Pacira Biosciences, Inc.NASDAQ: PCRX

Viatris Agrees to Acquire Pacira BioSciences, Advancing Its Innovative Medicines Strategy and Becoming a Leader in Non-Opioid Pain Therapies

· Issued by Pacira BioSciences, Inc. via PR Newswire
  • Adds Two Marketed, Patent-Protected, High-Margin Medicines in the U.S., EXPAREL® and ZILRETTA®, and Expects to Expand the Products' Reach Across Selected Markets Within Its International Infrastructure
  • Expands U.S. Innovative Medicines Commercial, Market Access, Medical Affairs and Global R&D Capabilities
  • Expected to Be Synergistic With Viatris' Fast-Acting Meloxicam Opportunity
  • Deal Anticipated to Close By the End of 2026 and to Be Immediately Accretive to Viatris' Financial Guidance Metrics
  • Transaction Consistent With Viatris' Disciplined and Balanced Capital Allocation Strategy and Preserves Financial Flexibility

PITTSBURGH and BRISBANE, Calif. , Oct. 8, 2026 /PRNewswire/ -- Viatris Inc. (Nasdaq: VTRS), a global healthcare company, and Pacira BioSciences, Inc. (Nasdaq: PCRX), a leader in innovative non-opioid pain therapies, today announced that they have entered into a definitive agreement under which Viatris has agreed to acquire all of the outstanding shares of common stock of Pacira for $36.50 per share in cash, representing an aggregate equity value of $1.65 billion.

Pacira brings two established, high-margin, patent-protected, in-market U.S. products – EXPAREL® (bupivacaine liposome injectable suspension) and ZILRETTA® (triamcinolone acetonide extended-release injectable suspension). Pacira generated approximately $746 million in total revenue and approximately $177 million in adjusted EBITDA during the last twelve months ended June 30, 2026.  Viatris plans to leverage its intellectual property expertise and proven ability to extend product lifecycles and sustain meaningful sales after the entry of competition to maximize the long-term value of the Pacira portfolio and expects to expand the products' reach across select markets within its global infrastructure.

"The pending acquisition of Pacira BioSciences is an important step in advancing our strategy to build our innovative medicines business," said Scott A. Smith, CEO, Viatris. "The addition of EXPAREL, for acute postsurgical pain, and ZILRETTA, for osteoarthritis knee pain, are synergistic with our fast-acting meloxicam market opportunity and position us as a leader in non-opioid pain management therapies, an area where patients and healthcare providers continue to seek more treatment options. Pacira also brings Viatris additional U.S. innovative commercial, market access, medical affairs and global R&D capabilities that are highly complementary to our existing infrastructure and portfolio. This transaction accelerates our path to sustained revenue and earnings growth and adds an innovative development pipeline in certain high-value, specialty-driven therapeutic areas with a high unmet need."

"The proposed transaction is expected to be immediately accretive to our financial guidance metrics," said Paul Campbell, Interim CFO, Chief Accounting Officer & Corporate Controller, Viatris. "Importantly, we expect to fund the transaction primarily from excess cash with the remainder from short-term borrowings. As such, we expect the transaction will have minimal impact on our gross leverage ratio. We believe the transaction is consistent with our disciplined and balanced approach to capital allocation, preserves our financial flexibility and provides opportunities to create additional value through both cost and revenue synergies."

"Our mission from the start has been to deliver innovative, non-opioid pain therapies to transform the lives of patients. Pacira has helped reshape pain management by advancing awareness, expanding patient access and driving the adoption of opioid-sparing therapies," said Frank D. Lee, CEO, Pacira BioSciences. "I am immensely proud of what our team has accomplished, from building a leading commercial portfolio that has helped nearly 20 million patients access non-opioid pain management, to advancing our 5x30 strategy and expanding our innovative pipeline. As we enter this next chapter, we are confident that Viatris' shared vision, substantial resources, and global scale will accelerate the impact of our mission and help bring our transformative therapies to even more patients."

A presentation with further details about the transaction can be found at investor.viatris.com.

Terms of the Transaction Under the terms of the transaction, Viatris will commence a tender offer to acquire all of the outstanding shares of Pacira's common stock for $36.50 per share in cash. Following completion of the tender offer, Viatris will acquire all remaining shares of Pacira's common stock not tendered in the tender offer through a second-step merger for the same consideration.

The transaction, which was unanimously approved by the boards of directors of both companies, is subject to customary closing conditions, including the tender of a majority of the outstanding shares of Pacira's common stock and expiration of the applicable regulatory waiting period. Pacira's board of directors unanimously recommends that Pacira's stockholders tender their shares in the tender offer. The transaction is expected to close by the end of 2026.

Upon completion of the transaction, Pacira will become a wholly owned subsidiary of Viatris and Pacira's common stock will no longer be listed for trading on the Nasdaq Global Select Market.

Advisors Morgan Stanley & Co. LLC is serving as financial advisor to Viatris, and Cravath, Swaine & Moore LLP is serving as legal advisor. Centerview Partners LLC also provided strategic and financial advice to Viatris.

Goldman Sachs & Co. LLC is serving as exclusive financial advisor to Pacira, and Ashurst Perkins Coie is serving as legal advisor.

Third-Quarter Conference Call As previously announced, Viatris will report third-quarter 2026 financial results on Thursday, Nov. 5, 2026. Company executives will host a conference call and live webcast at 8:30 a.m. ET on the same date to discuss Viatris' quarterly results and the Pacira transaction. Investors and the general public are invited to listen to a live webcast of the call at investor.viatris.com or by calling 844.308.3344 or 412.317.1896 for international callers. A replay of the webcast also will be available on the website.

