Verteporfin For Injection

1 INDICATIONS AND USAGE VISUDYNE ® (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), pathologic myopia or presumed ocular histoplasmosis. There is insufficient evidence to indicate VISUDYNE for the treatment of predominantly occult subfoveal CNV. VISUDYNE (verteporfin for injection) therapy is a photoenhancer indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. ( 1 )

2 DOSAGE AND ADMINISTRATION • Recommended Dose : 6 mg/m 2 body surface area. ( 2.2 ) • Reconstitution : Reconstitute each vial of VISUDYNE with 7 mL of Sterile Water for Injection to provide 7.5 mL containing 2 mg/mL of verteporfin. Reconstituted VISUDYNE must be protected from light and used within 4 hours. ( 2.3 ) • Dilution : Dilute desired dose of reconstituted VISUDYNE with 5% Dextrose for Injection to a total infusion volume of 30 mL. ( 2.3 ) • Infusion : Administer intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter. ( 2.3 ) • Light Administration : The recommended light dose is 50 J/cm 2 of neovascular lesion administered at an intensity of 600 mW/cm 2 . The wavelength of the laser light should be 689±3 nm. This light dose is administered over 83 seconds, starting 15 minutes after the start of the VISUDYNE infusion. ( 2.4 ) 2.1 Important Administration Instructions A course of VISUDYNE (verteporfin for injection) therapy is a two-step process requiring administration of both drug and light. • The first step is the administration of VISUDYNE. • The second step is the activation of VISUDYNE with light from a nonthermal diode laser. The physician should re-evaluate the patient 3 months after treatment and if choroidal neovascular leakage is detected on fluorescein angiography, therapy may be repeated. Lesion Size Determination The greatest linear dimension (GLD) of the lesion should be estimated by fluorescein angiography and color fundus photography. All classic and occult CNV, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement. Fundus cameras with magnification within the range of 2.4-2.6X are recommended. The GLD of the lesion on the fluorescein angiogram must be corrected for the magnification of the fundus camera to obtain the GLD of the lesion on the retina. Spot Size Determination The treatment spot size should be 1,000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border, ensuring full coverage of the lesion. The maximum spot size used in the clinical trials was 6,400 microns. The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve. 2.2 Recommended Dosage of VISUDYNE The recommended dose of VISUDYNE is 6 mg/m 2 body surface area. 2.3 VISUDYNE Administration Avoid contact with the eyes and skin during preparation and administration of VISUDYNE. Because of the potential to induce photosensitivity reactions, any exposed person must be protected from bright light [see Warnings and Precautions ( 5.1 ) and How Supplied/Storage and Handling ( 16 )] . Reconstitution Reconstitute each vial of VISUDYNE with 7 mL of Sterile Water for Injection. Each reconstituted vial provides 7.5 mL solution containing 2 mg/mL of verteporfin. Reconstituted VISUDYNE must be protected from light and used within 4 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted VISUDYNE is an opaque dark green solution. Dilution VISUDYNE may precipitate in saline solutions. Do not use normal saline or other parenteral solutions, except 5% Dextrose for Injection, for dilution of the reconstituted VISUDYNE. Do not mix VISUDYNE in the same solution with other drugs. The volume of reconstituted VISUDYNE required to achieve the desired dose of 6 mg/m 2 body surface area is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. After dilution, protect from light and use within 4 hours. Intravenous Infusion The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter. The clinical studies were conducted using a standard infusion line filter of 1.2 microns. Precautions should be taken to prevent extravasation at the injection site. If extravasation occurs, protect the site from light [see Warnings and Precautions ( 5.1 )] . 2.4 Light Administration Initiate 689 nm wavelength laser light delivery to the patient 15 minutes after the start of the 10-minute infusion with VISUDYNE. Photoactivation of VISUDYNE is controlled by the total light dose delivered. In the treatment of CNV, the recommended light dose is 50 J/cm 2 of neovascular lesion administered at an intensity of 600 mW/cm 2 . This dose is administered over 83 seconds. Light dose, light intensity, ophthalmic lens magnification factor and zoom lens setting are important parameters for the appropriate delivery of light to the predetermined treatment spot. Follow the laser system manuals for procedure set up and operations. The laser system must deliver a stable power output at a wavelength of 689±3 nm. Light is delivered to the retina as a single circular spot via a fiber optic and a slit lamp, using a suitable ophthalmic magnification lens. The following laser systems have been tested for compatibility with VISUDYNE and are approved for delivery of a stable power output at a wavelength of 689±3 nm: Coherent Opal Photoactivator laser console and modified Coherent LaserLink adapter, manufactured by Lumenis, Inc., 2400 Condensa Street, Santa Clara, CA 95051-0901, Zeiss VISULAS 690s laser and VISULINK PDT adapter manufactured by Carl Zeiss Meditec Inc., 5160 Hacienda Drive, Dublin, CA 94568, Ceralas I laser system and Ceralink Slit Lamp Adapter manufactured by Biolitec Inc., 515 Shaker Road, East Longmeadow, MA 01028, Quantel Activis laser console and the ZSL30 ACT, ZSL120 ACT and HSBMBQ ACT slit lamp adapters distributed by Quantel Medical, 601 Haggerty Lane, Bozeman, MT 59715. 