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. ( 1.1 ) • Visualization during vitrectomy. ( 1.2 ) 1.1 Ophthalmic 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. 1.2 Visualization 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. ( 2.1 ) • Recommended dose for visualization: 1 to 4 mg (25 to 100 microliters of 40 mg/mL suspension) administered intravitreally. ( 2.2 ) 2.1 Dosage 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. 2.2 Dosage 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. 2.3 Preparation 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. 2.4 Administration 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. ( 5.1 ) • Ophthalmic Effects: May include cataracts, infections, and glaucoma. Monitor intraocular pressure. Monitor intraocular pressure (IOP). ( 5.1 ) • Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome and hyperglycemia: Monitor patients for these conditions and taper doses gradually. ( 5.2 ) • Infections: Increased susceptibility to new infection and increased risk of exacerbation, dissemination, or reactivation of latent infection. ( 5.3 ) • Elevated blood pressure, salt and water retention, and hypokalemia: Monitor blood pressure and sodium, potassium serum levels. ( 5.4 ) • GI perforation: Increased risk in patients with certain GI disorders. ( 5.5 ) • Behavioral and mood disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis. ( 5.6 ) • Decreases in bone density: Monitor bone density in patients receiving long term corticosteroid therapy. ( 5.7 ) • Live or live attenuated vaccines: Do not administer to patients receiving immunosuppressive doses of corticosteroids. ( 5.8 ) • Negative effects on growth and development: Monitor pediatric patients on long-term corticosteroid therapy. ( 5.9 ) • Use in pregnancy: Fetal harm can occur with first trimester use. ( 5.10 ) • Weight gain: May cause increased appetite. ( 5.11 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 5.1 Ophthalmic 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. [ see Warnings and Precautions (5.3) ] . 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. 5.2 Alterations 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…

4 CONTRAINDICATIONS 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. [ See Adverse Reactions (6) ]. • Patients with systemic fungal infections. ( 4 ) • Hypersensitivity to triamcinolone or any component of this product. ( 4 )

7 DRUG INTERACTIONS • Amphotericin B: There have been cases reported in which concomitant use of Amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure ( See Potassium Depleting Agents). • Anticholinesterase agents: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. • Anticoagulant agents: Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. • Antidiabetic agents: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. • Antitubercular drugs: Serum concentrations of isoniazid may be decreased. • CYP 3A4 inducers (e.g., barbiturates, phenytoin, carbamazepine, and rifampin): Drugs, such as barbiturates, phenytoin, ephedrine, and rifampin, which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of corticosteroid and require that the dosage of corticosteroid be increased. • CYP 3A4 inhibitors (e.g., ketoconazole, macrolide antibiotics): Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects. • Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. • Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with concurrent use. • Digitalis: 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 corticosteroids thereby increasing their effect. • NSAIDs including aspirin and salicylates: Concomitant use of aspirin or other non-steroidal antiinflammatory agents and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. • Potassium depleting agents (e.g., diuretics, Amphotericin B): When corticosteroids are administered concomitantly with potassium-depleting agents, patients should be observed closely for development of hypokalemia. • Skin tests: Corticosteroids may suppress reactions to skin tests. • Toxoids and live or inactivated vaccines: Due to inhibition of antibody response, patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. • Anticoagulant agents: May enhance or diminish anticoagulant effects. Monitor coagulation indices. ( 7 ) • Antidiabetic agents: May increase blood glucose concentrations. Dose adjustments of antidiabetic agents may be required. ( 7 ) • CYP 3A4 inducers and inhibitors: May respectively increase or decrease clearance of corticosteroids necessitating dose adjustment. ( 7 ) • Non-steroidal antiinflammatory drugs (NSAIDs), including aspirin and salicylates: Increased risk of gastrointestinal side effects. ( 7 )

8.1 Pregnancy Teratogenic Effects: Pregnancy Category D [See Warnings and Precautions (5.10) ] 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.

8.3 Nursing 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.

6 ADVERSE REACTIONS 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.