About Viatris Viatris Inc. (Nasdaq: VTRS) is a global healthcare company whose mission is to empower people worldwide to live healthier at every stage of life. We meet the needs of patients around the world by acting decisively with ingenuity and resolve. Whether we're developing new medicines, working to maintain a resilient supply of needed therapies, or pursuing bold innovation, we strive to deliver solutions that are effective at scale and built to endure. We're purpose-built to make an impact with a broad portfolio that spans generics, value-added medicines, established brands and innovative medicines that address areas of significant unmet need. We are headquartered in the U.S., with global centers in Pittsburgh, Shanghai and Hyderabad, India. Learn more at viatris.com and investor.viatris.com, and connect with us on LinkedIn, Instagram, YouTube and X.

About Pacira BioSciences Pacira BioSciences, Inc. (Nasdaq: PCRX) delivers innovative, non-opioid pain therapies to transform the lives of patients. Pacira has two commercial-stage non-opioid treatments: EXPAREL® (bupivacaine liposome injectable suspension), a long-acting local analgesic for post-surgical pain management and ZILRETTA® (triamcinolone acetonide extended-release injectable suspension), an extended-release, intra-articular injection indicated for the management of osteoarthritis knee pain. Pacira is also advancing a pipeline of clinical-stage assets for musculoskeletal pain and adjacencies. Its most advanced product candidate, PCRX-201 (enekinragene inzadenovec), a novel locally administered gene therapy, is in Phase 2 clinical development for osteoarthritis of the knee. To learn more about Pacira, visit www.pacira.com.

About EXPAREL® (bupivacaine liposome injectable suspension) EXPAREL is indicated to produce postsurgical local analgesia via infiltration in patients aged 6 years and older, and postsurgical regional analgesia via an interscalene brachial plexus block in adults, a sciatic nerve block in the popliteal fossa in adults, and an adductor canal block in adults. The safety and effectiveness of EXPAREL have not been established to produce postsurgical regional analgesia via other nerve blocks besides an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. The product combines bupivacaine with multivesicular liposomes, a proven product delivery technology that delivers medication over a desired time period. EXPAREL represents the first and only multivesicular liposome local anesthetic that can be utilized in the peri- or postsurgical setting. By utilizing the multivesicular liposome platform, a single dose of EXPAREL delivers bupivacaine over time, providing significant reductions in cumulative pain scores with up to a 78 percent decrease in opioid consumption; the clinical benefit of the opioid reduction was not demonstrated. Additional information is available at www.EXPAREL.com.

Important Safety Information about EXPAREL for Patients EXPAREL should not be used in obstetrical paracervical block anesthesia. In studies in adults where EXPAREL was injected into a wound, the most common side effects were nausea, constipation, and vomiting. In studies in adults where EXPAREL was injected near a nerve, the most common side effects were nausea, fever, and constipation. In the study where EXPAREL was given to children, the most common side effects were nausea, vomiting, constipation, low blood pressure, low number of red blood cells, muscle twitching, blurred vision, itching, and rapid heartbeat. EXPAREL can cause a temporary loss of feeling and/or loss of muscle movement. How much and how long the loss of feeling and/or muscle movement depends on where and how much of EXPAREL was injected and may last for up to 5 days. EXPAREL is not recommended to be used in patients younger than 6 years old for injection into the wound, for patients younger than 18 years old, for injection near a nerve, and/or in pregnant women. Tell your health care provider if you or your child has liver disease, since this may affect how the active ingredient (bupivacaine) in EXPAREL is eliminated from the body. EXPAREL should not be injected into the spine, joints, or veins. The active ingredient in EXPAREL can affect the nervous system and the cardiovascular system; may cause an allergic reaction; may cause damage if injected into the joints; and can cause a rare blood disorder.

About ZILRETTA® (triamcinolone acetonide extended-release injectable suspension) On October 6, 2017, ZILRETTA was approved by the U.S. Food and Drug Administration as the first and only extended-release intra-articular therapy for patients confronting osteoarthritis (OA)-related knee pain. ZILRETTA employs proprietary microsphere technology combining triamcinolone acetonide—a commonly administered, short-acting corticosteroid—with a poly lactic-co-glycolic acid (PLGA) matrix to provide extended pain relief. The pivotal Phase 3 trial on which the approval of ZILRETTA was based showed that ZILRETTA significantly reduced OA knee pain for 12 weeks, with some people experiencing pain relief through Week 16. Learn more at www.zilretta.com.

Indication and Select Important Safety Information for ZILRETTAIndication: ZILRETTA is indicated as an intra-articular injection for the management of OA pain of the knee. Limitation of Use: The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated.Contraindication: ZILRETTA is contraindicated in patients who are hypersensitive to triamcinolone acetonide, corticosteroids or any components of the product.Warnings and Precautions:

  • Intra-articular Use Only: ZILRETTA has not been evaluated and should not be administered by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. ZILRETTA should not be considered safe for epidural or intrathecal administration.
  • Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration: Serious neurologic events have been reported following epidural or intrathecal corticosteroid administration. Corticosteroids are not approved for this use.
  • Hypersensitivity reactions: Serious reactions have been reported with triamcinolone acetonide injection. Institute appropriate care if an anaphylactic reaction occurs.
  • Joint infection and damage: A marked increase in joint pain, joint swelling, restricted motion, fever and malaise may suggest septic arthritis. If this occurs, conduct appropriate evaluation and if confirmed, institute appropriate antimicrobial treatment.

Adverse Reactions: The most commonly reported adverse reactions (incidence ≥1%) in clinical studies included sinusitis, cough, and contusions.

Please see ZILRETTALabel.com for full Prescribing Information.

