Visudyne Information
Visudyne () Description
Visudyne () (verteporfin for injection) is a light activated drug used in photodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:
The chemical names for the verteporfin regioisomers are:
9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[]porphine-9,13-dipropanoate
The molecular formula is CHNO with a molecular weight of approximately 718.8.
Each mL of reconstituted Visudyne () contains:
ACTIVE: Verteporfin, 2 mg
INACTIVES: Lactose, egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl palmitate and butylated hydroxytoluene
Visudyne () Clinical Pharmacology
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.
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. 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 were not significantly different from the control group, half-life however was significantly increased by approximately 20%.
Visudyne () Indications And Usage
Visudyne () (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.
There is insufficient evidence to indicate Visudyne () for the treatment of predominantly occult subfoveal choroidal neovascularization.
Visudyne () Contraindications
Visudyne () (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation.
Visudyne () Warnings
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.
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.
Use of incompatible lasers that do not provide the required characteristics of light for the photoactivation of Visudyne () could result in incomplete treatment due to partial photoactivation of Visudyne () , overtreatment due to overactivation of Visudyne () , or damage to surrounding normal tissue.
Visudyne () Precautions
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:
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 ). 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
Patients who receive Visudyne () will become temporarily photosensitive after the infusion. Patients should wear a wrist band 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 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 inhibitors, could also decrease the efficacy of Visudyne () therapy.
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/m based on AUC in male and female rats, respectively).
Teratogenic Effects
Rat fetuses of dams administered verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis (approximately 40-fold human exposure at 6 mg/m based on AUC 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/m based on AUC 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/m 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.
Verteporfin and its diacid metabolite have been found in the breast milk of one woman after a 6 mg/m infusion. The verteporfin breast milk levels were up to 66% of the corresponding plasma levels. Verteporfin was undetectable after 12 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.
Visudyne () Adverse Reactions
Severe chest pain, vaso-vagal and hypersensitivity reactions have been reported. Vaso-vagal 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 events 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 or more, 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 (
Ocular Treatment Site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion
Non-ocular Events: Chest pain and other musculoskeletal pain during infusion
Visudyne () 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.
Visudyne () Dosage And Administration
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 intravenous infusion of Visudyne () . The second step is the activation of Visudyne () with light from a nonthermal diode laser.
The physician should re-evaluate the patient every 3 months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.
Visudyne () How Supplied
Visudyne () (verteporfin for injection) is supplied in a single use glass vial with a gray bromobutyl stopper and aluminum flip-off cap. It contains a lyophilized dark green cake with 15 mg verteporfin. The product is intended for intravenous injection only.
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 ).
NDC 0078-0437-61
Store Visudyne () between 20°C and 25°C (68°F-77°F).
Visudyne () hotline number (1-877-736-2778)
Rx Only
Manufactured by:
Parkedale Pharmaceuticals, Inc.
Rochester, MI 48307
For:
QLT Inc.
Vancouver, Canada V5T 4T5
Co-developed and Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
