This document only addresses the following medications used to treat retinal vascular conditions of the eye:

1. Pegaptanib (Macugen^®_, Eyetech Inc., Palm Beach Gardens, FL) by intravitreal injection for age-related macular degeneration
2. Bevacizumab (Avastin^®_, Genentech, Inc., San Francisco, CA) by intravitreal injection for age-related macular degeneration, branch retinal vein occlusion, central retinal vein occlusion, diabetic macular edema, retinopathy of prematurity and rare eye disorders such as pseudoxanthoma elasticum, choroidal neovascularization and neovascular glaucoma
3. Ranibizumab (Lucentis^®_, Genentech, Inc., San Francisco, CA) by intravitreal injection for age-related macular degeneration, branch retinal vein occlusion, central retinal vein occlusion, and diabetic macular edema
4. Anecortave acetate (Retaane^®_, Alcon Research, Ltd., Forth Worth, TX ) conjunctival incision with posterior juxtascleral (extrascleral) placement of depot suspension as treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration

Note: Please see the following related documents for additional information:

• DRUG.00032 Intravitreal Corticosteroid Implants
• DRUG.00038 Bevacizumab (Avastin^®) for Oncologic Indications

I. Pegaptanib (Macugen^®) 

Medically Necessary: 

A series of intravitreal injections with pegaptanib is considered medically necessary as a treatment of established neovascular "wet" age-related macular degeneration (AMD).

Investigational and Not Medically Necessary: 

The use of pegaptanib for any condition other than established neovascular "wet" AMD is considered investigational and not medically necessary.

The use of pegaptanib for diabetic eye disease is considered investigational and not medically necessary.

The use of pegaptanib as a treatment for other forms of AMD to prevent progression to neovascular "wet" AMD is considered investigational and not medically necessary.

II. Bevacizumab (Avastin^®) 

Medically Necessary: 

A series of intravitreal injections with bevacizumab is considered medically necessary as a treatment of established neovascular "wet" AMD.

A series of intravitreal injections with bevacizumab is considered medically necessary as a treatment for any of the following:

1. Branch retinal vein occlusion; or
2. Central retinal vein occlusion; or
3. Diabetic macular edema; or
4. Neovascular glaucoma; or
5. Other rare causes of choroidal neovascularization for one or more of the following conditions:
   • angioid streaks; or
   • choroiditis (including, but not limited to histoplasmosis induced choroiditis); or
   • degenerative myopia, idiopathic; or
   • retinal dystrophies; or
   • trauma; or
6. Pseudoxanthoma elasticum; or
7. Retinopathy of prematurity.

Investigational and Not Medically Necessary: 

The use of intravitreal bevacizumab is considered investigational and not medically necessary for any other condition not listed above as medically necessary.

III. Ranibizumab (Lucentis^®)

Medically Necessary:

A series of intravitreal injections with ranibizumab is considered medically necessary as a treatment for any of the following:

1. Established neovascular "wet" AMD; or
2. Branch retinal vein occlusion; or
3. Central retinal vein occlusion; or
4. Diabetic macular edema.

Investigational and Not Medically Necessary:

The use of intravitreal ranibizumab is considered investigational and not medically necessary for any other condition not listed above as medically necessary.

IV. Anecortave Acetate (Retaane) Conjunctival Incision with Posterior Juxtascleral (Extrascleral) Placement of Depot Suspension 

Investigational and Not Medically Necessary:

Conjunctival incision with posterior juxtascleral (extrascleral) placement of anecortave acetate depot suspension is considered investigational and not medically necessary as a treatment of AMD and all other diagnoses.

I. Pegaptanib (Macugen^®) 

Two concurrent, prospective randomized, double blind controlled clinical trials using sham control have been reported regarding pegaptanib in the treatment of the wet form of AMD (VEGF [vascular endothelial growth factor] Inhibition Study in Ocular Neovascularization [VISION] Clinical Trial Group, 2006a, VISION Clinical Trial Group, 2006b). These studies were used as the basis of approval from the U.S. Food and Drug Administration (FDA) in 2004.

The populations of these studies included all forms of wet AMD. Predominantly classic, minimally classic and occult were included in these studies. The injections were repeated every 6 weeks. In both studies, the primary endpoint was the proportion of individuals losing less than 15 letters of visual acuity (considered a moderate visual loss) from baseline. While on average, both treated and control groups continued to experience vision loss, the rate of vision decline in the treated group was slower than that in the control group. This difference was statistically significant. At the end of 1 year, most of the individuals in these two studies were re-randomized. Treatment in the second year was less effective than during the first year.

Additional published literature confirms the safety of pegaptanib (Macugen AMD Study Group, 2007). The most common ocular adverse events were transient, mild to moderate in intensity, and attributed to the injection preparation and procedure.