Forward-Looking Statements This communication contains "forward-looking statements" within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. These statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may include, without limitation, statements about the transaction (in which, among other things, Viatris, through its wholly-owned subsidiary, will commence a tender offer to acquire all of the outstanding shares of common stock, $0.001 par value per share, of Pacira and, following the consummation of such tender offer, for such wholly-owned subsidiary of Viatris to be merged with and into Pacira), the expected timetable for completing the proposed transaction, the anticipated benefits and synergies of the proposed transaction, the ability to complete the transaction or to satisfy the various closing conditions, future opportunities for Viatris or Pacira and either of their products and any other statements regarding Viatris' or Pacira's future operations, strategic initiatives and priorities, restructuring activities, financial or operating results, capital allocation, dividend policy and payments, share repurchases, debt ratio and covenants, anticipated business levels, future earnings, planned activities, anticipated growth, market opportunities, strategies, imperatives, competitions, commitments, confidence in future results, efforts to create, enhance or otherwise unlock value, other expectations, plans, trends, outlooks, projections, prospects and targets for future periods, and any other statements that are not historical facts. Forward-looking statements may often be identified by the use of words such as "will", "may", "can", "could", "should", "would", "project", "believe", "anticipate", "expect", "plan", "estimate", "forecast", "potential", "pipeline", "intend", "continue", "target", "seek" and variations of these words or comparable words.

Because forward-looking statements inherently involve known and unknown risks and uncertainties, actual future results, levels of activity, performance or achievements may differ materially from those expressed or implied by such forward-looking statements, and there can be no assurance that estimates, assumptions and expectations will prove to have been correct. Factors that could cause or contribute to such differences include, but are not limited to: the ability of Viatris and Pacira to meet expectations regarding the timing, completion and accounting and tax treatments of the proposed transaction; the ability of Viatris and Pacira to consummate the proposed transaction; the conditions to the completion of the proposed transaction (including, but not limited to, that the stockholders of Pacira validly tender and not withdraw, in the aggregate, at least a majority of the shares of Pacira's common stock outstanding as of immediately following the expiration of the tender offer) not being satisfied or waived on the anticipated timeframe or at all; the regulatory approvals required for the proposed transaction not being obtained on the terms expected or on the anticipated schedule or at all; the possibility that competing offers may be made; the possibility that Viatris may be unable to achieve the intended or expected benefits, synergies and operating efficiencies in connection with the proposed transaction within the expected timeframe or at all or to successfully integrate Viatris and Pacira; Viatris' or Pacira's failure to achieve expected or targeted future financial and operating performance and results; the possibility that Viatris or Pacira may not realize the intended benefits of, or achieve the intended goals or outlooks with respect to, its strategic initiatives and priorities; actions and decisions of healthcare and pharmaceutical regulators; changes in relevant laws, regulations and policies and/or the application or implementation thereof, including but not limited to tax, healthcare and pharmaceutical laws, regulations and policies globally; the ability to attract, motivate and retain key personnel; Viatris' or Pacira's liquidity, capital resources and ability to successfully complete capital projections and obtain financing; Viatris' or Pacira's plans with respect to the repayment of indebtedness; any regulatory, legal or other impediments to Viatris' or Pacira's ability to bring new products to market; success of clinical trials and Viatris' or Pacira's (or, with respect to each, its partners') ability to execute on new product opportunities and develop, manufacture and commercialize products; any changes in or difficulties with Viatris' or Pacira's manufacturing facilities, including with respect to short- or long-term shutdowns, inspections, remediation and restructuring activities, product labeling or regulatory compliance, supply chain continuity, inventory management, or the ability to meet anticipated demand; the scope, timing and outcome of any ongoing legal proceedings, including government inquiries or investigations, and the impact of any such proceedings on Viatris or Pacira; any significant breach of data security or data privacy or disruptions to Viatris' or Pacira's information technology systems; risks associated with having significant operations globally; the strength and ability to protect Viatris' or Pacira's intellectual property and patent terms and preserve their respective intellectual property rights; changes in third-party relationships; the effect of any changes in Viatris' or Pacira's (or, with respect to each, its partners') customer and supplier relationships and customer purchasing patterns, including customer loss and business disruption being greater than expected following the proposed transaction; the impacts of competition, including decreases in sales or revenues as a result of the loss of market exclusivity for certain products; changes in the economic and financial conditions of Viatris or Pacira (or, with respect to each, its partners); uncertainties regarding future demand, pricing and reimbursement for Viatris' or Pacira's products; uncertainties and matters beyond the control of management, including but not limited to general political and economic conditions, wars or other conflicts, potential for adverse impacts from future tariffs and trade restrictions, inflation rates, interest rates and global exchange rates; and inherent uncertainties involved in the estimates and judgments used in the preparation of financial statements, and the providing of estimates of financial measures, in accordance with U.S. GAAP and related standards or on an adjusted basis.

For more detailed information on the risks and uncertainties associated with Viatris and Pacira, see the risks described in Part I, Item 1A of their respective Annual Reports on Form 10-K for the year ended December 31, 2025, and their other filings with the U.S. Securities and Exchange Commission (the "SEC"). You can access their respective filings with the SEC through the SEC website at www.sec.gov or through their respective websites, and each of Viatris and Pacira strongly encourages you to do so. Viatris routinely posts information that may be important to investors on our website at investor.viatris.com, and we use this website address as a means of disclosing material information to the public in a broad, non-exclusionary manner for purposes of the SEC's Regulation Fair Disclosure (Reg FD). The contents of our website are not incorporated into this communication or our filings with the SEC. Each of Viatris and Pacira undertakes no obligation to update any statements herein for revisions or changes after the date of this communication other than as required by law.

Non-GAAP Financial Measures This communication includes the presentation and discussion of certain financial information that differs from what is reported under accounting principles generally accepted in the United States ("U.S. GAAP"). These non-GAAP financial measures, including, but not limited to, adjusted EBITDA, adjusted earnings per share ("EPS"), free cash flow excluding transaction-related and restructuring-related costs, and gross leverage ratio, are presented in order to supplement investors' and other readers' understanding and assessment of the financial performance of Viatris and Pacira, as applicable.

