Limitation of Use

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

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 and should not be administered 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.

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

ZILRETTA is not interchangeable with other formulations of injectable triamcinolone acetonide.

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.

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

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.

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.

6.1 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.

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 pruritis, 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: Pruritis.

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, 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.

8.1 Pregnancy

8.2 Lactation

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.

Active Ingredient

The chemical name for triamcinolone acetonide is 9-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene- 3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is:

MW 434.50 with a molecular formula of C 24H 31FO 6

Triamcinolone acetonide occurs as a white to almost white, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. Each vial of ZILRETTA powder contains 40 mg of triamcinolone acetonide in 160 mg of microspheres, resulting in 32 mg of deliverable triamcinolone acetonide when prepared according to the Instructions for Use.

12.1 Mechanism of Action

Triamcinolone acetonide is a corticosteroid with anti-inflammatory and immunomodulating properties. It binds to and activates the glucocorticoid receptor, leading to activation of anti-inflammatory transcription factors such as lipocortins and inhibition of inflammatory transduction pathways by blocking the release of arachidonic acid and preventing the synthesis of prostaglandins and leukotrienes.

12.2 Pharmacodynamics

Studies indicate that following a single intramuscular dose of 60 to 100 mg of immediate-release triamcinolone acetonide injectable suspension, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. To assess potential effects of the systemic levels of triamcinolone acetonide associated with a single intra-articular (IA) administration of ZILRETTA on hypothalamic pituitary adrenal (HPA) axis function, serum and urine cortisol levels were monitored over 6 weeks post injection. Adrenal suppression with ZILRETTA occurred within 12-24 hours and then gradually returned to normal, within 30-42 days.

Corticosteroids may increase blood glucose concentrations.

In a study where 18 patients with osteoarthritis knee pain and controlled type 2 diabetes mellitus received a single IA injection of ZILRETTA into the knee, the change from baseline in average blood glucose over the 72 hours after injection as measured by a continuous glucose monitoring device was 8.2 mg/dL (95% confidence interval 0.1, 29.2).

12.3 Pharmacokinetics

ZILRETTA is an extended-release dosage form consisting of microspheres of poly(lactic-co-glycolic acid) (PLGA) containing triamcinolone acetonide. Plasma pharmacokinetic parameters for triamcinolone acetonide following IA administration of ZILRETTA or 40 mg immediate-release triamcinolone acetonide into the knee are provided in Table 4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Single and repeat administrations (one injection every three months for a total of three injections) of ZILRETTA in non-arthritic knee joints of healthy dogs have been studied at ~1.9 times the maximum recommended human dose (MRHD) of 32 mg (based on estimated drug concentrations within the knee joints). ZILRETTA microspheres were degraded by approximately 4-and 6-months post dosing in single and repeat dose studies, respectively.

Single administration resulted in a slightly increased incidence, severity (minimal to slight), and/or duration of microscopic changes (infiltration of macrophages, lymphocytes, plasma cells and fibrosis) and decreased Safranin O staining (decreased proteoglycan content in the cartilage of the knees) compared to administration of an equivalent dose of immediate-release triamcinolone acetonide. These responses were mostly reversed after 6 to 9 months post injection.

Repeat administration resulted in an increase in the incidence, severity (minimal to slight) and duration of microscopic changes (infiltration of macrophages, lymphocytes, plasma cells, neutrophils; fibrosis; neovascularization; granulation tissue; and debris) and decreased Safranin O staining (decreased proteoglycan content in the cartilage of the knees) compared to the equivalent dose of immediate-release triamcinolone acetonide. These local responses were still reversing at 6 months post the last injection. No effect on the animals according to observations related to gait/walking, pain/discomfort in the injected knee, local swelling, local redness or local tenderness were noted.

The clinical relevance of these findings in the arthritic knee is unknown.

STORAGE

To maintain expiry period, refrigerate the ZILRETTA single-dose kit (36°-46°F; 2°-8°C) before use.

If refrigeration is unavailable, store the ZILRETTA single-dose kit in the sealed, unopened kit at temperatures not exceeding 77°F (25°C) for up to six weeks and then discard. Do not expose the ZILRETTA single-dose kit to temperatures above 77°F (25°C).

Do not freeze. Store vials in carton.

Increased Risk of Infections

Inform patients that they may be more likely to develop infections when taking corticosteroids. Instruct patients to contact 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 Warnings and Precautions ( 5.5)] .

Risk of Drug Interactions

There are a number of medicines that can interact with corticosteroids such as triamcinolone acetonide. Advise patients to alert their health care provider(s) to assess the need to adjust their medication(s) [see Drug Interactions ( 7)] .

Risk of Adverse Psychiatric Reactions

Inform patients that corticosteroid use may be associated with adverse psychiatric reactions. Advise patients and/or caregivers to immediately report any new or worsening behavioral or mood disturbances to their health care provider [see Warnings and Precautions ( 5.12)] .

Manufactured for Flexion Therapeutics, Inc., 10 Mall Rd, Suite 301, Burlington, MA 01803

ZILRETTA and Flexion are registered trademarks of Flexion Therapeutics, Inc.
Copyright © 2020 Flexion Therapeutics, Inc. All rights reserved.

For more information, go to ZILRETTA.com or call 1-844-FLEXION (353-9466).

Part Number: 60-009-04
Version: 4, 01/2020