There are no data available regarding this treatment when used for more than 2 years. Additionally, there are no data to support the use as a preventive strategy for other forms of macular degeneration. Insufficient data is available for the use in other ophthalmologic processes such as diabetic retinopathy (Dahr, 2007; Krzystolik, 2006). In 2005, Cunningham and colleagues reported on the evaluation and safety of the use of pegaptanib for the treatment of diabetic macular edema (DME). In a randomized, double-masked controlled trial, 172 participants were randomized to 1 of 4 treatment arms (0.3mg injection, 1 mg injection, 3 mg injection or sham injection). Injections were given at the onset of the study and at weeks 6 and 12 thereafter. Additional injections could be given at the discretion of the investigators if judged to be indicated (for a maximum of 6 injections). The 3 pegaptanib treatment groups showed better visual acuity at week 36 when compared to the sham group. However, it is unknown if these results are better than if focal photocoagulation had been given also. It is also unknown if the beneficial outcomes would persist for 3 years as has been shown for focal photocoagulation. The investigators were also unable to identify statistical differences between the pegaptanib doses. While the results look promising, the authors concluded that "confirmation of these preliminary observations of pegaptanib safety, patient tolerance, and significant efficacy across a broad spectrum of patients with DME in sufficiently powered prospective clinical trials is planned." Clinical trials are underway to assess the safety and efficacy of pegaptanib for diabetic macular edema. However, at this time, current published literature is limited to small group sizes and retrospective analyses.

II. Bevacizumab (Avastin^®)

Clinical trials have appeared in the medical literature suggesting that another vascular endothelial growth factor (VEGF) antagonist, bevacizumab, may be effective in the treatment of wet AMD (Avery, 2006b; Rich, 2006; Spaide, 2006b). In a retrospective study, Spaide (2006b) studied 266 individuals who received intravitreal injections of bevacizumab. The individuals were followed for three months. The authors reported mean visual acuity improved from 20/184 at baseline to 20/109 and 38% had improvement in visual acuity. A retrospective study by Avery (2006b) followed 79 individuals for 8 weeks with a mean visual acuity improvement from 20/200 to 20/125 (P<0001). Rich and colleagues (2006) reported short term results for 53 eyes of 50 individuals who received intravitreal bevacizumab injections. At 3 months, no serious drug-related ocular or systemic adverse events were identified and the mean visual acuity improved from 20/160 to 20/125 (P < 0.001) and the mean central retinal thickness decreased by 99.6 microm (P < 0.001).

According to a letter from the American Academy of Ophthalmology (AAO):

Although the scientific studies related to the use of intravitreal injections of bevacizumab for the treatment of neovascular AMD are supportive, but not conclusive of its safety and efficacy, a large number of retinal specialists believe that it is a reasonable and medically necessary treatment for some patients with neovascular AMD.

Although prospective randomized trials regarding bevacizumab have not yet been conducted, the AAO position and additional data suggest broad and general acceptance of this therapy among retinal specialists. A phase III randomized, double blind study sponsored by the National Institute for Health is evaluating the safety and efficacy of ranibizumab and bevacizumab on a fixed schedule versus ranibizumab and bevacizumab on a variable schedule as treatments for neovascular "wet" AMD. The study is currently enrolling individuals and the estimated study completion date is 2011.

Arevalo and colleagues (2010) report the results of a 24-month study in which 180 subjects received at least 1 injection of intravitreal bevacizumab for subfoveal choroidal neovascularization secondary to age-related macular degeneration. Individuals received best-corrected visual acuity testing, ophthalmoscopic exam, optical coherence tomography and fluorescein angiography at baseline and at 1-, 3-, 6-, 12-, and 24-months thereafter. Systemic adverse events included elevated blood pressure, cerebrovascular accidents, myocardial infarctions, iliac artery aneurysms, toe amputations and death. Ocular complaints included bacterial endophthalmitis, tractional retinal detachments, uveitis and rhegmatogenous retinal detachment and vitreous hemorrhage. At 24-months, all individuals showed stability or improvement in best-corrected visual acuity, optical coherence tomography and fluorescein angiography. Another recent study also reported on the use of intravitreal bevacizumab for age-related macular degeneration with 54-week follow-up. Tufail et al (2010) randomized 131 subjects to either intervention with bevacizumab or standard treatment of photodynamic treatment with verteporfin, pegaptanib or sham control. In the bevacizumab group, more letters were gained from baseline when compared to the standard treatment group.

There are rare causes of choroidal neovascularization (degenerative myopia, idiopathic, angioid streaks, trauma, choroiditis, retinal dystrophies, ocular histoplasmosis) for which there are no other approved therapies. There is an unmet medical need for treatment and the extremely low incidence of disease will make comparative treatment trials virtually impossible. There is strong biologic plausibility from small case series that intravitreal bevacizumab may be of benefit (Chan, 2007b; Finger, 2008). Also, specialty consensus opinion suggests that the drug may be used for these rare disorders due to the lack of other available treatment.

Neovascular glaucoma is a severe form of glaucoma with devastating visual outcome caused by the growth of new blood vessels which obstruct aqueous humor outflow. This causes an increase in intraocular pressure (IOP). In a study by Costagliola (2008), 23 individuals were scheduled to receive intravitreal injections of bevacizumab at four week intervals. At the end of the scheduled protocol (three injections of intravitreal bevacizumab), IOP was reduced, and visual acuity, pain and edema were significantly improved.

Use of intravitreal bevacizumab has been suggested for other retinal conditions including radiation retinopathy (Finger, 2007) and proliferative diabetic retinopathy (Avery, 2006a; Jorge, 2006; Spaide, 2006a). However, many of the studies were small retrospective case series with limited follow-up. Intravitreal bevacizumab has also been suggested for central retinal vein occlusion (Costa, 2007; Iturralde, 2006; Mohamed, 2007; Moschos, 2008; Rosenfeld, 2005), branch retinal vein occlusion (Ahmadi, 2009; Gunduz, 2008; Kreutzer, 2008; Rensch, 2009) and diabetic macular edema (Arevalo, 2007; Arevalo, 2009; Haritoglou, 2006). Since ranibizumab is derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab, specialty consensus suggests that bevacizumab may be appropriate for the same disorders as ranibizumab including branch retinal vein occlusion, central retinal vein occlusion and diabetic macular edema.