Viatris Free cash flow refers to U.S. GAAP net cash provided by operating activities less capital expenditures. Free cash flow excluding transaction-related costs or restructuring-related costs refers to free cash flow further adjusted to exclude transaction-related costs and restructuring-related costs, as applicable. Adjusted EBITDA refers to U.S. GAAP net earnings (loss) adjusted for income tax provision (benefit), interest expense and depreciation and amortization (to calculate EBITDA), and further adjusted for share-based compensation expense, litigation settlements and other contingencies, net, loss on divestitures of businesses, impairment of goodwill and restructuring, acquisition and divestiture-related and other special items. Adjusted EPS refers to adjusted net earnings (loss) divided by the weighted average number of diluted shares of common stock outstanding. Adjusted net earnings (loss) refers to U.S. GAAP net (loss) earnings adjusted for purchase accounting amortization; impairment of goodwill; litigation settlements and other contingencies, net; interest expense; loss on divestitures of businesses; acquisition and divestiture-related costs; restructuring costs; share-based compensation expense; other special items included in cost of sales, research and development expense, selling, general and administrative expense, other (income) expense, net; and tax effect of the above items and other income tax related items. Gross leverage ratio refers to the ratio of notional gross debt to adjusted EBITDA. Notional gross debt is the sum of Viatris' long-term debt, including current portion, and short-term borrowings and other current obligations, adjusted for net premiums on various debt issuances and deferred financing fees.

Viatris is not providing forward-looking financial guidance metrics for U.S. GAAP net earnings (loss), U.S. GAAP diluted EPS or U.S. GAAP net cash provided by operating activities because it is unable to predict with reasonable certainty the ultimate outcome of certain significant items, including integration, acquisition and divestiture-related expenses, restructuring expenses, asset impairments, litigation settlements, future share repurchases, and other contingencies, such as changes to contingent consideration, acquired in-process research and development ("IPR&D") and certain other gains or losses as well as related income tax accounting, because certain of these items have not occurred, are out of Viatris' control and/or cannot be reasonably predicted without unreasonable effort. These items are uncertain, depend on various factors, and could have a material impact on U.S. GAAP reported results for a guidance period. Investors and other readers should consider non-GAAP measures only as supplements to, not as substitutes for or as superior measures to, the measures of financial performance prepared in accordance with U.S. GAAP.

Pacira BioSciences This press release contains a Pacira financial measure that does not comply with U.S. GAAP, adjusted EBITDA (earnings before interest, taxes, depreciation and amortization), because this non-GAAP financial measure excludes the impact of items that Pacira's management believes affect comparability or underlying business trends.

This measure supplements Pacira's financial results prepared in accordance with U.S. GAAP. Pacira management uses this measure to better analyze its financial results and to help make managerial decisions. In Pacira's management's opinion, this non-GAAP measure is useful to investors and other users of Pacira's financial statements by providing greater transparency into the ongoing operating performance of Pacira and its future outlook. Such a measure should not be deemed to be an alternative to U.S. GAAP requirements or a measure of liquidity for Pacira. The non-GAAP measure presented here is also unlikely to be comparable with non-GAAP disclosures released by other companies.

The Pacira financial measures included herein are consistent with such measures as reported in Pacira's earnings releases as furnished to the SEC. A reconciliation of Pacira's adjusted EBITDA, a non-GAAP financial measure, to the most directly comparable U.S. GAAP financial measure, U.S. GAAP net income (loss), is set forth below.

PACIRA BIOSCIENCES, INC

RECONCILIATION OF U.S. GAAP NET INCOME TO ADJUSTED EBITDA

Three Months Ended

Twelve MonthsEnded

(in Millions)(Unaudited)

September30, 2025

December31, 2025

March 31, 2026

June 30,2026

June 30,2026

GAAP Net Income

$

5.4

$

1.6

$

2.9

$

4.7

$

14.6

Interest Income

(8.5)

(2.3)

(1.9)

(1.9)

(14.7)

Interest Expense

4.3

3.9

3.7

3.6

15.5

Income Tax Expense

4.1

(1.1)

2.1

(2.1)

3.0

Depreciation Expense

6.9

7.0

7.0

7.0

27.9

Amortization of Acquired Intangible Assets

14.3

14.3

14.3

14.3

57.3

EBITDA

26.5

23.5

28.1

25.5

103.6

Other Adjustments:

Divestiture and Acquisition-Related Expenses, and Other

7.3

1.4

0.9

6.5

16.1

    Changes in the Fair Value of Contingent Consideration

0.6

0.2

(2.3)

1.7

0.2

Stock-Based Compensation

14.0

13.5

13.5

15.0

56.0

Loss on Early Extinguishment of Debt

1.0

-

-

-

1.0

Adjusted EBITDA

$

49.4

$

38.7

$

40.2

$

48.7

$

177.0

Certain Key Terms and Presentation Matters Financial guidance metrics: Refers to Viatris total revenues, adjusted EBITDA, free cash flow excluding transaction-related and restructuring-related costs and adjusted EPS. Financial guidance metrics exclude any acquired IPR&D for unsigned deals to be incurred in any future period as it cannot be reasonably forecasted.

Transaction-related costs: Refers to the impact of any acquisition- and divestiture-related transaction costs, including taxes.

Restructuring-related costs: Refers to the impact of any cash costs associated with the restructuring activities of the enterprise-wide strategic review, which are expected to be primarily related to severance and employee benefits expense, as well as other costs, including those related to contract terminations, vendor consolidations, product transfer costs and network-related simplification and modernization costs.

