Triesence

1 INDICATIONS AND USAGE TRIESENCE suspension is a synthetic corticosteroid indicated for: • Treatment of the following ophthalmic diseases: sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. • Visualization during vitrectomy.

1.1Ophthalmic Diseases

TRIESENCE (triamcinolone acetonide injectable suspension) 40 mg/mL is indicated for: • sympathetic ophthalmia, • temporal arteritis, • uveitis, and • ocular inflammatory conditions unresponsive to topical corticosteroids.

1.2Visualization During Vitrectomy

TRIESENCE suspension is indicated for visualization during vitrectomy.

2 DOSAGE AND ADMINISTRATION • Initial recommended dose for all indications except visualization: 4 mg (100 microliters of 40 mg/mL suspension) with subsequent dosage as needed over the course of treatment. • Recommended dose for visualization: 1 to 4 mg (25 to 100 microliters of 40 mg/mL suspension) administered intravitreally.

2.1Dosage for Treatment of Ophthalmic Diseases The

initial recommended dose of TRIESENCE suspension is 4 mg (100 microliters of 40 mg/mL suspension) with subsequent dosage as needed over the course of treatment.

2.2Dosage for Visualization During Vitrectomy The

recommended dose of TRIESENCE ® suspension is 1 to 4 mg (25 to 100 microliters of 40 mg/mL suspension) administered intravitreally.

2.3Preparation for Administration

STRICT ASEPTIC TECHNIQUE IS MANDATORY. The vial should be vigorously shaken for 10 seconds before use to ensure a uniform suspension. Prior to withdrawal, the suspension should be inspected for clumping or granular appearance (agglomeration). An agglomerated product results from exposure to freezing temperatures and should not be used.

After withdrawal, TRIESENCE suspension should be injected without delay to prevent settling in the syringe. Careful technique should be employed to avoid the possibility of entering a blood vessel or introducing organisms that can cause infection.

2.4Administration The

injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection. Following the injection, patients should be monitored for elevation in intraocular pressure (IOP) and for endophthalmitis.

Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. Each vial should only be used for the treatment of a single eye.

If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, and injection needles should be changed before TRIESENCE suspension is administered to the other eye.

5 WARNINGS AND PRECAUTIONS • TRIESENCE suspension should not be administered intravenously. • Ophthalmic Effects: May include cataracts, infections, and glaucoma. Monitor intraocular pressure (IOP). • Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome and hyperglycemia: Monitor patients for these conditions and taper doses gradually. • Infections: Increased susceptibility to new infection and increased risk of exacerbation, dissemination, or reactivation of latent infection. • Elevated blood pressure, salt and water retention, and hypokalemia: Monitor blood pressure and sodium, potassium serum levels. • GI perforation: Increased risk in patients with certain GI disorders. • Behavioral and mood disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis. • Decreases in bone density: Monitor bone density in patients receiving long term corticosteroid therapy. • Live or live attenuated vaccines: Do not administer to patients receiving immunosuppressive doses of corticosteroids. • Negative effects on growth and development: Monitor pediatric patients on long-term corticosteroid therapy. • Use in pregnancy: Fetal harm can occur with first trimester use. • Weight gain: May cause increased appetite. To report SUSPECTED ADVERSE REACTIONS, contact Harrow Eye, LLC at 833-4HARROW or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

5.1Ophthalmic Effects

TRIESENCE suspension should not be administered intravenously. Strict aseptic technique is mandatory. Risk of infection Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

Corticosteroids may enhance the establishment of secondary ocular infections due to fungi or viruses. If an infection occurs during corticosteroid therapy, it should be promptly controlled by suitable antimicrobial therapy . Elevated Intraocular Pressure Increases in IOP associated with triamcinolone acetonide injection have been observed in 20% to 60% of patients. This may lead to glaucoma with possible damage to the optic nerve.

Effects on IOP may last up to 6 months following injection and are usually managed by topical glaucoma therapy. A small percentage of patients may require aggressive non-topical treatment. Intraocular pressure as well as perfusion of the optic nerve head should be monitored and managed appropriately.

Endophthalmitis The rate of infectious culture positive endophthalmitis is 0.5%. Proper aseptic techniques should always be used when administering triamcinolone acetonide. In addition, patients should be monitored following the injection to permit early treatment should an infection occur. Cataracts Use of corticosteroids may produce cataracts, particularly posterior subcapsular cataracts.

Patients with Ocular Herpes Simplex Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

5.2Alterations in Endocrine Function Hypothalamic-pituitary-adrenal

(HPA) axis suppression, Cushing's syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage.

This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

5.3Increased Risks Related to Infections Corticosteroids

may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may mask some signs of infection and may reduce resistance to new infections.

Corticosteroids may exacerbate infections and increase risk of disseminated infection. The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. Chickenpox and measles can have a more serious or even fatal course in non-immune children or adults on corticosteroids.

In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids may increase risk of reactivation or exacerbation of latent infection. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Corticosteroids should not be used in cerebral malaria.