Retinopathy of prematurity is a leading cause of childhood blindness throughout the world. For neonates, it is believed that exposure to high levels of oxygen obliterate the vessels in the retina. Current treatment is peripheral retinal ablation with laser therapy which is destructive (i.e., the laser destroys the majority of cells that produce VEGF in the retina), has complications and does not prevent all vision loss. Bevacizumab is an emerging treatment for retinopathy of prematurity. Recently there have been several small case series studies which have shown improvement in retinopathy of prematurity after use of intravitreal bevacizumab (Ahmed, 2010; Erol, 2010; Wu, 2011). Mintz-Hittner and colleagues (2011) reported on a controlled (but not masked) study of 150 infants with retinopathy of prematurity who were randomized to receive either intravitreal bevacizumab or conventional laser therapy. The primary outcome was whether retinopathy of prematurity recurred in the eyes and required re-treatment using bevacizumab before 54 weeks' postmenstrual age. In infants with zone I retinopathy of prematurity, 94% had no evidence of recurrence compared to 58% of the infants treated with conventional laser therapy. In addition, there were more structural complications (need for vitrectomy, detachment, macular dragging) in the infants treated with laser therapy. The authors concluded that:

Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina.

The limited number of infants studied makes it difficult to draw conclusions regarding the safety of this treatment. The authors noted that the "study was too small to address the question of whether intravitreal bevacizumab is safe" and that additional research is necessary. However, the primary alternative treatment is also not without risk. Laser photocoagulation requires intubating, sedating, and immobilizing the child and may permanently destroy the peripheral retina. The available scientific literature suggests that intravitreal bevacizumab for retinopathy of prematurity improves net health outcomes and is at least as beneficial as the established alternatives at this time.

III. Ranibizumab (Lucentis^®)

On June 30, 2006, the FDA approved ranibizumab for the treatment of individuals with neovascular "wet" age-related macular degeneration. This approval was based on the results of three randomized, double-masked, sham or active-controlled clinical trials in individuals with neovascular AMD. The combined number of individuals for all 3 trials was 1323. In the first study, individuals with minimally classic or occult choroidal neovascularization (CNV) lesions received monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) or monthly sham injections over a 24-month period. In a second study, individuals with predominantly classic CNV lesions received one of the following: 1) monthly intravitreal injections of ranibizumab (0.3 mg) and sham photodynamic therapy (PDT); 2) monthly intravitreal injections of ranibizumab (0.5 mg) and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT over a 12-month period. The primary efficacy endpoint was the proportion of individuals who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all ranibizumab-treated individuals (approximately 95%) maintained their visual acuity. Thirty-four to forty percent of ranibizumab-treated individuals experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. In the third study, 184 individuals with neovascular AMD (with or without a classic CNV component) received ranibizumab. Sixty individuals received 0.3 mg intravitreal injections, 61 individuals received 0.5 mg intravitreal injections and 63 individuals received sham injections once a month for three consecutive doses, followed by a dose administered once every 3 months. The primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline. After an initial increase in visual acuity (following monthly dosing), on average, individuals dosed once every three months with ranibizumab lost visual acuity, returning to baseline at month 12. Ninety percent of ranibizumab-treated individuals maintained their visual acuity at month 12.

The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) study was a 2-year, double-blind, sham-controlled study in which 716 randomly assigned individuals with AMD received either monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections for 24 months (Boyer, 2007; Rosenfeld, 2006a). Rosenfeld and colleagues (2006a) reported results at 12 months and 24 months. At 12 months, 94.5% of the 0.3 mg dose group and 94.6% of the 0.5 mg dose group lost fewer than 15 letters, as compared with 62.2% of individuals receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg dose group and 33.8% of the 0.5-mg dose group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five individuals (1.0%) and serious uveitis in six individuals (1.3%) given ranibizumab. A subgroup analysis compared efficacy outcomes across subgroups based on individuals' gender, age, baseline visual acuity score, baseline CNV lesion size, CNV lesion type, and duration of neovascular AMD (Boyer, 2007). Ranibizumab treatment was associated with an average increase from baseline visual acuity in all subgroups evaluated and was superior to sham treatment across all subgroups. Predictors of visual acuity outcomes were, in decreasing order of importance, baseline visual acuity score, CNV lesion size, and age.

The FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) trial was a phase I/II randomized, single-masked study evaluating the safety, tolerability and efficacy of ranibizumab in combination with PDT in 162 individuals with predominantly classic subfoveal wet AMD. One hundred six individuals received monthly ranibizumab (0.5 mg) and 56 individuals received sham injections. The PDT was performed 7 days before initial ranibizumab or sham treatment and then quarterly as needed. At 12 months, 90.5% of the ranibizumab-treated individuals and 67.9% of the control group had lost fewer than 15 letters (P<.001). The most frequent ranibizumab-associated serious ocular adverse events were intraocular inflammation (11.4%) and endophthalmitis (1.9%; 4.8% if including presumed cases).

