document does not replace the official Medicare source materials, which provide detailed information on Medicare coverage requirements. In the event of a conflict between this document and Medicare source materials, the Medicare source materials will prevail. The inclusion of a code in this guideline does not guarantee coverage or reimbursement. Benefit coverage is determined by the member's specific plan document, applicable state and federal laws, and CMS guidelines. Other policies and standards may also apply. Providers are expected to maintain documentation to support coverage decisions and make it available upon request. POLICY HISTORY / REVISION INFORMATION Version Approval Date Summary of Changes 1 9/27/2023 New Policy 2 02/25/2025 Annual Review. The policy has been revised and reformatted to enhance clarity with no alteration to the intent or clinical criteria. References reviewed and policy updated where applicable. Effective 05/15/2025.