Important Information about the Transaction and Where to Find It The tender offer for the outstanding shares of Pacira's common stock described in this communication has not yet commenced. This document is for informational purposes only and it is neither a recommendation, nor an offer to purchase nor a solicitation of an offer to sell shares of Pacira's common stock, nor is it a substitute for the tender offer materials that Viatris will file with the SEC on Schedule TO.  At the time any such tender offer is commenced, Viatris will prepare and file a Tender Offer Statement, containing an offer to purchase, a form of letter of transmittal and other related tender offer documents, with the SEC, and Pacira will file a Solicitation/Recommendation Statement on Schedule 14D-9 relating to such tender offer with the SEC.  The offer to purchase shares will only be made pursuant to the offer to purchase, the letter of transmittal and other related tender offer documents filed as a part of the Schedule TO. Pacira's stockholders are strongly advised to read these tender offer materials carefully and in their entirety when they become available, as they may be amended or supplemented from time to time, because they will contain important information about such tender offer that Pacira's stockholders should consider prior to making any decisions with respect to such tender offer, including the terms and conditions of the tender offer.  The offer to purchase, letter of transmittal and other related tender offer documents, as well as the Solicitation/Recommendation Statement on Schedule 14D-9, will be sent to all stockholders of Pacira at no expense to them.  Once filed, stockholders of Pacira will be able to obtain a free copy of these documents and each of Viatris' and Pacira's other documents filed with the SEC at the website maintained by the SEC at www.sec.gov. In addition, a copy of the offer to purchase, form of letter of transmittal and other related tender offer documents (once they become available) may be obtained free of charge by directing a request to Viatris at InvestorRelations@viatris.com.  A copy of the Solicitation/Recommendation Statement on Schedule 14D-9 (once it becomes available) also may be obtained free of charge by directing a request to Pacira at secretary@Pacira.com.

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SOURCE Viatris Inc.

Attached document

Contents
  1. HIGHLIGHTS OF PRESCRIBING INFORMATION · page 1
  2. ZILRETTA ® (triamcinolone acetonide extended-release injectable · page 1
  3. __________________INDICATIONS AND USAGE _________________ · page 1
  4. _______________DOSAGE AND ADMINISTRATION ______________ · page 1
  5. ___________________ CONTRAINDICATIONS ___________________ · page 1
  6. ______________ DOSAGE FORMS AND STRENGTHS _____________ · page 1
  7. _______________WARNINGS AND PRECAUTIONS _______________ · page 1
  8. ___________________ ADVERSE REACTIONS ___________________ · page 1
  9. To report SUSPECTED ADVERSE REACTIONS, contact Pacira · page 1
  10. See 17 for PATIENT COUNSELING INFORMATION. · page 1
  11. FULL PRESCRIBING INFORMATION: CONTENTS* · page 1
  12. 1 INDICATIONS AND USAGE · page 1
  13. 4 CONTRAINDICATIONS · page 1
  14. 7 DRUG INTERACTIONS · page 1
  15. 11 DESCRIPTION · page 1
  16. FULL PRESCRIBING INFORMATION · page 2
  17. 1 INDICATIONS AND USAGE · page 2
  18. Limitation of Use · page 2
  19. 2 DOSAGE AND ADMINISTRATION · page 2
  20. 2.1 Important Dosage and Administration Information · page 2
  21. 2.2 Preparation and Administration of Intra-Articular Suspension · page 2
  22. 2.3 Non-Interchangeability with Other Formulations of Triamcinolone Acetonide for Intra-articular Use · page 3
  23. 3 DOSAGE FORMS AND STRENGTHS · page 3
  24. 4 CONTRAINDICATIONS · page 3
  25. 5 WARNINGS AND PRECAUTIONS · page 3
  26. 5.1 Warnings and Precautions Specific for ZILRETTA · page 3
  27. 5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration · page 3
  28. 5.3 Hypersensitivity Reactions · page 4
  29. 5.4 Joint Infection and Damage · page 4
  30. 5.5 Increased Risk of Infections · page 4
  31. 5.6 Alterations in Endocrine Function · page 4
  32. 5.7 Cardiovascular Effects · page 5
  33. 5.8 Renal Effects · page 5
  34. 5.9 Increased Intraocular Pressure · page 5
  35. 5.10 Gastrointestinal Perforation · page 5
  36. 5.11 Alterations in Bone Density · page 5
  37. 5.12 Behavioral and Mood Disturbances · page 5
  38. 6 ADVERSE REACTIONS · page 5
  39. 6.1 Clinical Trials · page 6
  40. 6.2 Post-marketing Experience · page 7
  41. 6.3 Corticosteroid Adverse Reactions · page 7
  42. 7 DRUG INTERACTIONS · page 8
  43. 8 USE IN SPECIFIC POPULATIONS · page 10
  44. 8.1 Pregnancy · page 10
  45. Risk Summary · page 10
  46. Data · page 10
  47. Animal Data · page 10
  48. 8.2 Lactation · page 11
  49. Risk Summary · page 11
  50. 8.3 Females and Males of Reproductive Potential · page 11
  51. 8.4 Pediatric Use · page 11
  52. 8.5 Geriatric Use · page 11
  53. 11 DESCRIPTION · page 11
  54. Active Ingredient · page 12
  55. 12 CLINICAL PHARMACOLOGY · page 12
  56. 12.1 Mechanism of Action · page 12
  57. 12.2 Pharmacodynamics · page 12
  58. 12.3 Pharmacokinetics · page 13
  59. 13 NONCLINICAL TOXICOLOGY · page 13
  60. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility · page 13
  61. Carcinogenesis · page 13
  62. Impairment of Fertility · page 13
  63. 13.2 Animal Toxicology and/or Pharmacology · page 14
  64. 14 CLINICAL STUDIES · page 14
  65. STORAGE · page 15
  66. 17 PATIENT COUNSELING INFORMATION · page 16
  67. Increased Risk of Infections · page 16
  68. Risk of Drug Interactions · page 16
  69. Risk of Adverse Psychiatric Reactions · page 16

Page 1

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZILRETTA safely and effectively. See full prescribing information for ZILRETTA.

