Drug Criteria & Outcomes
Verteporfin: For macular degeneration
By Kyle Robottom, PharmD Candidate
Medical University of South Carolina
Charleston
Indications:
Verteporfin (Visudyne), by Ciba Vision, of Duluth, GA, is approved for the treatment of age-related macular degeneration in patients with predominantly classic subfoveal choroidal neovascularization.1,2
Pharmacology:
Following intravenous infusion, verteporfin is transported in the plasma primarily by lipoproteins. Upon activation by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Vessel occlusion results from the light-activated verteporfin causing local damage to neovascular endothelium. The damaged endothelium releases procoagulant 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 selectively accumulate in neovasculature, including choroidal neovasculature. Animal models show some drug present in the retina, as well. Thus, it is possible that collateral damage to retinal structures such as the retinal pigmented epithelium and outer nuclear layer of the retina may occur following photoactivation. Following verteporfin therapy, the temporary occlusion of choroidal neovascularization has been confirmed by fluorescein angiography..1,2
Pharmacokinetics:
Following intravenous infusion, verteporfin exhibits a bi-exponential elimination half-life of approximately five to six hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. Verteporfin is metabolized to a small extent to its di-acid 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. Verteporfin is almost entirely eliminated in the feces, with less than 0.01% of the dose recovered in the urine. Half-life was increased by approximately 20% in a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment). However, area under the curve and Cmax were not significantly different from the control group.1,2
Selected clinical trials:
The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group conducted two multicenter, double-blind, placebo-controlled, randomized clinical trials involving 609 patients (verteporfin, n = 402; placebo, n = 207) with classic containing subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration.3 The studies were conducted to assess if photodynamic therapy with verteporfin could safely reduce the risk of vision loss in patients with CNV secondary to age-related macular degeneration. Results from the two identical study protocols, which ran concurrently in North America and Europe, were published together.3
Patients were included in the studies if they met the following criteria: CNV secondary to age-related macular degeneration, CNV under the geometric center of the foveal avascular zone, evidence of classic CNV on fluorescein angiography, area of CNV at least 50% of the area of the total neovascular lesion, greatest linear dimension of lesion < 5,400 nm, and age > 50 years. Patients were excluded if the following criteria were present: tear of retinal pigment epithelium, any significant ocular disease, inability to obtain photographs to document CNV, history of treatment of CNV other than nonfoveal confluent laser photocoagulation, participation in another ophthalmic clinical trial or use of other investigational drugs within 12 weeks prior to the start of the study, active hepatitis or other clinically significant liver disease, porphyria, prior photodynamic therapy for CNV, intraocular surgery within last two months, or capsulotomy within last month in the study eye.3
Patients were randomized, in a 2:1 ratio, to receive either verteporfin 6 mg/m2 intravenously or placebo. Placebo consisted of intravenous administration of dextrose 5% in water, followed by the same light application used in the verteporfin group. A planned analysis of safety and efficacy was conducted at one year, with 94% of patients completing the one-year examination. During the course of the study, retreatment was allowed every three months if fluorescein angiograms showed any recurrence or persistence of leakage. At the one-year analysis, visual acuity, contrast sensitivity, and fluorescein angiographic outcomes were statistically better in the verteporfin group (p < 0.001).3
The subgroup analysis of patients with predominantly classic CNV lesions (defined as an area of CNV occupying 50% or more of the area of the entire lesion) was more likely to exhibit a treatment benefit (verteporfin, n = 159; placebo, n = 84). For the primary efficacy endpoint (percentage of patients who lost less than three lines of visual acuity), this subgroup displayed a 28% difference between verteporfin and placebo (67% for verteporfin compared to 39% for placebo, p < 0.001). Severe vision loss (six or more lines of visual acuity from baseline) was seen in 12% of verteporfin-treated patients vs. 33% of placebo-treated patients.3
Patients with predominantly classic CNV lesions that did not contain occult CNV exhibited the greatest benefit. When assessed with less than three line-lost criteria, this group showed a 49% difference between treatment groups (77% vs. 27%). Severe vision loss was demonstrated in 10% of verteporfin-treated patients compared to 41% of patients treated with placebo. Those groups less likely to benefit from verteporfin therapy include: older patients (more than 75 years of age), patients with dark irises, patients with occult lesions, and patients with less than 50% classic CNV.3
The authors concluded that verteporfin photodynamic therapy is safe and effective for the treatment of patients with CNV secondary to age-related macular degeneration.3
Adverse reactions:
In clinical trials, the most commonly reported adverse reactions associated with verteporfin therapy were headache, injection-site reactions (e.g., extravasation, rash), and visual disturbances (e.g., blurred vision, decreased visual acuity, visual field defects). Less commonly reported adverse reactions were ocular treatment site reactions, cardiovascular effects (e.g., atrial fibrillation, hypertension, peripheral vascular disorder, and varicose veins), elevated liver function tests, and elevated serum creatinine. In up to 4% of patients, severe vision decreases, defined as four lines or more, have been reported within seven days of treatment. In some patients, partial recovery of vision was achieved. Following exposure to sunlight, photosensitivity reactions (skin sunburn) have occurred.1-3
Contraindications:
Verteporfin is contraindicated in patients with a known hypersensitivity to any active or inactive ingredients of this preparation and in patients with porphyria.1,2
Warnings/Precautions:
Following verteporfin therapy, patients should avoid exposure of skin and eyes to direct sunlight or bright indoor light for five days. Standard precautions should be taken with verteporfin infusion to avoid extravasation.1,2