2.5 Concurrent Bilateral Treatment The controlled trials only allowed treatment of one eye per patient. In patients who present with eligible lesions in both eyes, physicians should evaluate the potential benefits and risks of treating both eyes concurrently. If the patient has already received previous VISUDYNE therapy in one eye with an acceptable safety profile, both eyes can be treated concurrently after a single administration of VISUDYNE. The more aggressive lesion should be treated first, at 15 minutes after the start of infusion. Immediately at the end of light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of infusion. In patients who present for the first time with eligible lesions in both eyes without prior VISUDYNE therapy, it is prudent to treat only one eye (the most aggressive lesion) at the first course. One week after the first course, if no significant safety issues are identified, the second eye can be treated using the same treatment regimen after a second VISUDYNE infusion. Approximately 3 months later, both eyes can be evaluated and concurrent treatment following a new VISUDYNE infusion can be started if both lesions still show evidence of leakage.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Local Adverse Reactions – Extravasation [see Warnings and Precautions ( 5.1 )] • Exposure to Sun or Direct Light [see Warnings and Precautions ( 5.2 )] • Decreased Vision after Treatment [see Warnings and Precautions ( 5.3 )] • Porphyria and Hypersensitivity [see Contraindications ( 4 )] Most common adverse reactions (incidence ˃10%) are injection site reactions and visual disturbances. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Severe chest pain, vasovagal and hypersensitivity reactions have been reported. Vasovagal and hypersensitivity reactions on rare occasions can be severe. These reactions may include syncope, sweating, dizziness, rash, dyspnea, flushing and changes in blood pressure and heart rate. General symptoms can include headache, malaise, urticaria, and pruritus. The most frequently reported adverse reactions to VISUDYNE (verteporfin for injection) are injection site reactions (including pain, edema, inflammation, extravasation, rashes, hemorrhage and discoloration) and visual disturbances (including blurred vision, flashes of light, decreased visual acuity and visual field defects, including scotoma). These events occurred in approximately 10%-30% of patients. The following events, listed by Body System, were reported more frequently with VISUDYNE therapy than with placebo therapy and occurred in 1%-10% of patients: Ocular Treatment Site: Blepharitis, cataracts, conjunctivitis/conjunctival injection, dry eyes, ocular itching, severe vision decrease with or without subretinal/retinal or vitreous hemorrhage Body as a Whole: Asthenia, fever, flu syndrome, infusion related pain primarily presenting as back pain, photosensitivity reactions Cardiovascular: Atrial fibrillation, hypertension, peripheral vascular disorder, varicose veins Dermatologic: Eczema Digestive: Constipation, gastrointestinal cancers, nausea Hemic and Lymphatic: Anemia, white blood cell count decreased, white blood cell count increased Hepatic: Elevated liver function tests Metabolic/Nutritional: Albuminuria, creatinine increased Musculoskeletal: Arthralgia, arthrosis, myasthenia Nervous System: Hypesthesia, sleep disorder, vertigo Respiratory: Cough, pharyngitis, pneumonia Special Senses: Cataracts, decreased hearing, diplopia, lacrimation disorder Urogenital: Prostatic disorder Severe vision decrease, equivalent of >4 lines, within 7 days after treatment has been reported in 1%-5% of patients. Partial recovery of vision was observed in some patients. Photosensitivity reactions usually occurred in the form of skin sunburn following exposure to sunlight. The higher incidence of back pain in the VISUDYNE group occurred primarily during infusion. The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of VISUDYNE in clinical practice where these reactions were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to VISUDYNE, or a combination of these factors: Ocular Treatment Site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion, retinal pigment epithelial tear. Non-ocular Events: Chest pain and other musculoskeletal pain during infusion, anaphylactic reaction during or following infusion, injection site necrosis.

12.3 Pharmacokinetics Following intravenous infusion, verteporfin exhibits a bi-exponential elimination with a terminal elimination half-life of approximately 5-6 hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m 2 . At the intended dose, pharmacokinetic parameters are not significantly affected by gender. Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine. In a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment), AUC and C max were not significantly different from the control group; half-life, however, was significantly increased by approximately 20%.