ZILRETTA® (triamcinolone acetonide extended-release injectable suspension), for intra-articular use Initial U.S. Approval: 1957

ZILRETTA ® (triamcinolone acetonide extended-release injectable

__________________INDICATIONS AND USAGE _________________

ZILRETTA is an extended-release synthetic corticosteroid indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. (1)

Limitation of Use

The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated. (2.1)

_______________DOSAGE AND ADMINISTRATION ______________

• 32 mg (5 mL) administered as a single intra-articular injection in the knee. (2.1)

• See Instructions for Use (IFU) for instructions on reconstitution of ZILRETTA with the supplied diluent. (2.2)

• It is normal for some residue to be left behind on the vial walls after withdrawing the suspension. (2.2)

• ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide. (2.3)

___________________ CONTRAINDICATIONS ___________________

______________ DOSAGE FORMS AND STRENGTHS _____________

ZILRETTA is an injectable suspension that delivers 32 mg of triamcinolone acetonide. It is supplied as a single-dose kit containing one vial of ZILRETTA microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter. (3)

Patients with hypersensitivity to triamcinolone acetonide or any component of the product. (4)

_______________WARNINGS AND PRECAUTIONS _______________

• Intra-articular Use Only: Do not administer ZILRETTA by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. (5.1)

• Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration: Serious neurologic events have been reported following epidural or intrathecal corticosteroid administration. Corticosteroids are not approved for this use. (5.2)

• Hypersensitivity Reactions: Serious reactions have been reported with triamcinolone acetonide injection. Institute appropriate care upon occurrence of an anaphylactic reaction. (5.3)

• Joint Infection and Damage: May cause joint pain accompanied by joint swelling. If this occurs, conduct appropriate evaluation to exclude septic arthritis and institute appropriate antimicrobial therapy if septic arthritis is confirmed. (5.4)

___________________ ADVERSE REACTIONS ___________________

Most commonly reported adverse reactions (incidence ≥1%) in clinical studies include sinusitis, cough, and contusions. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Pacira

Pharmaceuticals, Inc. at 1-844-353-9466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2024

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

2.2 Preparation and Administration of Intra-Articular Suspension

2.3 Non-Interchangeability with Other Formulations of Triamcinolone Acetonide for Intra-articular Use

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Warnings and Precautions Specific for ZILRETTA

5.2 Serious Neurologic Adverse Reactions with Epidural and

Intrathecal Administration

5.3 Hypersensitivity Reactions

5.4 Joint Infection and Damage

5.5 Increased Risk of Infections

5.6 Alterations in Endocrine Function

5.7 Cardiovascular Effects

5.8 Renal Effects

5.9 Increased Intraocular Pressure

5.10 Gastrointestinal Perforation

5.11 Alterations in Bone Density

5.12 Behavioral and Mood Disturbances ADVERSE REACTIONS

6.1 Clinical Trials

6.2 Post-marketing Experience

6.3 Corticosteroid Adverse Reactions

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ZILRETTA (triamcinolone acetonide extended-release injectable suspension) is indicated as an intraarticular injection for the management of osteoarthritis pain of the knee.

Limitation of Use

The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated. [see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

• ZILRETTA is administered as a single intra-articular extended-release injection of triamcinolone acetonide, to deliver 32 mg (5 mL).

• ZILRETTA is for intra-articular use only. Do NOT administer by the following routes: epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, subcutaneous.

• ZILRETTA is not suitable for use in small joints, such as the hand.

• The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated [see Adverse Reactions (6) and Nonclinical Toxicology (13.2)].

• The efficacy and safety of ZILRETTA for management of osteoarthritis pain of shoulder and hip have not been evaluated.

2.2 Preparation and Administration of Intra-Articular Suspension

Refer to the Instructions for Use for directions on the preparation and administration of ZILRETTA.

ZILRETTA is supplied as a single-dose kit containing a vial of ZILRETTA microsphere powder, a vial of sterile diluent, and a sterile vial adapter.

ZILRETTA must be prepared using the diluent supplied in the kit.

Preparation of ZILRETTA requires close attention to the Instructions for Use to ensure successful administration.

Use proper aseptic technique throughout the dose preparation and administration procedure.

ZILRETTA is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.

Promptly inject ZILRETTA after preparation to avoid settling of the suspension. If needed, the ZILRETTA suspension can be stored in the vial for up to 4 hours at ambient conditions. Gently swirl the vial to resuspend any of the settled microspheres prior to preparing the syringe for injection.

The usual technique for intra-articular injection should be followed. Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of ZILRETTA.

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2.3 Non-Interchangeability with Other Formulations of Triamcinolone Acetonide for Intra-articular Use

ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide.

3 DOSAGE FORMS AND STRENGTHS

ZILRETTA is an injectable suspension that delivers 32 mg of triamcinolone acetonide. ZILRETTA is supplied as a single-dose kit, containing:

• One vial of ZILRETTA white to off-white microsphere powder

• One vial of 5 mL sterile, colorless to pale yellow, clear diluent

• One sterile vial adapter

4 CONTRAINDICATIONS

ZILRETTA is contraindicated in patients who are hypersensitive to triamcinolone acetonide, corticosteroids or any components of the product [see Warnings and Precautions (5.3) and How Supplied/Storage and Handling (16)].

5 WARNINGS AND PRECAUTIONS

5.1 Warnings and Precautions Specific for ZILRETTA

ZILRETTA has not been evaluated and should not be administered by the following routes:

• Epidural

• Intrathecal

• Intravenous

• Intraocular

• Intramuscular

• Intradermal

• Subcutaneous

[see Warnings and Precautions (5.2)].

5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration

Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke [see Adverse Reactions (6)]. These serious neurologic events have been reported with and without use of fluoroscopy.