Another study in the same participant population, the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) Study is a 2-year, multicenter, double-blind study, in which 423 individuals with AMD were randomly assigned to monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy. The primary end point was the proportion of individuals losing fewer than 15 letters from baseline visual acuity at 12 months. Of the 423 individuals enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison). Follow-up is continued through 2 years of treatment (Brown, 2009). Of the 423 individuals who started the study, at least 77% in each group have completed the 2-year study. Consistent with the results measured at month 12, at month 24 the visual acuity benefit from ranibizumab therapy showed 89.9% to 90% had lost less than 15 letters from baseline versus 65.7% of individuals treated with verteporfin therapy.

Additional studies have confirmed the safety and efficacy of ranibizumab (Heir, 2006; Rosenfeld, 2006b). The most common post injection adverse event was mild transient ocular inflammation.

The use of ranibizumab has been suggested for the treatment of diabetic macular edema (DME) (Chun, 2006; Nguyen, 2006) and retinal vein occlusion. Current treatment for DME includes laser photocoagulation. However, a large proportion of treated eyes remain unresponsive. Intravitreal triamcinolone acetonide and pars plana vitrectomy are other treatment options for DME but both treatments have limited efficacy and significant side effects.

Previous studies for the use of ranibizumab for DME have been small case series with limited follow-up. Investigators acknowledged large randomized controlled trials with several years of follow-up are necessary to determine the clinical efficacy of ranibizumab in DME. The Diabetic Retinopathy Clinical Research Network (Elman, 2010) reports on one-year and two-year data for ranibizumab for DME. In this phase III study, a total of 854 study eyes were randomized to one of four treatment arms: sham injection plus prompt laser, ranibizumab plus prompt laser, ranibizumab plus deferred laser, or triamcinolone plus prompt laser. Approximately half of the eyes treated with ranibizumab had a greater than 10 letter gain from baseline and approximately 30% gained greater than 15 letters (equivalent to three lines on the eye chart). For the eyes treated with ranibizumab plus laser, the results were similar whether the laser was prompt or delayed. Additional studies are reporting outcomes data on the use of ranibizumab for DME (Nguyen, 2010) and in June 2010, the FDA approved ranibizumab for macular edema following retinal vein occlusion.

In 2010, Massin et al, reports the Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study). Individuals (n=151) with diabetic macular edema were randomized to receive intravitreal ranibizumab or sham. At 12-months, the ranibizumab group had an improvement of 7.8 letters compared with -0.1 letters in the sham group. Best-corrected visual acuity in the ranibizumab group improved by 10.3 letters from baseline compared to a decline of 1.4 letters from baseline in the sham group. While this study suggests ranibizumab is effective in improving best-corrected visual acuity for those with diabetic macular edema, further clinical trials are necessary to confirm long-term safety and efficacy.

Campochiaro and colleagues (2010) reported on the six-month results of a phase III study assessing the safety and efficacy of intraocular injections of ranibizumab for those with branch retinal vein occlusion. A total of 397 individuals were randomized to receive either intraocular injection of ranibizumab or sham injections. There was a mean improvement of 7.5 letters one week after the first treatment with the ranibizumab injections. After six months of treatment with ranibizumab there was a mean improvement of between 3 and 4 lines of vision compared to 1.5 lines in the sham group. At six-month follow-up there was a 65% improvement for those treated with ranibizumab versus 42% for those in the sham group.

IV. Conjunctival Incision with Posterior Juxtascleral (Extrascleral) Placement of Anecortave Acetate (Retaane) Depot Suspension

The Anecortave Acetate Clinical Study, a blinded, randomized controlled trial, enrolled 128 individuals with subfoveal CNV at 18 clinical sites, followed participants for two years, and was completed in June 2003. The study eye was randomized to 30 mg, 15 mg, 3 mg, or placebo from a central coordinating center. Anecortave acetate or placebo was administered at baseline; retreatment at the 6-month visit occurred at the discretion of an unmasked ophthalmologist based on perceived benefit. Compared to placebo, 15 mg (the most efficacious dose) was accompanied by a 25.5% absolute risk benefit for losing fewer than 15 letters of visual acuity. No serious clinically relevant treatment-related safety issues were reported from either the study medication (anecortave acetate) or the procedure for administration. Adverse ocular events seen in excess in individuals treated with anecortave vs. placebo were 15.3% excess of vision abnormalities and 7.1% excess of ocular foreign body sensation. Cataracts were found in 27% and 30% and decreased visual acuity was noted in 25% and 30% in the treatment and placebo groups, respectively. These occurrences included study eyes, untreated eyes, or both eyes and are commonly experienced in individuals with AMD. Other adverse events that were reported as mild and transient included ptosis, ocular pain, visual abnormalities (e.g., hazy vision, black spots, light flashes), subconjunctival hemorrhage, and ocular pruritis.

A phase III randomized control trial compared the one-year safety and efficacy of anecortave acetate 15 mg with photodynamic therapy (PDT) with verteporfin in 530 individuals with predominantly classic CNV. Anecortave acetate 15 mg was comparable to PDT for maintaining vision, with no statistical difference in the responder rates between the two groups. Percent responders, defined as individuals losing less than 3 lines of vision at month 12, in the anecortave acetate 15 mg and PDT groups were 45% and 49%, respectively. The month 12 outcome for anecortave acetate was improved in individuals for whom reflux was controlled and who were treated within the 6-month window. The most frequent reported adverse event in both treatment groups was decreased visual acuity, defined as a loss of vision of greater than or equal to 4 lines from the previous visit, occurring at an incidence of 31.9% and 30.3%, respectively.

