ZILRETTA, Triamcinolone Acetonide Form

Triamcinolone acetonide extended-release injectable suspension (Zilretta®) is an extended- release synthetic corticosteroid. FDA Approved Indication(s) Zilretta is indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. Limitation(s) of use: The efficacy and safety of repeat administration of Zilretta have not been demonstrated.
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 Zilretta is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Osteoarthritis of the Knee (must meet all):

1. Diagnosis of osteoarthritis of the knee supported by imaging (e.g., X-ray, MRI);
   2. Prescribed by or in consultation with a rheumatologist, orthopedist, or sports medicine physician;
2. Age ≥ 18 years;
   
   4. Failure of ≥ 4-week trial of one of the following (a or b), unless clinically significant adverse effects are experienced or all are contraindicated: a. Oral nonsteroidal anti-inflammatory drug (NSAID) at continuous therapeutic dosing (prescription strength); b. Topical NSAID if member is ≥ 75 years old or unable to take oral NSAIDs; *Prior authorization may be required for topical NSAIDs
3. Trial of at least one other intra-articular glucocorticoid injection for the knee with a documented positive, but inadequate response (e.g., 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);
   *Prior authorization may be required for intra-articular glucocorticoids

4. Dose does not exceed 32 mg as a single intra-articular injection into the knee. Approval duration: 3 months (one dose per knee) Page 1 of 8

   CLINICAL POLICY Triamcinolone ER Injection B. Other diagnoses/indications (must meet 1 or 2):

5. 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, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
6. 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 health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Osteoarthritis of the Knee
7. Re-authorization is not permitted. Zilretta is not indicated for repeat administration in the same knee. For an untreated knee, members must meet the initial approval criteria.
   Approval duration: Not applicable B. Other diagnoses/indications (must meet 1 or 2):
8. 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, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

9. 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 health insurance marketplace, and CP.PMN.53 for Medicaid.
   Page 2 of 8

   CLINICAL POLICY Triamcinolone ER Injection 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 health insurance marketplace, and CP.PMN.53 for Medicaid.
   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration MRI: magnetic resonance imaging NSAID: non-steroidal anti-inflammatory drug TA: triamcinolone acetonide 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.
   Drug Name Dosing Regimen Dose Limit/ Maximum Dose Oral NSAIDs diclofenac
   etodolac (Lodine) fenoprofen (Nalfon)
   ibuprofen (Motrin)
   indomethacin (Indocin) indomethacin ER ketoprofen
   ketoprofen ER meloxicam (Mobic)
   naproxen (Naprosyn)
   naproxen sodium (Anaprox DS) oxaprozin (Daypro) piroxicam (Feldene) salsalate (Disalcid) sulindac Topical NSAIDs diclofenac 1.5% solution diclofenac 2% solution (Pennsaid) diclofenac 1% gel (Voltaren)
   Intra-articular Glucocorticoids triamcinolone acetonide (Kenalog) 50 mg PO BID to TID 400-500 mg PO BID 400-600 mg PO TID to QID 400-800 mg PO TID to QID 25-50 mg PO BID to TID 75 mg PO QD to BID 25-75 mg PO TID to QID 200 mg PO QD 7.5-15 mg PO QD 250-500 mg PO BID 275-550 mg PO BID 600-1,200 mg PO QD 10-20 mg PO QD 1,500 mg PO BID or 1,000 mg PO TID 150 mg-200 mg PO BID 150 mg/day 1,200 mg/day 3,200 mg/day 3,200 mg/day 200 mg/day 150 mg/day 300 mg/day 200 mg/day 15 mg/day 1,500 mg/day 1,650 mg/day 1,800 mg/day 20 mg/day 3,000 mg/day 400 mg/day 40 drops QID on each painful knee 40 mg (2 pumps) BID on each affected knee 2-4 g applied to affected area QID 32 g/day 160 drops/knee/day 160 drops/knee/day 40 mg (1 mL) for large joints 80 mg/treatment Page 3 of 8

   CLINICAL POLICY Triamcinolone ER Injection Drug Name Dosing Regimen Dose Limit/ Maximum Dose 10-20 mg for large joints Oral NSAIDs Aristospan (triamcinolone hexacetonide) methylprednisolone acetate (Depo-Medrol) hydrocortisone acetate 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. 25-50 mg for large joints 20-80 mg for large joints 20 mg/treatment 75 mg/treatment 80 mg/treatment Appendix C: Contraindications/Boxed Warnings • Contraindication(s): patients with hypersensitivity to triamcinolone acetonide or any component of the product • Boxed warning(s): none reported Appendix D: General Information • Zilretta (extended-release triamcinolone acetonide [TA-ER]) is designed to deliver TA • over 12 weeks using extended-release microsphere technology. In contrast, Bodick, et al., 2015, reports that, historically, immediate-release intraarticular glucocorticoids, while demonstrating a large initial analgesic effect, wane over one to four weeks. In an evaluation of TA-ER vs immediate-release triamcinolone acetonide (TA-IR) synovial and systemic pharmacokinetics, Krause, et al, 2017, reports that TA-ER demonstrated prolonged residency in the joint (through week 12) relative to TA-IR (through week 6), and consequently showed diminished peak plasma steroid levels relative to TA-IR through week 6. Russell, et al, 2017, reports that in patients with knee osteoarthritis and type-2 diabetes mellitus, TA-ER was associated with a significant and clinically relevant reduction in blood glucose elevation relative to TA-IR 72 hours post- injection.
   In the Zilretta pivotal trial, Conaghan, et al, 2018, reported superiority of TA-ER versus placebo to 12 weeks in average daily pain (ADP) scores (primary endpoint) and continuing TA-ER activity out to 24 weeks. While TA-ER did not show superior outcomes relative to TA-IR over 12 weeks in ADP scores (secondary endpoint), it was superior to TA-IR at week 12 when evaluated using the exploratory endpoints Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A/B/C and Knee injury and Osteoarthritis Outcome Score Quality of Life (KOOS QoL) subscales. • Conaghan also reports that patients treated with TA-ER used significantly less rescue • medication than those treated with TA-IR. • A phase 3b, open-label, single-arm study by Spitzer et al., 2019, evaluated the safety and efficacy of repeat administration of Zilretta in 208 patients, of whom 179 received a second injection of Zilretta after a median of 16.6 weeks. Additional injections after the second dose were not allowed. o The proportion of patients who experienced arthralgia in any joint was nearly doubled during the second injection period (19.0%) compared to the first injection period (10.6%); there were also slightly higher rates of index-knee treatment-emergent AEs during the second injection period (17.3%) compared to the first (14.0%). Page 4 of 8

   CLINICAL POLICY Triamcinolone ER Injection o The FDA highlights this concern in the Zilretta Prescribing Information, Section 6.1 Adverse Reactions – Clinical Studies, stating “The data from this study are insufficient to fully characterize the safety of repeat administration of Zilretta.” As a result, the label continues to retain a limitation of use concerning the unknown benefit of repeat administration. V. Dosage and Administration
   Indication Osteoarthritis of the knee Dosing Regimen 32 mg (5 mL) as a single intra-articular extended- release injection Maximum Dose 32 mg (5 mL) VI. Product Availability
   Injectable suspension of microspheres (single-dose vial for reconstitution): 32 mg/5 mL VII.