Verteporfin For

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 )

For injection: 15 mg of verteporfin as a dark green lyophilized cake in a single-dose vial for reconstitution. VISUDYNE is intended for intravenous injection only. Each reconstituted vial provides 7.5 mL solution containing 2 mg/mL of verteporfin. For injection: 15 mg of verteporfin as a dark green lyophilized cake in a single-dose vial for reconstitution. ( 3 ) Each reconstituted vial provides 7.5 mL solution containing 2 mg/mL of verteporfin. ( 3 )

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 )

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.

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 1-800-321-4576 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.

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 A2 inhibitors, could also decrease the efficacy of VISUDYNE therapy.

8.1 Pregnancy Risk Summary There are no data with the use of VISUDYNE in pregnant women to inform a drug-associated risk. Intravenous administration of verteporfin to pregnant rats during the period of organogenesis produced an increase in the incidence of anophthalmia/microphthalmia and wavy ribs at exposures approximately 40-fold the human exposure at the recommended clinical dose. Verteporfin did not produce adverse fetal effect in rats or rabbits at exposures 6- to 20-fold the human exposure at the recommended clinical dose. There are no adequate and well-controlled studies in pregnant women. VISUDYNE should be used during pregnancy only if the benefit justifies the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Rat fetuses of dams administered verteporfin for injection intravenously during organogenesis exhibited an increase in the incidence of anophthalmia/microphthalmia and wavy ribs at doses ≥10 mg/kg/day (approximately 40-fold the human exposure at the recommended dose of 6 mg/m 2 , based on AUC in female rats). No teratogenic effects were observed in rat fetuses at a dose of 2 mg/kg/day (approximately 6-fold the human exposure at the recommended dose of 6 mg/m 2 , based on AUC in female rats). In pregnant rabbits, a decrease in maternal body weight gain and food consumption was observed in animals that received verteporfin for injection intravenously at doses up to 10 mg/kg/day during organogenesis. The no observed adverse effect level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 6-fold the recommended human dose of 6 mg/m 2 , based on body surface area). No teratogenic effects were observed in rabbit fetuses at doses up to 10 mg/kg/day (approximately 20-fold the recommended human dose of 6 mg/m 2 , based on body surface area).

8.2 Lactation Risk Summary Verteporfin and its diacid metabolite have been found in human breast milk following an intravenous infusion at the recommended human dose of 6 mg/m 2 . Verteporfin was present in breast milk at levels up to 66% of the corresponding plasma levels and declined below the limit of quantification (2 ng/mL) within 24 hours. The diacid metabolite had lower peak concentrations but persisted up to at least 48 hours. Because of the potential for serious adverse reactions in nursing infants from VISUDYNE, a decision should be made whether to discontinue nursing or postpone treatment, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Approximately 90% of the patients treated with VISUDYNE in the clinical efficacy trials were over the age of 65. A reduced treatment effect was seen with increasing age.

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.