ZILRETTA® (triamcinolone acetonide extended-release injectable suspension)
ZILRETTA is the first and only extended-release, intra-articular therapy for patients confronting osteoarthritis-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 over 12 weeks. ZILRETTA received approval from the U.S. Food and Drug Administration on October 6, 2017 and the company initiated the full commercial launch on November 20, 2017.
A clinical trial evaluating repeat administration of ZILRETTA completed enrollment in July 2017 and topline study results are expected in Q3 2018. Topline results from a clinical trial evaluating the pharmacokinetics (PK) and safety of concurrent injections of ZILRETTA in patients with bilateral OA of the knee are anticipated in Q2 2018. In December 2017, Flexion initiated a randomized, open-label Phase 2 clinical trial to evaluate the PK and safety of ZILRETTA in patients with OA of the shoulder or hip. Topline results from that trial, known as the “SHIP” study, are expected in H2 2018. In May 2018, Flexion initiated an open-label study assessing the effect of a single administration of ZILRETTA on synovitis in patients with OA of the knee. Topline results are anticipated in 2019.
Indication and Important Safety Information
Indication: ZILRETTA is indicated as an intra-articular injection for the management of osteoarthritis pain of the knee.
Limitation of Use: ZILRETTA is not intended for repeat administration.*
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. Serious events have been reported with epidural and intrathecal administration of corticosteroids and none are approved for this use. ZILRETTA should not be considered safe for epidural or intrathecal administration.
- Hypersensitivity Reactions: Rare instances of anaphylaxis, including serious cases, have occurred in patients with hypersensitivity to corticosteroids.
- Joint Infection and Damage: A marked increase in pain accompanied by local swelling, restriction of joint motion, fever, and malaise are suggestive of septic arthritis. Examine joint fluid to exclude a septic process. If diagnosis is confirmed, institute appropriate antimicrobial therapy. Avoid injecting corticosteroids into a previously infected or unstable joint. Intra-articular administration may result in damage to joint tissues.
- Increased Risk of Infections: Infection with any pathogen in any location of the body may be associated with corticosteroid use. Corticosteroids may increase the susceptibility to new infection and decrease resistance and the ability to localize infection.
- Alterations in Endocrine Function: Corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with potential for adrenal insufficiency after withdrawal of treatment, which may persist for months. In situations of stress during that period, institute corticosteroid replacement therapy.
- Cardiovascular and Renal Effects: Corticosteroids can cause blood pressure elevation, salt and water retention, and increased potassium excretion. Monitor patients with congestive heart failure, hypertension and renal insufficiency for edema, weight gain, and electrolyte imbalance. Dietary salt restriction and potassium supplementation may be needed.
- Increased Intraocular Pressure: Corticosteroid use may be associated with increased intraocular pressure. Monitor patients with elevated intraocular pressure for potential treatment adjustment.
- Gastrointestinal Perforation: Corticosteroid administration may increase risk of gastrointestinal perforation in patients with certain GI disorders and fresh intestinal anastomoses. Avoid corticosteroids in these patients.
- Alterations in Bone Density: Corticosteroids decrease bone formation and increase bone resorption. Special consideration should be given to patients with or at increased risk of osteoporosis prior to treatment.
- Behavior and Mood Disturbances: Corticosteroids may cause adverse psychiatric reactions. Prior to treatment, special consideration should be given to patients with previous or current emotional instability or psychiatric illness. Advise patients to immediately report any behavior or mood disturbances.
Adverse Reactions: The most commonly reported adverse reactions (incidence ≥1%) in clinical studies included sinusitis, cough and contusions.
Please see full Prescribing Information for ZILRETTA.
To report SUSPECTED ADVERSE REACTIONS, contact Flexion Therapeutics at 1-844-FLEXION or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
* The efficacy and safety of repeat administration of ZILRETTA have not been evaluated.
ZILRETTA is formulated as a suspension of microspheres measuring approximately 45 microns in diameter. Within each microsphere, small crystals of TA are embedded in a poly lactic-co-glycolic acid (PLGA) co-polymer matrix (Figure 1A).
In vitro, release of TA from the microsphere commences immediately, and scanning electron micrographs reveal the formation of nano-channels, approximately 500 nanometers in diameter, on the microsphere surface (Figure 1B). These nano-channels, limit both egress of TA from the microsphere’s interior and internal hydration of the polymer, prolonging drug release and slowing PLGA erosion. In the final stage of release, the PLGA matrix degrades to oligomeric poly-acid units and then to lactic and glycolic acids, followed by elimination as carbon dioxide and water.
Figure 1. ZILRETTA, an intra-articular, extended-release formulation of TA in a poly lactic-co-glycolic acid (PLGA) co-polymer matrix.
(A) Within each microsphere, small crystals of TA (red) are embedded in a PLGA matrix (green).
(B) In the initial phase of release, small channels (green circles) of approximately 500 nanometers in diameter appear on the surface of the microsphere to slow the release of TA from the microsphere.