Pegaptanib (Macugen®) Formulary Evaluation

By Tiffani Twilley, PharmD Candidate
Samford University
Written while on clinical rotations at Huntsville (AL) Hospital


  • Pegaptanib sodium injection (Macugen®) is a sterile, aqueous solution for intravitreous injection.1
  • Verteporfin (Visudyne®) is a light-activated drug for injection used in photodynamic therapy (PDT).2


  • Pegaptanib: Treatment of neovascular (wet) age-related macular degeneration.1,3-5
  • Verteporfin: Treatment of predominantly classic subfoveal choroidal neovascularization (CNV), which is a type of neovascular (wet) degeneration, caused by age-related degeneration, pathologic myopia, or presumed ocular histoplasmosis. Unlabeled uses include treatment of: psoriasis, psoriatic arthritis, rheumatoid arthritis, nonmelanoma skin cancers, circumscribed choroidal hemangioma.2,3

Mechanism of Action

Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist that binds to extracellular VEGF165, which is thought to be the primary isoform in neovascularization. VEGF is a protein that is secreted and selectively binds to and activates receptors on the surface of vascular endothelial cells inducing angiogenesis, increasing vascular permeability, and inflammation. These processes are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), a common cause of blindness. Through inhibition of VEGF binding to VEGF receptors, pegaptanib was found to be effective at suppressing pathological neovascularization in animal studies.1,3-5

Verteporfin is transported in the plasma primarily by lipoproteins. It is activated by light in the presence of oxygen and generates highly reactive, short-lived singlet oxygen and reactive oxygen radicals. Once activated, local damage occurs in the neovascular endothelium resulting in selective vessel occlusion of the newly formed vessels. It is these vessels that can hemorrhage, which leads to vision loss. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclooxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation, and vasoconstriction.2,3


To date, most pharmacokinetic studies have been conducted in animals.

  • Absorption

Following intravitreous administration, pegaptanib is slowly absorbed from the eye into systemic circulation. The rate of absorption from the eye of pegaptanib appears to be the rate-limiting step in the disposition of the drug. Within 24 hours after intravitreous administration of labeled pegaptanib, most of the drug was distributed throughout the retina and the vitreous and aqueous fluid. Within one to four days following a 3 mg monocular dose (10 times the recommended dose), the mean maximum plasma concentration was 80 ng/mL. The mean area under the curve is about 25 ug hr/mL at this dose.1,3-5

The extent of exposure and the maximal plasma concentration of verteporfin are proportional to the dose between 6 and 20 mg/m2.2,3

  • Distribution

Within 24 hours after intravitreous administration of radiolabeled pegaptanib to both eyes of rabbits, most of the drug was distributed throughout the retina and vitreous and aqueous fluid. Following intravitreous and intravenous administration of radiolabeled pegaptanib, the highest concentrations were obtained in the kidneys, excluding the eye for the intravitreous dose.1,3,4

Verteporin appears to preferentially accumulate in neovasculature including choroidal neovasculature.2,3


Pegaptanib is metabolized by endo- and exonucleases, presumed to be present in most tissue types, producing 2'- fluorouridine as one metabolite. This finding is based on preclinical data.1,3,4

Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent enzyme systems (including the cytochrome P450 isoenzymes) do not appear to play a role in the metabolism.2,3

  • Elimination

The average (+ standard deviation) half-life of pegaptanib is 10 (+4) days following a 3 mg monocular dose (10 times the recommended dose). Based on animal studies, pegaptanib is excreted as parent drug and metabolites primarily in the urine.1,3,5

Verteporfin exhibits a bi-exponential elimination with a half-life of approximately five to six hours. Elimination is by the fecal route with less than 0.01% of the dose recovered in urine.2,3


Pegaptanib is supplied in a single-use 1 mL glass syringe containing 0.3 mg of the drug in a volume of 90 mcL. It is administered 0.3 mg every six weeks by intravitreous injection into the affected eye. The length of therapy is based on clinical judgment; however, efficacy has only been proven for two years. The patient's medical history for hypersensitivity reactions should be evaluated prior to administration. In the special populations that have been studied (e.g., gender, renal insufficiency, and elderly), no dose adjustments were required. Studies have not been conducted in patients with hepatic impairment. The safety and efficacy of use in both eyes concurrently has not been studied.