In summary, conjunctival incision with posterior juxtascleral placement of anecortave acetate depot suspension appears to be technically feasible and clinically safe. The adverse events reported were mostly mild and transient and were commonly experienced with ocular procedures. Outside of the controlled setting of a clinical trial, adverse events will be of greater potential concern. Anecortave acetate has not yet received FDA approval, and further studies on long-term health outcomes are needed.

On July 11, 2008, Alcon submitted a press release that stated it was terminating the development of anecortave acetate in age-related macular degeneration. On July 2, 2009 Alcon released a statement that it was discontinuing the development of anecortave acetate for intraocular pressure reduction.

Age-related macular degeneration (AMD) is an eye disease characterized by progressive degeneration of the macula, the central part of the retina at the back of the eye. When this is caused by the development of a subretinal neovascular membrane, the condition is commonly referred to as "wet" or neovascular AMD. Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people over 55 years of age in the developed world. The neovascular "wet" form of this disease represents 10% of the overall disease prevalence but is responsible for roughly 90% of the vision loss due to AMD. It is more common in Caucasians and its incidence increases with age as it is estimated that 10 to 15% of those in their 80s have some form of AMD.

In neovascular AMD also known as "wet" AMD, abnormal blood vessels develop behind the retina. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal position at the back of the eye. Damage to the macula occurs rapidly. With wet AMD, loss of central vision can occur quickly. Wet AMD is considered to be advanced AMD and is more severe than the dry form.

Angiogenesis is the growth of new blood vessels. In neovascular AMD, the growth is uncontrolled. VEGF, a cytokine, appears to have a key role in angiogenesis and vascular permeability. Overexpression of VEGF is thought to contribute to the development of AMD, diabetic retinopathy, and other retinal disorders associated with neovascularization. Research has focused on development of compounds designed to bind to and inhibit VEGF. VEGF Inhibition thereby inhibits angiogenesis and decreases vascular permeability and can be an effective treatment of AMD.

Retinal vein occlusion occurs when there is a blockage of the blood supply from the retina. Depending on where the blockage occurs, the condition can be characterized as central retinal vein occlusion or branch retinal vein occlusion. This condition most often affects older individuals and can be caused by a blood clot, diabetes, glaucoma, atherosclerosis or hypertension. Symptoms include sudden blurred vision or loss of vision. Retinal vein occlusion is the second most common type of retinal vascular disease and is estimated to involve 180,000 eyes per year.

The macula is the part of the eye where sharp, straight-ahead vision occurs. Fluid can leak into the center of the macula, causing the macula to swell, resulting in blurred vision. Common in diabetics, this is known as diabetic macular edema.

I. Pegaptanib (Macugen)

Pegaptanib, a selective VGEF antagonist, is an oligonucleotide, twenty-nucleotides in length, to which two polyethylene glycol (PEG) units are attached. This oligonucleotide (aptamer) has a complex 3-dimensional structure that binds to upregulated VEGF, preventing it from binding to its receptors. It is administered by a series of intravitreous injections (into the interior space of the eye) and given every 6 weeks. 

The proposed benefit of pegaptanib is slowed progression of neovascular "wet" AMD.

Intraocular injections pose a risk for infection, retinal detachment and traumatic lens injury. This treatment requires a series of such injections. These injections require the treating physician to adhere to appropriate aseptic technique, educate individuals regarding worrisome symptoms and monitor individuals after each injection as increases in intraocular pressure have been seen within 30 minutes of these injections. Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post-marketing experience following the Macugen intravitreal administration procedure. Medical history for hypersensitivity reaction should be evaluated prior to performing the intravitreal procedure.

II. Bevacizumab (Avastin)   

Bevacizumab, which was initially FDA approved for the treatment of metastatic colon cancer, is a monoclonal antibody that binds to VEGF. Intravitreal usage of bevacizumab is a non-FDA approved use which has been widely reported by practicing ophthalmologists to be beneficial in select individuals with neovascular AMD. Based on response, repeat intravitreal injections may be required. The proposed benefit of bevacizumab is slowed progression of neovascular "wet" AMD. 

Intraocular injections pose a risk of infection, retinal detachment and traumatic lens injury. This treatment requires a series of such injections. These injections require the treating physician to adhere to appropriate aseptic technique, educate individuals regarding worrisome symptoms and monitor individuals after each injection as increases in intraocular pressure have been seen within 30 minutes of these injections. In a case series of 79 individuals, Avery (2006b) reported bevacizumab by intravitreal injection was well tolerated and no participant was noted to develop uveitis, endophthalmitis, ocular toxicity, or thromboembolic events. Garg (2008) reported a 1.6% incidence of retinal pigment epithelial (RPE) tears out of 920 eyes treated with bevacizumab. The investigators suggested that RPE tears may also be a part of the underlying disease process.

Neovascular glaucoma is a rare and devastating ocular disease that can result in the loss of vision. Many times it is first recognized when an individual complains of a sudden loss of vision, a red or uncomfortable eye, or pain. New blood vessels grow in the eye and there is a build up of internal eye pressure referred to as intraocular pressure (IOP). The IOP causes a decrease in vision and must be reduced. Bevacizumab works by binding to VEGF and inhibiting the interaction of VEGF to Flt1 and KDR receptors on the surface of endothelial cells. As a result of the binding process, the increase of endothelial cells and formation of new blood vessels is prevented.

