Zilretta

1 INDICATIONS AND USAGE ZILRETTA (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. ZILRETTA is an extended-release synthetic corticosteroid indicated as an intra-articular 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.

Limitation of Use The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated. .

2 DOSAGE AND ADMINISTRATION 32 mg (5 mL) administered as a single intra-articular injection in the knee. See Instructions for Use (IFU) for instructions on reconstitution of ZILRETTA with the supplied diluent. It is normal for some residue to be left behind on the vial walls after withdrawing the suspension. ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide.

2.1Important 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 . The efficacy and safety of ZILRETTA for management of osteoarthritis pain of shoulder and hip have not been evaluated.

2.2Preparation 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.

2.3Non-Interchangeability with Other Formulations of Triamcinolone Acetonide

for Intra-articular Use ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide.

Intra-articular Use Only : Do not administer ZILRETTA by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. 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 upon occurrence of an anaphylactic reaction. 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.

5.1Warnings 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 .

5.2Serious 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 . 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 . 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.

5.3Hypersensitivity 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 . Institute appropriate care upon occurrence of an anaphylactic reaction.

5.4Joint 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 . 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.

5.5Increased 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 .

5.6Alterations 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.

5.7Cardiovascular 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.

5.8Renal 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.

5.9Increased 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.

5.10Gastrointestinal 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.

5.11Alterations 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.

5.12Behavioral 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.

4 CONTRAINDICATIONS ZILRETTA is contraindicated in patients who are hypersensitive to triamcinolone acetonide, corticosteroids or any components of the product . Patients with hypersensitivity to triamcinolone acetonide or any component of the product.

8.1Pregnancy 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 . 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/m 2 ) 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.

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

The following serious adverse reactions are described elsewhere in the labeling. Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration Hypersensitivity Reactions Joint Infection and Damage Increased Risk of Infections Alterations in Endocrine Function Cardiovascular Effects Renal Effects Increased Intraocular Pressure Gastrointestinal Perforation Alternations in Bone Density Behavioral and Mood Disturbances Most commonly reported adverse reactions (incidence ≥1%) in clinical studies include sinusitis, cough, and contusions. 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 .

6.1Clinical 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) Sinusitis 2% 1% Cough 2% 1% Contusions 2% 1% 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 Swelling 3% 2% Contusions 2% 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. .

6.2Post-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 . Infections and Infestations : Septic arthritis . 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.

6.3Corticosteroid 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 . Cardiovascular : Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, hypertension , 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 , fluid retention, sodium retention.

Gastrointestinal : Abdominal distention, bowel/bladder dysfunction (after intrathecal administration) , 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) , 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 , 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 . Ophthalmic : Exophthalmos, glaucoma, increased intraocular pressure , 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.