Verteporfin is supplied in a single-use glass vial containing 15 mg of verteporfin. Intended for intravenous injection only, a course of verteporfin therapy is a two-step process requiring administration of both the drug and light. A desired dose of 6 mg/m2 body surface area is then drawn from the vial and diluted with 5% dextrose for injection to a total infusion volume of 30 mL. The full infusion is then given intravenously over 10 minutes at a rate of 3 mL/min using an appropriate syringe pump and in-line filter. The laser light is then initiated 15 minutes after the start of the 10-minute infusion of verteporfin that activates the drug. The laser is directed toward and confined to the specific target area within the eye. Verteporfin should be used cautiously in patients with moderate-to-severe hepatic impairment due to lack of studies in this population.


Pegaptanib is contraindicated for use in patients with ocular or periocular infections, or with known hypersensitivity to pegaptanib or any other excipient in this product.

Verteporfin is contraindicated in patients with porphyria or a known hypersensitivity to any component of this preparation.



  • For ophthalmic intravitreal injection only.
  • Pegaptanib intravitreous injections have been associated with endophthalmitis. To prevent, utilize proper aseptic technique when administering pegaptanib. Monitor patients during the week following the injection to identify and treat infections early.
  • Increases in intraocular pressure have been seen within 30 minutes of injection with pegaptanib. Monitor intraocular pressure as well as the perfusion of the optic nerve head and manage appropriately.
  • Rare reports of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in association with pegaptanib administration in conjunction with administration of other drugs as part of the procedure. A direct causal relationship between pegaptanib and these reactions has not been established.
  • Safety and efficacy in children has not been studied.
  • Verteporfin2,3
  • Extravasation is a risk, and methods to avoid this include: establish free-flowing IV line before starting infusion, use the largest arm vein possible (preferably antecubital), and avoid small veins in the back of the hand. If extravasation occurs, stop infusion immediately and apply cold compresses.
  • Possible hemodynamic effects may occur when verteporfin is administered in anesthetized patients. Supervise patients during infusion.
  • Photosensitivity risk is increased; exposure of skin or eyes to direct sunlight or bright indoor light should be avoided for five days. If extravasation occurs, the area must be thoroughly protected from direct light until the swelling and discoloration have faded to prevent local burn.
  • In patients who experience a severe decrease of vision of four lines on the eye chart (5 letters = l line) or more within one week after treatment, re-treatment should be delayed until vision completely recovers to pretreatment levels.
  • Incompatible lasers that do not provide the right characteristics of light may result in incomplete treatment.
  • Risk of mutagenesis, due to the fact that PDT is used, has been reported to result in DNA damage. It is not known how the potential for DNA damage with PDT translates into human risk.
  • Verteporfin should be considered carefully in patients with moderate-to-severe hepatic impairment or biliary obstruction because no clinical studies have been conducted in these patients.

Reduced effect has been seen with increasing age.

Drug Interactions


Although no drug interactions have been found, drug interaction studies have not been conducted. Pegaptanib is metabolized by nucleases and is not affected by the CYP450 system in general.


Drug interaction studies in humans have not been conducted, and CYP450 does not appear to play a role in verteporfin metabolism. However, based on the mechanism of action of this drug, many drugs, if used concomitantly, could have an effect on therapy (e.g., calcium channel blockers, polymyxin B, and radiation therapy), which could enhance the uptake of verteporfin by the vascular endothelium.

Efficacy may be decreased by drugs that decrease clotting, cause vasoconstriction, or inhibit platelet aggregation (i.e., thromboxane A2 inhibitors). Photosensitizing agents could increase the risk for photosensitivity reactions. Drugs such as dimethyl sulfoxide, beta-carotene, ethanol, and mannitol that activate oxygen species or scavenge radicals, decrease verteporfin activity.

Adverse Effects


  • Serious adverse effects include: endophthalmitis (1.3%), retinal detachment (0.7%), iatrogenic traumatic cataract (0.6%), anaphylaxis/anaphylactoid reactions including angioedema (rare).
  • Most frequently (10-40%) reported adverse events include: blurred vision, cataract, conjuctival hemorrhage, corneal edema, eye discharge, eye irritation, eye pain, hypertension, increased ocular pressure (IOP), ocular discomfort, punctate keratitis, reduced visual acuity, visual disturbances, vitreous floaters, and vitreous opacities.
  • Approximately 6-10% of patients reported the following: blepharitis, conjunctivitis, photopsia, vitreous disorder, bronchitis, diarrhea, dizziness, headache, nausea, and urinary tract infection.