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Reports of serious medical events have been associated with the intrathecal route of corticosteroid administration [see Adverse Reactions (6)].

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The safety and effectiveness of epidural and intrathecal administration of corticosteroids have not been established, and corticosteroids are not approved for this use. In particular, the formulation of ZILRETTA should not be considered safe to use for epidural or intrathecal administration.

5.3 Hypersensitivity Reactions

Rare instances of anaphylaxis have occurred in patients with hypersensitivity to corticosteroids. Cases of serious anaphylaxis, including death, have been reported in individuals receiving triamcinolone acetonide injection, regardless of the route of administration [see Adverse Reactions (6)]. Institute appropriate care upon occurrence of an anaphylactic reaction.

5.4 Joint Infection and Damage

Intra-articular injection of corticosteroid may be complicated by joint infection. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and a diagnosis of septic arthritis is confirmed, institute appropriate antimicrobial therapy [see Adverse Reactions (6)].

Avoid injection of a corticosteroid into an infected site. Local injection of a corticosteroid into a previously infected joint is not usually recommended. Examine any joint fluid present to exclude a septic process.

Corticosteroid injection into unstable joints is generally not recommended.

Intra-articular injection may result in damage to joint tissues.

5.5 Increased Risk of Infections

Intra-articularly injected corticosteroids are systemically absorbed. Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Advise patients to inform their health care provider if they develop fever or other signs or symptoms of infection. Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed [see Patient Counseling Information (17)].

5.6 Alterations in Endocrine Function

Corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with the potential for adrenal insufficiency after withdrawal of treatment, which may persist for months.

In situations of stress during that period (as in trauma, surgery, or illness), institute corticosteroid replacement therapy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients.

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5.7 Cardiovascular Effects

Corticosteroids can cause elevations of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives.

Monitor patients with congestive heart failure or hypertension for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.8 Renal Effects

Corticosteroids can cause salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives. All corticosteroids increase calcium excretion.

Monitor patients with renal insufficiency for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.9 Increased Intraocular Pressure

Corticosteroid use may be associated with development or exacerbation of increased intraocular pressure. Monitor patients with elevated intraocular pressure for potential treatment adjustment.

5.10 Gastrointestinal Perforation

Corticosteroid administration is associated with increased risk of gastrointestinal perforation in patients with certain GI disorders such as active or latent peptic ulcers, diverticulosis, diverticulitis, ulcerative colitis and in patients with fresh intestinal anastomoses.

Avoid corticosteroids in these patients because signs of peritoneal irritation following gastrointestinal perforation may be minimal or absent.

5.11 Alterations in Bone Density

Corticosteroids decrease bone formation and increase bone resorption through their effect on calcium regulation and inhibition of osteoblast function.

Special consideration should be given to patients with or at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy.

5.12 Behavioral and Mood Disturbances

Corticosteroid use may be associated with new or aggravated adverse psychiatric reactions ranging from euphoria, insomnia, mood swings, and personality changes to severe depression and frank psychotic manifestations.

Special consideration should be given to patients with previous or current emotional instability or psychiatric illness before initiating corticosteroid therapy. Advise patients and/or caregivers to immediately report any new or worsening behavior or mood disturbances to their health care provider.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling.

• Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration [see Warnings and Precautions (5.2)]

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• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]

• Joint Infection and Damage [see Warnings and Precautions (5.4)]

• Increased Risk of Infections [see Warnings and Precautions (5.5)]

• Alterations in Endocrine Function [see Warnings and Precautions (5.6)]

• Cardiovascular Effects [see Warnings and Precautions (5.7)]

• Renal Effects [see Warnings and Precautions (5.8)]

• Increased Intraocular Pressure [see Warnings and Precautions (5.9)]

• Gastrointestinal Perforation [see Warnings and Precautions (5.10)]

• Alternations in Bone Density [see Warnings and Precautions (5.11)]

• Behavioral and Mood Disturbances [see Warnings and Precautions (5.12)]

6.1 Clinical Trials

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to a single 32 mg intra-articular injection of ZILRETTA in clinical studies in patients with moderate to severe pain due to osteoarthritis of the knee. Clinical studies included randomized, double-blind, parallel-group, placebo and/or active-controlled, and

pharmacokinetic/pharmacodynamic studies with follow-up ranging from 6-24 weeks. A total of 424 patients received ZILRETTA and 262 received placebo. Treatment emergent adverse reactions reported by greater than or equal to 1% of patients in the ZILRETTA arms are summarized below (Table 1 and 2).

Overall, the incidence and nature of adverse reactions was similar to that observed with placebo.

Table 1: Most Commonly Reported Treatment-Emergent Adverse Reactions with ZILRETTA (Incidence ≥1%) in Patients with Osteoarthritis of the Knee

Preferred Term (MedDRA)ZILRETTA (N=424)Placebo (N=262)
Sinusitis2%1%
Cough2%1%
Contusions2%1%

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Table 2: Most Commonly Reported Treatment-Emergent Injected Knee Adverse Reactions with ZILRETTA (Incidence ≥1%) in Patients with Osteoarthritis of the Knee

Preferred Term (MedDRA)ZILRETTA (N=424)Placebo (N=262)
Joint Swelling3%2%
Contusions2%1%

The safety of repeat administration of ZILRETTA was evaluated in a multicenter, open-label, single-arm study in patients with osteoarthritis pain of the knee. A total of 179 patients received a repeat injection on or after Week 12 (median 16.6 weeks) and were followed for 52 weeks from the initial injection. As assessed by adverse event rates for the periods of baseline to second dose and second dose to the comparable period after the second dose, there were higher rates of reported mild to moderate arthralgia after the second dose (16%) than after the first dose (6%). The data from this study are insufficient to fully characterize the safety of repeat administration of ZILRETTA. [See also Nonclinical Toxicology (13.2)].