Retinopathy of prematurity causes loss of vision by way of macular dragging and detachment of the retina, primarily occurring in premature and low birth weight infants. Pre-term birth is considered before 31 weeks gestational age. Infants born before 31 weeks gestation are at risk for an immature retina leading to the development of abnormal retinal fibrovascular tissue. With appropriate screening and treatment, the incidence of blindness in infants due to retinopathy of prematurity is relatively low (approximately 1 case in 820 infants).

III. Ranibizumab (Lucentis)

Derived from the same parent molecule as the full-length humanized anti-VEGF antibody bevacizumab, ranibizumab is an anti-VEGF antibody fragment that competitively binds VEGF and inhibits its activity. Ranibizumab was specifically developed for intraocular use. As a smaller molecule, ranibizumab may possibly have better penetration through all the layers of the retina compared with a full-sized antibody.

Ranibizumab is usually administered by intravitreal injection once a month. Although less effective, treatment may be reduced to one injection every three months after the first four injections if monthly injections are not feasible. Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. The proposed benefit of ranibizumab is slowed progression of neovascular "wet" AMD. 

Intravitreal injections have been associated with endophthalmitis, retinal detachments and iatrogenic traumatic cataracts. Individuals should be closely monitored post injection as increases in intraocular pressure have been noted within 60 minutes of intravitreal injection with ranibizumab. In the clinical trials, a low rate (less than 4%) of arterial thromboembolic events was observed. The most common adverse reactions are conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation. Ranibizumab is contraindicated in individuals with ocular or periocular infections or known hypersensitivity to ranibizumab or any of the excipients in ranibizumab.

On January 24, 2007, Genentech, the manufacturer of ranibizumab, informed healthcare providers of preliminary safety information in an ongoing study (SAILOR) which confirmed the higher incidence of stroke in the 0.5 mg dose group compared to the 0.3 mg dose group (1.2% versus 0.3%, respectively; P=0.02) of individuals with neovascular age-related macular degeneration who received intravitreal ranibizumab (U.S. Food and Drug Administration, 2007). The rates of stroke for both dose groups are lower than the rates seen in the controlled clinical trials and included in the approved labeling. The planned frequency of dosing was not the same as that described in the approved labeling. Additional analysis of data is planned.

In the FOCUS study (Antoszyk, 2008), arterial thromboembolic events occurred at 7.1% in the group of individuals receiving photodynamic therapy plus sham therapy versus 4.8% in the group of individuals receiving photodynamic therapy plus ranibizumab. The PIER Study by Regillo and colleagues (2008) showed no arterial thromboembolic events in the 61 individuals receiving 0.5mg intravitreal injections of ranibizumab.

IV. Anecortave Acetate (Retaane) Conjunctival Incision with Posterior Juxtascleral (Extrascleral) Placement of Depot Suspension

Anecortave acetate is a synthetic cortisone that has been chemically modified into an angiostatic cortisene that inhibits the proteolysis required for vascular endothelial cell migration, thereby inhibiting ocular neovascularization. Anecortave acetate is a slow-release depot suspension that may be delivered at 6-month intervals and allows for sustained delivery to the affected area near the macula when administered by the novel procedure of posterior juxtascleral placement. Retaane received an approvable letter from the FDA in May 2005 for treatment of age-related macular degeneration but has not yet received final FDA approval. In 2008 and 2009 the manufacturer released statements that they were no longer developing the product for age-related macular degeneration and intraocular pressure reduction. Anecortave acetate is no longer on the market and clinical trials have shown it was not effective.

In the conjunctival incision with posterior juxtascleral placement of the depot suspension procedure, after topical anesthesia, a 1.0–1.5-mm to 2–3-mm incision into the superotemporal quadrant of the orbit is made 8 mm posterior to the limbus between the superior and lateral rectus muscle insertions. The incision is made down through the conjunctiva and Tenon's capsule to reveal bare white sclera but the sclera is not incised. A specially designed, blunt-tipped, curved, 56° cannula is then carefully inserted into the juxtascleral (episcleral) plane between the outer surface of the sclera and Tenon's capsule and fed forward until the cannula tip is near the macula. Gentle pressure is applied around the inserted cannula during administration of the depot suspension and removal of the cannula to prevent reflux and a semi-pressure patch is applied.

The proposed benefit of anecortave acetate is slowed progression of subfoveal choroidal neovascularization due to wet AMD. Advantages to the posterior juxtascleral placement of a pharmacologic agent may include reduced risk for retinal detachment, endophthalmitis, and other safety issues associated with repeated intravitreal injections (a common route of administration for pharmaceutical agents in the treatment of ocular disorders).

Adverse events related to the posterior juxtascleral placement injection procedure include ptosis, ocular pain, subconjunctival hemorrhage, ocular pruritis, ocular hyperemia, and ocular foreign body sensation. 

Age-related macular degeneration (AMD): A slowly progressive, painless disease affecting the macula that blurs the sharp, central vision needed for "straight-ahead" activities such as reading, sewing, and driving.

Branch retinal vein occlusion: An occlusion near the retina in a branch retinal vein.

Central retinal vein occlusion: An occlusion of the central retinal vein where it enters the eye.

Choroid: Sponge like membrane in the eye located between the sclera and the retina.

Diabetic macular edema: The leakage of fluid from retinal blood vessels which in turn causes the macula to swell.