  • Severe vision decrease (of four lines or more) within seven days of treatment was reported in 1-5% of patients.
  • Photosensitivity in the form of sunburn following exposure to sunlight.
  • Back pain during infusion.
  • Most frequently (10-30%) reported adverse events include: injection site reactions including extravasation and rashes, and visual disturbances such as blurred vision, decreased visual acuity, and visual field defects.
  • Approximately 1-10% of patients reported: blepharitis, cataracts, conjunctivitis, diplopia, dry eyes, ocular itching, severe vision loss, atrial fibrillation, hypertension, sleep disorder, vertigo, constipation, nausea, anemia, increased or decreased WBC count, albuminuria, increased creatinine, arthralgia, and cough.


Pegaptanib is pregnancy Category B. It is unknown whether pegaptanib is excreted in breast milk; caution is recommended when administering to nursing women.1,3

Verteporfin is pregnancy Category C. It is unknown whether verteporfin is excreted in breast milk; caution is recommended when administering to nursing women.2,3



Pegaptanib should be inspected prior to administration for visible particulate matter and/or discoloration. To administer, attach the threaded plastic plunger rod to the rubber stopper inside the barrel of the syringe. Do not pull back on the plunger and remove the syringe needle cap.


For administration, reconstitute each vial with 7 mL of sterile water for injection to provide 7.5 mL containing 2 mg/mL. Once reconstituted (opaque and dark-green), protect from light and use within four hours. The full infusion should be given intravenously over 10 minutes at a rate of 3 mL/min using an appropriate syringe pump and in-line filter.


Pegaptanib should be stored in the refrigerator. Do not freeze or shake vigorously.1,3

Verteporfin should be stored between 20° and 25° C (68° and 77° F). Reconstituted verteporfin must be protected from light and used within four hours.2,3

Patient Instructions

Following administration of pegaptanib, the patient is at increased risk of developing endophthalmitis.1,3 Seek immediate medical care if the eye becomes red, sensitive to light, painful, or develops a change in vision.

Following verteporfin treatment, photosensitivity will increase.2,3 Avoid direct sunlight and bright lights for five days. Patients should protect all parts of the skin and eyes by wearing protective clothing and sunglasses. UV sunscreens are not effective in protecting against photosensitivity. Encourage patients to expose their skin to ambient indoor light to help inactivate drug in the skin.

Clinical Studies

Trial 1: Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2,805-2,816.

Objective: Two concurrent clinical trials were conducted to evaluate the short-term safety and efficacy of pegaptanib in patients with a broad spectrum of visual acuities, lesion sizes, and angiographic subtypes of lesions at baseline.

Study design: This study was a summarization of two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials conducted at 117 different sites in the United States, Canada, Europe, Israel, Australia, and South America.

Intervention: Patients were randomly assigned to receive either sham injection or intravitreous injection of pegaptanib into one eye every six weeks over a period of 48 weeks, for a total of nine treatments. Those in the pegaptanib intervention group received one of three strengths: 0.3 mg, 1 mg, or 3 mg.

Adjunctive therapy: All patients underwent an ocular antisepsis procedure and all received injected subconjunctival anesthetic.

Patient Population

Inclusion criteria for the study were as follows:

  • Patients 50 years of age or older and had subfoveal sites of choroidal neovascularization secondary to age-related macular degeneration and a range of best-corrected visual acuity of 20/40 to 20/320 in the study eye and 20/800 or better in the other eye.
  • Patients with all angiographic subtypes of lesions with a total size up to and including 12 optic-disk areas (including blood, scar, or atrophy, and neovascularization).

Outcomes and Results

The primary endpoint was the proportion of patients who lost fewer than 15 letters of visual acuity (defined as three lines on the study eye chart) between baseline and week 54. Results can be found in Table 1, above.

The secondary endpoint was the proportion of patients treated with pegaptanib who maintained or gained visual acuity (no change in the number of letters or a gain of one or more letters on the eye chart). Results of the secondary endpoint are shown in Table 2, above.

Study Strengths

  • Prospective, randomized, double-blind, multicenter study.
  • Characteristics of patients at baseline were similar among treatment groups.
  • Appropriate inclusion criteria and length of study.


  • Lack of power to validate statistics.
  • Strengths and limitations not included in the article.
  • Different administration of the pegaptanib and the sham injection.
  • Patients allowed to receive PDT with verteporfin during the trial.

Authors' Conclusion

The results of this study showed the difference in treatment with pegaptanib compared to placebo to be statistically and clinically significant in regards to treatment benefit in a wide range of patients with neovascular age-related macular degeneration, regardless of the size or angiographic subtype of the lesion or baseline visual acuity. However, long-term data are needed to fully demonstrate the safety and efficacy of pegaptanib.