6.2 Post-marketing Experience

The following adverse reactions, presented alphabetically by body system, have been identified during post-approval use of ZILRETTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Endocrine: Increased blood glucose (in diabetic patients).

General and administration site conditions: Pain including injection site pain or discomfort and leg pain.

Immune system: Hypersensitivity reactions including pruritus, rash, angioedema, and anaphylaxis [see Contraindications (4), Warnings and Precautions (5.3)].

Infections and Infestations: Septic arthritis [see Warning and Precautions (5.4)].

Musculoskeletal: Arthralgia, joint swelling or effusion, muscle spasms.

Nervous system: Headache.

Reproductive system: Postmenopausal vaginal bleeding (similar to a menstrual period).

Skin and Subcutaneous Tissue: Pruritus.

6.3 Corticosteroid Adverse Reactions

The following adverse reactions, presented alphabetically by body system, are from voluntary reports or clinical studies of corticosteroids. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Anaphylactic reactions: Anaphylaxis including death, angioedema [see Warnings and Precautions (5.3)].

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, hypertension [see Warnings and Precautions (5.7)], fat embolism,

Page 8

hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of Cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients [see Warnings and Precautions (5.7)], fluid retention, sodium retention.

Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration) [see Warnings and Precautions (5.2)], elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease) [see Warnings and Precautions (5.10)], ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders [see Warnings and Precautions (5.12)], vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids [see Warnings and Precautions (5.2)].

Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)], posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

7 DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with ZILRETTA. Table 3 contains drug interactions associated with systemic corticosteroids.

Page 9

Table 3: Drug Interactions Associated with Systemic Corticosteroids

AminoglutethimideAminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.
Amphotericin B injection and potassium-depleting agentsWhen corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), observe patients closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.
AntibioticsMacrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.
AnticholinesterasesConcomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, withdraw anticholinesterase agents at least 24 hours before initiating corticosteroid therapy.
Anticoagulants, oralCoadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, monitor coagulation indices frequently to maintain the desired anticoagulant effect.
AntidiabeticsBecause corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.
Antitubercular drugsSerum concentrations of isoniazid may be decreased.
CYP 3A4 inducers (e.g., barbiturates, phenytoin, carbamazepine, and rifampin)Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of corticosteroids and require that the dosage of corticosteroid be increased.
CYP 3A4 inhibitors (e.g., ketoconazole)Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects.
CholestyramineCholestyramine may increase the clearance of corticosteroids.
CyclosporineIncreased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.
Digitalis glycosidesPatients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.
Estrogens, including oral contraceptivesEstrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs)Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.
Skin testsCorticosteroids may suppress reactions to allergy related skin tests.

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VaccinesPatients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. If possible, defer routine administration of vaccines or toxoids until corticosteroid therapy is discontinued.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data regarding the use of ZILRETTA in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published studies on the association between corticosteroids and fetal outcomes have reported inconsistent findings and have important methodological limitations. The majority of published literature with corticosteroid exposure during pregnancy includes the oral, topical and inhaled dosage formulations; therefore, the applicability of these findings to a single intra-articular injection of triamcinolone acetonide is limited. In animal reproductive studies from the published literature, pregnant mice, rats, rabbits, or primates administered triamcinolone acetonide during the period of organogenesis at doses that produced exposures less than the maximum recommended human dose (MRHD) caused resorptions, decreased fetal body weight, craniofacial and/or other abnormalities such as omphalocele (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

The exposure margins listed below are based on body surface area comparisons (mg/m2) to the highest daily triamcinolone acetonide exposure at the MRHD of 32 mg triamcinolone acetonide via ZILRETTA.

Pregnant mice dosed with triamcinolone acetonide via intramuscular or subcutaneous injection at doses equivalent to 0.8 times the MRHD or higher during organogenesis caused cleft palate and a higher rate of resorption. In pregnant rats dosed with triamcinolone acetonide via intramuscular or subcutaneous injection at doses equivalent to 0.3 times the MRHD or higher during organogenesis caused developmental abnormality (cleft palate, omphalocele, late resorption, and growth retardation) and fetal mortality. No notable maternal toxicity was observed in rodents.

Pregnant rabbits dosed with triamcinolone acetonide via intramuscular injection for 4 days during organogenesis at doses equivalent to 0.15 times the MRHD or higher caused resorption and cleft palate. No notable maternal toxicity was observed.

Pregnant primates dosed with triamcinolone acetonide via intramuscular injection for 4 days during organogenesis at doses equivalent to 3 times the MRHD or higher caused severe craniofacial CNS and skeletal/visceral malformation and higher prenatal death. No notable maternal toxicity was observed.

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No peri- and post-natal development studies of triamcinolone acetonide in animals have been conducted.

8.2 Lactation

Risk Summary

There are no available data on the presence of triamcinolone acetonide in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, corticosteroids have been detected in human milk and may suppress milk production. It is not known whether intra-articular administration of ZILRETTA could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZILRETTA and any potential adverse effects on the breastfed infant from ZILRETTA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Corticosteroids may result in menstrual pattern irregularities such as deviations in timing and duration of menses and an increased or decreased loss of blood.

8.4 Pediatric Use

The safety and effectiveness of ZILRETTA in pediatric patients have not been established.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults. Carefully observe pediatric patients, including weight, height, linear growth, blood pressure, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Weigh potential growth effects of treatment against clinical benefits obtained and the availability of treatment alternatives.

8.5 Geriatric Use

Of the total number of patients administered 32 mg ZILRETTA in clinical studies (N=424), 143 patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between elderly and younger subjects, and other reported clinical experience with triamcinolone acetonide has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

ZILRETTA (triamcinolone acetonide extended-release injectable suspension) is a microsphere formulation of triamcinolone acetonide, a corticosteroid, to be administered by intra-articular injection.

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