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knee were joint swelling (3% vs 2%) and contusions (2% vs
1%). Overall, the incidence and nature of adverse reactions
were similar to those observed with placebo.
The safety of repeat administration of ZILRETTA was
evaluated in a multicenter, open-label, single-arm study
in patients with osteoarthritis (OA) knee pain. 179 patients
received a repeat injection on or after Week 12 (median 16.6
weeks) and were followed for 52 weeks from 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%). Data from this study
are insufficient to fully characterize the safety of repeat
administration of ZILRETTA.
6.2 Post-marketing Experience The following adverse
reactions (alphabetical 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, 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: Pruritis.
6.3 Corticosteroid Adverse Reactions The following adverse
reactions (alphabetical by body system) are from voluntary
reports or clinical studies of corticosteroids (CSs). 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 (CHF), 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: 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 intraarticular [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.
No drug-drug interaction studies have been conducted with
ZILRETTA. Drug interactions associated with systemic 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 potassiumdepleting 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


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