Featured Product Guide - Q4 2020 - 56

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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 (CHF) in susceptible patients,
fluid retention, sodium retention. Gastrointestinal (GI): 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 [IA] or
intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness,
osteoporosis, pathologic fracture of long bones, post-injection flare (following
IA 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. After intrathecal administration-arachnoiditis, meningitis, paraparesis/
paraplegia, sensory disturbances. After epidural administration-spinal cord
infarction, paraplegia, quadriplegia, cortical blindness, stroke (including brainstem).
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.
7. DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with ZILRETTA. Drug
interactions associated with systemic corticosteroids (CSs) include the following.
Aminoglutethimide: Aminoglutethimide may lead to a loss of CS-induced adrenal
suppression. Amphotericin B injection and potassium-depleting agents: When CSs
are administered concomitantly with potassium-depleting agents (ie, 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 CHF. Antibiotics:
Macrolide antibiotics have been reported to cause a significant decrease in CS
clearance. Anticholinesterases: Concomitant use of anticholinesterase agents and
CSs may produce severe weakness in patients with myasthenia gravis. If possible,
withdraw anticholinesterase agents at least 24 hours before initiating CS therapy.
Anticoagulants, oral: Co-administration of CSs and warfarin usually results in
inhibition of response to warfarin, though there have been some conflicting reports.
Therefore, monitor coagulation indices frequently to maintain desired anticoagulant
effect. Antidiabetics: Because CSs may increase blood glucose concentrations,
dosage adjustments of antidiabetic agents may be required. Antitubercular drugs:
Serum concentrations of isoniazid may be decreased. CYP3A4 inducers (eg,
barbiturates, phenytoin, carbamazepine, and rifampin): Drugs that induce hepatic
microsomal drug-metabolizing enzyme activity may enhance metabolism of CSs
and require that the CS dosage be increased. CYP3A4 inhibitors (eg, ketoconazole):
Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the
metabolism of certain CSs by up to 60%, leading to an increased risk of CS side
effects. Cholestyramine: Cholestyramine may increase the clearance of CSs.
Cyclosporine: Increased activity of cyclosporine and CSs may occur when used
concurrently. Convulsions have been reported with this concurrent use. Digitalis
glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias
due to hypokalemia. Estrogens, including oral contraceptives: Estrogens may
decrease the hepatic metabolism of certain CSs, thereby increasing their effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or
other NSAIDs) and CSs increases the risk of GI side effects. Aspirin should be
used cautiously in conjunction with CSs in hypoprothrombinemia. Clearance of
salicylates may be increased with concurrent use of CSs. Skin tests: CSs may
suppress reactions to allergy-related skin tests. Vaccines: Patients on prolonged
CS therapy may exhibit a diminished response to toxoids and live or inactivated
vaccines due to inhibition of antibody response. CSs may also potentiate the
replication of some organisms contained in live attenuated vaccines. If possible,
defer routine administration of vaccines or toxoids until CS therapy is discontinued.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary: There are no data regarding use of ZILRETTA
in pregnant women to inform a drug-associated risk of adverse developmental
outcomes. Published studies on the association between CSs and fetal outcomes

56

have reported inconsistent findings and have important methodological limitations.
The majority of published literature with CS exposure during pregnancy includes
oral, topical, and inhaled dosage formulations; therefore, the applicability of these
findings to a single IA injection of triamcinolone acetonide (TA) is limited. In animal
reproductive studies from the published literature, pregnant mice, rats, rabbits,
or primates administered TA 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 US
general population, the estimated risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.
8.2 Lactation Risk Summary: There are no available data on presence of TA in
human or animal milk, effects on the breastfed infant, or effects on milk production.
However, CSs have been detected in human milk and may suppress milk
production. It is not known whether IA 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.
8.3 Females and Males of Reproductive Potential CSs 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 CSs 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 availability of treatment alternatives.
8.5 Geriatric Use Of the total number of patients administered 32mg ZILRETTA in
clinical studies (N=424), 143 patients were ≥65 years old. No overall differences
in safety or effectiveness were observed between elderly and younger subjects,
and other reported clinical experience with TA has not identified differences in
responses between elderly and younger patients. However, greater sensitivity of
some older individuals cannot be ruled out.
13. NONCLINICAL TOXICOLOGY
13.2 Animal Toxicology and/or Pharmacology Single and repeat administrations
(1 injection every 3 months for a total of 3 injections) of ZILRETTA in non-arthritic
knee joints of healthy dogs have been studied at ~1.9xMRHD of 32mg (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 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 knee cartilage) vs administration
of an equivalent dose of immediate-release (IR) TA. These responses were mostly
reversed after 6 to 9 months post injection. Repeat administration resulted in an
increase in 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 knee cartilage) vs the equivalent
dose of IR TA. 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 injected knee, local swelling, local redness, or local
tenderness were noted. The clinical relevance of these findings in the arthritic knee
is unknown.
The Brief Summary is based on the ZILRETTA Prescribing Information
Part Number: 60-009-04, Version 4, 01/2020
Manufactured for Flexion Therapeutics, Inc.,
10 Mall Rd., Suite 301, Burlington, MA 01803
For more information, go to ZILRETTA.com or call 1-844-FLEXION (353-9466).

© 2020 Flexion Therapeutics, Inc. All rights reserved.
ZILRETTA and Flexion are registered trademarks of Flexion Therapeutics, Inc.
v4 January 2020. Z-00029v2

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Featured Product Guide - Q4 2020

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