In the event that extravasation occurs, the infusion should be stopped immediately and cold compresses should be applied. The extravasated area should be protected from direct light until the swelling and discoloration have faded to ensure that a local burn does not occur. If emergency surgery is necessary within 48 hours following extravasation, as much of the internal tissue as possible should be protected from intense light.1,2
If patients experience a severe decrease of vision of four lines or more within one week after treatment, they should not be retreated, at least until their vision completely returns to pretreatment level. At this point, the physician should consider the potential risk vs. potential benefit of treatment.1,2
There is no clinical experience with administration of verteporfin to patients with moderate to severe hepatic impairment; therefore, use in these patients should be carefully considered. There are no clinical data evaluating verteporfin therapy in anesthetized, humans; however, animal studies at a greater than tenfold higher dose showed that severe hemodynamic effects, including death, resulted from a verteporfin bolus injection.1,2
Incompatible lasers should not be used with verteporfin, as undertreatment, overtreatment, or damage to the surrounding tissue could occur.1,2
Pregnancy/lactation:
Verteporfin is rated pregnancy category C. There are no adequate and well-controlled studies of verteporfin use in pregnant women. In animal studies, doses of 40- and 125-fold human exposure produced fetal abnormalities. Verteporfin should only be used in a pregnant patient if the potential benefit justifies the potential risk to the fetus. It is not known if verteporfin is excreted in breast milk. Caution should be used when verteporfin is administered to a woman who is nursing.1,4,5
Dosage and administration:
Verteporfin therapy is a two-step process requiring administration of verteporfin followed by activation of the drug with light from a non-thermal diode laser. Verteporfin is administered via intravenous infusion at a dose of 6 mg/m2 given over 10 minutes. Lesion size determination, spot size determination, and light administration should be done as directed in the product labeling. The physician should re-evaluate the patient every three months, and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.1,2
The potential of a severe, possibly permanent decrease in vision exists with an overdose of verteporfin and/or light due to nonperfusion of normal retinal vessels. An overdose of verteporfin will also cause an increase in the duration of time that a patient remains photosensitive to bright light. For these patients, an extension in the photosensitivity precautions is recommended.1,2
Following verteporfin therapy, patients will become temporarily photosensitive (five days) and should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light (e.g., tanning salons, bright halogen lighting and high-power lighting) during this time period. If patients must go outdoors during daylight hours, they should protect themselves by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions. Patients should be encouraged to expose their skin to ambient indoor light as it will help inactivate the verteporfin in the skin through a process called photobleaching.1,2
Drug interactions:
To date, no drug interaction studies have been performed with verteporfin in humans. Verteporfin is rapidly eliminated by the liver, although metabolism is limited. Verteporfin does not appear to be metabolized via the cytochrome P450 system. However, calcium channel blockers, polymyxin B, or radiation therapy could enhance verteporfin uptake by vascular epithelium. Other photosensitizing agents could increase the potential for photosensitivity reactions. Drugs that scavenge radicals or quench active oxygen species could decrease verteporfin activity. Drugs that decrease clotting, vasoconstrictors, or platelet aggregation could decrease verteporfin efficacy.1
Drug-food interactions:
To date, there are no known drug-food interactions with verteporfin.1
Dosage form available:
Verteporfin is available in a 15 mg single-use vial, which is reconstituted with 7 mL of sterile water to a concentration of 2 mg/mL.1,2
Samples status:
Sampling of this agent would not be appropriate.
Filtration requirement:
Verteporfin must be administered using a syringe pump and in-line filter.1,2
Discussion:
Age-related macular degeneration (AMD) is the most common cause of legal blindness for people older than age 50, in the Western world. AMD has few treatment options and no proven preventative therapy. Laser photocoagulation is the one treatment proved to be effective in clinical trials, but only a minority of patients are eligible for this therapy. Verteporfin photodynamic therapy uses light-activated drugs to stop or slow abnormal cell growth in AMD. Phase I and II clinical trials have demonstrated the safety and short-term effects of verteporfin therapy on vision. Multicenter, randomized, placebo- controlled, double-blind, phase III trials with verteporfin are ongoing. The one-year follow-up data indicate that visual acuity, contrast sensitivity, and angiographic outcomes are significantly better in verteporfin-treated eyes than in placebo-treated eyes (p < 0.005). At the one-year analysis, 67% of verteporfin-treated eyes vs. 39% of placebo-treated eyes lost less than three lines of vision. Verteporfin is generally well-tolerated. Headache, injection-site reactions, and visual disturbances are the most commonly reported adverse reactions. Verteporfin can safely reduce the risk of vision loss in eyes with predominantly classic choroidal neovascularization (area of classic CNV ³ 50% area of entire lesion). In the absence of occult CNV, the benefits are of an even greater magnitude. Verteporfin therapy is safe and effective for the treatment of predominantly classic subfoveal CNV secondary to AMD. Although verteporfin is expensive, it presents a unique therapeutic option for patients with CNV secondary to AMD.1,6
References:
1. Visudyne package insert. Duluth, GA: CIBA Vision, A Novartis Co.; 2000 April.
2. Burnham TH, ed. Drug Facts and Comparisons. St. Louis: Facts and Comparisons Inc.; 10/2000.
3. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin. Arch Ophthalmol 1999; 117:1329-45.
4. Personal communication, Nov. 14, 2000, Ciba Vision, Duluth, GA.
5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams and Wilkins; 1998.
6. Margherio RR, Margherio AR, DeSantis ME. Laser treatments with verteporfin therapy and its potential impact on retinal practices. Journal of Retinal and Vitreous Diseases. 2000; 20(4):325-30.
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