Verteporfin

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 )

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.

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 c

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.

5 WARNINGS AND PRECAUTIONS • Extravasation : If extravasation occurs, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of local burn. ( 5.1 ) • Exposure to Sun or Direct Light : Following injection with VISUDYNE (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. ( 5.2 ) • Anaphylactic Reactions : Immediately discontinue administration of VISUDYNE and initiate appropriate therapy if an anaphylactic or other serious allergic reaction occurs during or following infusion. ( 5.4 ) 5.1 Local Adverse Reactions - Extravasation Standard precautions should be taken during infusion of VISUDYNE (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to: • A free-flowing intravenous (IV) line should be established before starting VISUDYNE infusion and the line should be carefully monitored. • Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecubital, be used for injection. • Small veins in the back of the hand should be avoided. Extravasation of VISUDYNE, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site. Localized (skin) necrosis at the injection site following extravasation has also been reported. If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of local burn, which could be severe. Cold compresses should be applied to the injection site. Oral medications for pain relief may be administered. 5.2 Exposure to Sun or Direct Light Following injection with VISUDYNE (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light. 5.3 Decreased Vision After Treatment Patients who experience severe decrease of vision of 4 lines or more within 1 week after treatment should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician. 5.4 Anaphylactic Reactions Cases of anaphylactic reactions have been reported in patients receiving VISUDYNE. Medical supervision is recommended during infusion. If an anaphylactic or other serious allergic reaction occurs during or following infusion, administration of VISUDYNE should be discontinued immediately and appropriate therapy should be initiated.

4 CONTRAINDICATIONS VISUDYNE (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation [see Adverse Reactions ( 6 )] . VISUDYNE (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation. ( 4 )

10 OVERDOSAGE Overdose of drug and/or light in the treated eye may result in non-perfusion of normal retinal vessels with the possibility of severe decrease in vision that could be permanent. An overdose of drug will also result in the prolongation of the period during which the patient remains photosensitive to bright light. In such cases, it is recommended to extend the photosensitivity precautions for a time proportional to the overdose.