Neovascular (wet) AMD: A subset of AMD representing approximately 10% of all cases but accounting for 90% of the severe vision loss. AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid which  thickens the macula and damages the photoreceptors. Damage to the macula can occur rapidly, resulting in sudden loss of central vision. Wet AMD is considered to be advanced AMD and more severe than the dry form.

Neovascular glaucoma: A severe form of glaucoma with devastating visual outcome caused by the growth of new blood vessels which obstruct aqueous humor outflow.

Neovascularization: The formation of abnormal new blood vessels.

Pseudoxanthoma elasticum: An inherited disorder of the connective tissue in the skin, eyes, gastrointestinal and cardiovascular system.

Retinal vein occlusion: A blockage in the blood supply from the retina.

Retinopathy: Damage to the retina.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

I. Intravitreal Injections of pegaptanib 

When services are Medically Necessary:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of pegaptanib for the following diagnoses

II. Intravitreal Injections of bevacizumab  

When services are Medically Necessary:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of bevacizumab, for the following diagnoses:

III. Intravitreal Injections of ranibizumab  

When services are Medically Necessary:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above for intravitreal injection of ranibizumab for the following diagnoses

IV. Conjunctival incision with placement of pharmacologic agent 

When Services are Investigational and Not Medically Necessary:
For the procedure code listed below for all diagnoses; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