5.4Alterations in Cardiovascular/Renal Function Corticosteroids

can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium and calcium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary.

These agents should be used with caution in patients with hypertension, congestive heart failure, or renal insufficiency. Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with caution in these patients.

5.5Use in Patients With Gastrointestinal Disorders There

is an increased risk of gastrointestinal perforation in patients with certain GI disorders. Signs of GI perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids. Corticosteroids should be used with caution if there is a probability of impending perforation, abscess or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or latent peptic ulcer.

5.6Behavioral and Mood Disturbances Corticosteroid

use may be associated with central nervous system effects ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

5.7Decrease in Bone Density Corticosteroids

decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy and bone density should be monitored in patients on long term corticosteroid therapy.

5.8Vaccination Administration of

live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

5.9Effect on Growth and Development Long-term

use of corticosteroids can have negative effects on growth and development in children. Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully monitored.

5.10Use in Pregnancy Triamcinolone

acetonide can cause fetal harm when administered to a pregnant woman. Human and animal studies suggest that use of corticosteroids during the first trimester of pregnancy is associated with an increased risk of orofacial clefts, intrauterine growth restriction and decreased birth weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus .

5.11Weight Gain Systemically

administered corticosteroids may increase appetite and cause weight gain.

5.12Neuromuscular Effects Although

controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium).

This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

5.13Kaposi's Sarcoma Kaposi's

sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Corticosteroids are contraindicated in patients with systemic fungal infections. Triamcinolone is contraindicated in patients who are hypersensitive to corticosteroids or any components of this product. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. . • Patients with systemic fungal infections. • Hypersensitivity to triamcinolone or any component of this product.

8.1Pregnancy Teratogenic Effects: Pregnancy Category

D Multiple cohort and case controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip with or without cleft palate from about 1/1000 infants to 3- 5/1000 infants. Two prospective case control studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero. Triamcinolone acetonide was teratogenic in rats, rabbits, and monkeys.

In rats and rabbits, triamcinolone acetonide was teratogenic at inhalation doses of 0.02 mg/kg and above and in monkeys, triamcinolone acetonide was teratogenic at an inhalation dose of 0.5 mg/kg (1/4 and 7 times the recommended human dose). Dose-related teratogenic effects in rats and rabbits included cleft palate and/or internal hydrocephaly and axial skeletal defects, whereas the effects observed in monkeys were cranial malformations. These effects are similar to those noted with other corticosteroids.

Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

8.3Nursing Mothers Corticosteroids

are secreted in human milk. Reports suggest that steroid concentrations in human milk are 5% to 25% of maternal serum levels, and that total infant daily doses are small, less than 0.2% of the maternal daily dose. The risk of infant exposure to steroids through breast milk should be weighed against the known benefits of breastfeeding for both the mother and baby.

Because clinical trials 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. Adverse event data were collected from 300 published articles containing data from controlled and uncontrolled clinical trials which evaluated over 14000 eyes treated with different concentrations of triamcinolone acetonide. The most common dose administered within these trials was triamcinolone acetonide 4 mg administered as primary or adjunctive therapy primarily as a single injection.

The most common reported adverse events following administration of triamcinolone acetonide were elevated IOP and cataract progression. These events have been reported to occur in 20% to 60% of patients. Less common reactions occurring in up to 2% include endophthalmitis (infectious and non-infectious), hypopyon, injection site reactions (described as blurring and transient discomfort), glaucoma, vitreous floaters, and detachment of retinal pigment epithelium, optic disc vascular disorder, eye inflammation, conjunctival hemorrhage, and visual acuity reduced.

Cases of exophthalmos have also been reported. Common adverse reactions for systemically administered corticosteroids include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite, and weight gain. Other reactions reported to have occurred with the administration of corticosteroids include: Allergic Reactions: Anaphylactoid reaction, anaphylaxis, angioedema Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, 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 scalp, edema, facial erythema, hyper or hypo-pigmentation, impaired wound healing, increased sweating, petechiae and ecchymoses, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria Endocrine: Abnormal fat deposits, decreased carbohydrate tolerance, development of Cushingoid state, hirsutism, manifestations of latent diabetes mellitus and increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, moon facies, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in children Fluid and Electrolyte Disturbances: Potassium loss, hypokalemic alkalosis, sodium retention Gastrointestinal: Abdominal distention, elevation in serum liver enzymes levels (usually reversible upon discontinuation), hepatomegaly, hiccups, malaise, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, ulcerative esophagitis Metabolic: Negative nitrogen balance due to protein catabolism Musculoskeletal: Aseptic necrosis of femoral and humeral heads, charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, vertebral compression fractures Neurological: Arachnoiditis, convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually following discontinuation of treatment, insomnia, meningitis, neuritis, neuropathy, paraparesis/paraplegia, paresthesia, sensory disturbances, vertigo Reproductive: Alteration in motility and number of spermatozoa