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 lipo-oxygenase (leukotriene) and cyclo-oxygenase (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 choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.

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/m2. 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 Cmax were not significantly different from the control group; half-life, however, was significantly increased by approximately 20%.

Clinical Studies

General

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 antecutibal, 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.

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 a local burn, which could be severe. Cold compresses should be applied to the injection site. (see Warnings). Oral medications for pain relief may be administered.

Visudyne therapy should be considered carefully in patients with moderate to severe hepatic impairment or biliary obstruction since there is no clinical experience with verteporfin in such patients.

There is no clinical data related to the use of Visudyne in anesthetized patients. At a >10-fold higher dose given by bolus injection to sedated or anesthetized pigs, verteporfin caused severe hemodynamic effects, including death, probably as a result of complement activation. These effects were diminished or abolished by pretreatment with antihistamine and they were not seen in conscious nonsedated pigs. VISUDYNE resulted in a concentration-dependent increase in complement activation in human blood in vitro. At 10 µg/mL (approximately 5 times the expected plasma concentration in human patients), there was mild to moderate complement activation. At ≥100 µg/mL, there was significant complement activation. Signs (chest pain, syncope, dyspnea, and flushing) consistent with complement activation have been observed in <1% of patients administered Visudyne. Patients should be supervised during Visudyne infusion.

Information for Patients

Patients who receive Visudyne will become temporarily photosensitive after the infusion. Patients should wear a wristband to remind them to avoid direct sunlight for 5 days. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light. Sources of bright light include, but are not limited to, tanning salons, bright halogen lighting and high power lighting used in surgical operating rooms or dental offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 5 days following Visudyne administration.

If treated patients must go outdoors in daylight during the first 5 days after treatment, they should protect all parts of their skin and their eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.

Patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help inactivate the drug in the skin through a process called photobleaching.

Following Visudyne treatment, patients may develop visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist.

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate the carcinogenic potential of verteporfin.

Photodynamic therapy (PDT) as a class has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE), and mutations. In addition, other photodynamic therapeutic agents have been shown to increase the incidence of SCE in Chinese hamster ovary (CHO) cells irradiated with visible light and in Chinese hamster lung fibroblasts irradiated with near UV light, increase mutations and DNA-protein cross-linking in mouse L5178 cells, and increase DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. Verteporfin was not evaluated in these latter systems. It is not known how the potential for DNA damage with PDT agents translates into human risk.

No effect on male or female fertility has been observed in rats following intravenous administration of verteporfin for injection up to 10 mg/kg/day (approximately 60- and 40-fold human exposure at 6 mg/m2 based on AUCinf in male and female rats, respectively).

Pregnancy

Teratogenic Effects: Pregnancy Category C

Rat fetuses of dams administered verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis (approximately 40-fold human exposure at 6 mg/m2 based on AUCinf in female rats) exhibited an increase in the incidence of anophthalmia/microphthalmia. Rat fetuses of dams administered 25 mg/kg/day (approximately 125 fold the human exposure at 6 mg/m2 based on AUCinf in female rats) had an increased incidence of wavy ribs and anophthalmia/microphthalmia.

In pregnant rabbits, a decrease in body weight gain and food consumption was observed in animals that received verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis. The no observed adverse effect level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 7-fold human exposure at 6 mg/m2 based on body surface area). There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day.

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.

Nursing Mothers

Verteporfin and its diacid metabolite have been found in the breast milk of one woman after a 6 mg/m2 infusion. The verteporfin breast milk levels were 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

Lesion Size Determination

The greatest linear dimension (GLD) of the lesion is 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 1000 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 6400 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.

Visudyne® Administration

Reconstitute each vial of Visudyne with 7 mL of sterile Water for Injection to provide 7.5 mL containing 2 mg/mL. Reconstituted Visudyne must be protected from light and used within 4 hours. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discoloration prior to administration. Reconstituted Visudyne is an opaque dark green solution. 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/m2 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 a maximum of 4 hours. 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 PRECAUTIONS).

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 choroidal neovascularization, the recommended light dose is 50 J/cm2 of neovascular lesion administered at an intensity of 600 mW/cm2. 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 operation.

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.

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.

Spills and Disposal

Spills of Visudyne should be wiped up with a damp cloth. Skin and eye contact should be avoided due to the potential for photosensitivity reactions upon exposure to light. Use of rubber gloves and eye protection is recommended. All materials should be disposed of properly.

Accidental Exposure

Because of the potential to induce photosensitivity reactions, it is important to avoid contact with the eyes and skin during preparation and administration of Visudyne. Any exposed person must be protected from bright light (See WARNINGS).

NDC 50236-001-15

Store Visudyne between 20°C and 25°C (68°F-77°F).

REV: JANUARY 2010

301293 CC# 100020

QLT Inc.

Vancouver, Canada     V5T 4T5

Distributed by:

QLT Ophthalmics Inc.

Menlo Park CA 94025

Visudyne® is a registered trademark of Novartis AG