Trial 2: Visudyne in Minimally Classic Choroidal Neovascularization (VIM) Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration. Arch Ophthalmol 2005;123:448-457.

Objective: The purpose of the study was to compare the treatment efficacy and safety of photodynamic therapy with verteporfin using a standard (SF, 600 mW/cm2) or reduced (RF, 300 mW/cm2) light fluence rate to placebo in patients with subfoveal minimally classic CNV with age-related macular degeneration. The light fluence rate is the wavelength of photodynamic therapy being administered.

Study design: This study was a Phase 2, multicenter, double-blind, placebo-controlled, randomized clinical trial conducted in 19 ophthalmology practices across North America and Europe.

Intervention: Each patient was randomized to one of two fluence groups: standard (SF, 600 mW/cm2) or reduced (RF, which is 300 mW/cm2) light fluence rate. At the same time patients also were assigned to receive either verteporfin infusion 6 mg/m2 (intervention) or placebo (control). Treatment was repeated every three months, if the treating physician noted fluorescein leakage from CNV on angiography.

Patient Population

Inclusion criteria for the study were as follows:

  • Best-corrected visual acuity letter score (following the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy vision protocol) of at least 30 (Snellen equivalent, which is the standard eye chart used in practice, approximately 20/250 or better) for lesions of four macular photocoagulation study (MPS) disc areas or less and a 30-65 (approximate Snellen equivalent 20/50) for lesions of greater than four but no greater than six MPS disc areas.
  • Fluorescein angiographic evidence of subfoveal CNV due to AMD in which at least 50% of the lesion was CNV.
  • Fluorescent pattern of some classic CNV (bright area of fluorescence in early-phase frames with leakage at the boundaries of this area through the middle- and late-phase frames) that was less than 50% of the entire area of the lesion using previously defined terms.

Outcomes and Results: The primary endpoint was at least 15 letters (three lines) of visual acuity loss at 12 months. Results are tabulated in Table 3, below.

Study Strengths

  • Multicenter, double-blind, randomized study.
  • Appropriate inclusion criteria.
  • Equivalent baseline patient characteristics.


  • Small sample size.
  • Lack of power to validate statistics.

Authors' Conclusion

Based on the findings of this study, verteporfin has been proven to safely reduce the risks of loss of visual acuity (at least 15 letters or at least three lines), as well as progression to predominantly classic CNV for at least two years in patients with subfoveal minimally classic lesions that are caused by age-related macular degeneration that measures six MPS disc areas or fewer. In addition, the VIM Study Group would consider recommending verteporfin as therapy for the treatment of small minimally classic lesions like those enrolled in the trial.


One pre-filled 1 mL single-use syringe (contains 0.3 mg of pegaptanib) costs $995. One single-use vial containing 15 mg of verteporfin costs $1,678. Approximate costs of a photodynamic therapy laser used in the verteporfin procedure is $28,500 and would be used routinely to perform the procedure. This laser also could be rented for approximately $786/month.

Formulary Recommendation

Pegaptanib has been proven effective in treating age-related macular degeneration regardless of the lesion size or baseline visual acuity; therefore, it can be used in a broad spectrum of patients. Verteporfin therapy has previously been the treatment regimen for this disease. At this time, pegaptanib administration is considered mainly an outpatient procedure, with the drug cost at about $995 every six months. The procedure with verteporfin is done up to every three months if needed with a drug cost of $1678, and this does not include the cost of laser treatment. Both of these treatments are continued or stopped based upon clinical judgment. At this time, pegaptanib is recommended as nonformulary status for inpatients, with its administration being mainly in the outpatient setting. Each institution should decide if they will offer the verteporfin plus laser procedure to patients based on hospital-specific factors. The use of these drugs should be restricted to ophthalmic surgeon specialists.


  • Macugen [package insert]. New York City: Eyetech Pharmaceuticals Inc.; 2004.
  • Visudyne [package insert]. East Hanover, NJ: Novartis; 2004.
  • Efacts. Facts and Comparisons. Available at: Accessed Aug. 6, 2005.
  • Riley TN, DeRuiter J. Review of select NMEs of late 2004. US Pharm 2005;30:HS-12-HS-17.
  • Abramowicz M, ed. Pegaptanib sodium (macugen) for macular degeneration. The Medical Letter 2005;47:55-56.