Verteporfin

12.1 Mechanism of Action VISUDYNE (verteporfin for injection) therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light. Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipoxygenase (leukotriene) and cyclooxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of the CNV following VISUDYNE therapy has been confirmed in humans by fluorescein angiography.

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

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.

7 DRUG INTERACTIONS Drug interaction studies in humans have not been conducted with VISUDYNE. Verteporfin is rapidly eliminated by the liver, mainly as unchanged drug. Metabolism is limited and occurs by liver and plasma esterases. Microsomal cytochrome P450 does not appear to play a role in verteporfin metabolism. Based on the mechanism of action of verteporfin, many drugs used concomitantly could influence the effect of VISUDYNE therapy. Possible examples include the following: Calcium channel blockers, polymyxin B or radiation therapy could enhance the rate of VISUDYNE uptake by the vascular endothelium. Other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics and griseofulvin) could increase the potential for skin photosensitivity reactions. Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol, would be expected to decrease VISUDYNE activity. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A 2 inhibitors, could also decrease the efficacy of VISUDYNE therapy.