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2. Adán A, Navarro M, Casaroli-Marano RP, et al.. Intravitreal bevacizumab as initial treatment for choroidal neovascularization associated with presumed ocular histoplasmosis syndrome. Graefes Arch Clin Exp Ophthalmol. 2007; 245(12):1873-1875.
3. Ahmadi AA, Chuo JY, Banashkevich A, et al. The effects of intravitreal bevacizumab on patients with macular edema secondary to branch retinal vein occlusion. Can J Ophthalmol. 2009; 44(2):154-159.
4. Ahmed AE, Channa R, Durrani J, et al. Early experience with intravitreal bevacizumab combined with laser treatment for retinopathy of prematurity. Middle East Afr J Ophthalmol. 2010; 17(3):264-267.
5. Antoszyk AN, Tuomi L, Chung CY, Singh A. FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol. 2008; 145(5):862-874.
6. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology. 2007; 114(4):743-750.
7. Arevalo JF, Sánchez JG, Wu L, et al. Intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration at twenty-four months: the Pan-American Collaborative Retina Study. Ophthalmology. 2010; 117(10):1974-1981.
8. Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology. 2009; 116(8):1488-1497.
9. Augustin AJ, D'Amico DJ, Mieler WF, et al. Safety of posterior juxtascleral depot administration of the angiostatic cortisene anecortave acetate for treatment of subfoveal choroidal neovascularization in patients with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2005; 243(1):9-12.
10. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006a; 113(10):1695. e1-15.
11. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006b; 113(3):363-372.
12. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol. 2006; 142(1):1-9.
13. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol. 2008; 145(2):249-256.
14. Boyer DS, Antoszyk AN, Awh CC, et al. MARINA Study Group. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007; 114(2):246-252.
15. Brown DM, Kaiser PK, Michels M, et al. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1432-1444.
16. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009; 116(1):57-65.
17. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010; 117(6):1102-1112.
18. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, secondary to punctate inner choroidopathy, or of idiopathic origin. Am J Ophthalmol. 2007a; 143(6):977-983.
19. Chan WM, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (Avastin) for myopic choroidal neovascularization: six-month results of a prospective pilot study. Ophthalmology. 2007b; 114(12):2190-2196.
20. Chang LK, Spaide RF, Brue C, et al. Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration. Arch Ophthalmol. 2008; 126(7):941-945.
21. Chun DW, Heier JS, Topping TM, et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. 2006; 113(10):1706-1712.
22. Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab (avastin) for central and hemicentral retinal vein occlusions: IBeVO study. Retina. 2007; 27(2):141-149.
23. Costagliola C, Cipollone U, Rinaldi M, et al. Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: a survey on 23 cases throughout 12-month follow-up. Br J Clin Pharmacol. 2008; 66(5):667-673.
24. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005; 112(10):1747-1757.
25. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007; 27(2):150-158.
26. D'Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology. 2003; 110(12):2372-2385.
27. D'Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy. Retina. 2003; 23(1):14-23.
28. Erol N, Gürsoy H, Sahin A, Basmak H. Intravitreal bevacizumab following laser therapy for severe retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2010; 47:e1-4.
29. Finger PT, Chin K. Anti-vascular endothelial growth factor bevacizumab (avastin) for radiation retinopathy. Arch Ophthalmol. 2007; 125(6):751-756.
30. Finger RP, Charbel Issa P, Ladewig M, et al. Intravitreal bevacizumab for choroidal neovascularisation associated with pseudoxanthoma elasticum. Br J Ophthalmol. 2008; 92(4):483-487.
31. Garg S, Brod R, Kim D, et al. Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration. Clin Experiment Ophthalmol. 2008; 36(3):252-256.
32. Gragoudas, ES, Adamis AP, Cunningham ET Jr., et al. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004; 351(27):2805-2816.
33. Gündüz K, Bakri SJ. Intravitreal bevacizumab for macular oedema secondary to branch retinal vein occlusion. Eye. 2008; 22(9):1168-1171.
34. Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006; 26(9):999-1005.
35. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006; 113(4):633-642.
36. Heier JS, Boyer DS, Ciulla TA, et al. FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol. 2006; 124(11):1532-1542.
37. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. 2006; 26(3):279-284.
38. Jorge R, Costa RA, Calucci D, et al. Intravitreal bevacizumab (Avastin) for persistent new vessels in diabetic retinopathy (IBEPE study). Retina. 2006; 26(9):1006-1013.
39. Kreutzer TC, Alge CS, Wolf AH, et al. Intravitreal bevacizumab for the treatment of macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol. 2008; 92(3):351-355.
40. Kriechbaum K, Michels S, Prager F, et al. Intravitreal Avastin for macular oedema secondary to retinal vein occlusion: a prospective study. Br J Ophthalmol. 2008; 92(4):518-522.
41. Krzystolik MG, Filippopoulos T, Ducharme JF, Loewenstein JI. Pegaptanib as an adjunctive treatment for complicated neovascular diabetic retinopathy. Arch Ophthalmol. 2006; 124(6):920-921.
42. Macugen AMD Study Group, Apte RS, Modi M, Masonson H, et al. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology. 2007; 114(9):1702-1712.
43. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010; 33(11):2399-2405.
44. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011; 364(7):603-615.
45. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007; 114(3):507-519, 524.
46. Moschos MM, Moschos M. Intraocular bevacizumab for macular edema due to CRVO. A multifocal-ERG and OCT study. Doc Ophthalmol. 2008; 116(2):147-152.
47. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study. Ophthalmology. 2010; 117(11):2146-2151.
48. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006; 142(6):961-969.
49. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008; 145(2):239-248.
50. Rensch F, Jonas JB, Spandau UH. Early intravitreal bevacizumab for non-ischaemic branch retinal vein occlusion. Ophthalmologica. 2009; 223(2):124-127.
51. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina. 2006; 26(5):495-511.
52. Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006a; 355(14):1419-1431.
53. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005; 36(4):336-339.
54. Rosenfeld PJ, Heier JS, Hantsbarger G, et al. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006b; 113(4):623-632.
55. Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularisation associated with pathological myopia. Br J Ophthalmol. 2007; 91(2):161-165.
56. Schadlu R, Blinder KJ, Shah GK, et al. Intravitreal bevacizumab for choroidal neovascularization in ocular histoplasmosis. Am J Ophthalmol. 2008; 145(5):875-878.
57. Schmidt-Erfurth U, Michels S, Michels R, et al. Anecortave acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Eur J Ophthalmol. 2005; 15(4):482-485.
58. Slakter JS, Bochow TW, D'Amico DJ, et al. Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration. Ophthalmology. 2006; 113(1):3-13.
59. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina. 2006a; 26(3):275-278.
60. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006b; 26(4):383-390.
61. Steinbrook R. The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006; 355(14):1409-1412.
62. The Diabetic Retinopathy Clinical Research Network, Elman M, Aiello L, Beck R, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010; 117(6):1064-1077.
63. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010; 340:c2459.
64. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr., et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006b; 113(9):1508-1521
65. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D'Amico DJ, Masonson HN, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006a; 113(6):992-1001.
66. Wu WC, Yeh PT, Chen SN, et al. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in taiwan. Ophthalmology. 2011; 118(1):176-183.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®_. Bethesda, MD. American Society of Health-System Pharmacists^®_; 2011.
2. Avastin^® [Product Information]. San Francisco, CA. Genentech, Inc. October 2006. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0168lbl.pdf.Accessed on February 14, 2011.
3. Bevacizumab. In DrugPoints^® System. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at http://www.thomsonhc.com. Accessed on February 14, 2011.
4. Blue Cross Blue Shield Association. Special Report: Current and Evolving Strategies in the Treatment of Age-Related Macular Degeneration. TEC Assessment, 2005; 20(11).
5. Lucentis^® [Product Information]. San Francisco, CA. Genentech, Inc., June 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125156s053lbl.pdf. Accessed on February 14, 2011.
6. Macugen^® [Product Information]. Mellville, NY. OSI Eyetech, Inc., July 2006. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021756s006,s007lbl.pdf. Accessed on February 14, 2011.
7. National Comprehensive Cancer Network^®_. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information: http://www.nccn.org.
8. Pegaptanib. In DrugPoints^® System. Greenwood, CO: Thomson Healthcare. Updated periodically. Available at   http://www.thomsonhc.com. Accessed on February 14, 2011.
9. Ranibizumab. In DrugPoints^®_. Greenwood, CO: Thomson Healthcare. Updated periodically. Available at http://www.thomsonhc.com. Accessed on February 14, 2011.

1. National Eye Institute. U.S. National Institutes of Health. Age-Related Macular Degeneration. Last modified September 2009. Available at: http://www.nei.nih.gov/health/maculardegen/armd_facts.asp. Accessed on February 14, 2011.
2. National Library of Medicine. Medical Encyclopedia macular degeneration. Updated 08/31/2010. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001000.htm. Accessed on February 14, 2011.

Age-Related Macular Degeneration
AMD
Anecortave Acetate
Avastin^®
Bevacizumab
Branch retinal vein occlusion
Central retinal vein occlusion
Conjunctival Incision with Posterior Juxtascleral Placement
Diabetic macular edema
Laser Therapy-Eye
Lucentis^®
Macugen^®
Macular Degeneration
Neovascular Glaucoma
Ranibizumab
Retaane
Retinopathy of Prematurity

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.