Injections for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness and serious decreases in vision among patients age 50 and older.[1] AMD blurs the central vision needed for “straight ahead” activities such as reading and driving.[2] It can be diagnosed only by an ophthalmologist or other eye care professional. Signs of AMD include haziness, distortion and blind spots in the center of your vision.[3], [4]

The most damaging version of the disease, neovascular or “wet” AMD, once carried a dismal prognosis of rapid and substantial vision loss. That has changed in recent years with the Food and Drug Administration’s (FDA) approval of two highly effective drugs to treat this disease: ranibizumab (LUCENTIS) and aflibercept (EYLEA). A third drug, bevacizumab (AVASTIN), is also widely used, even though it is not FDA-approved for treatment of this condition.

While one of these drugs is sold with claims of reduced cost and greater convenience, these claims fail to hold up under close scrutiny. Meanwhile, hidden risks have led Public Citizen’s Health Research Group to recommend that you do not use two of these drugs for wet AMD, at least for now.

FDA-approved injections for wet AMD

There are two types of advanced AMD, often called “wet” AMD and “dry” AMD.[5] Both involve damage to the part of the eye used for straight-ahead vision, but with wet AMD, this damage is caused by the growth of abnormal blood vessels, which can leak blood and fluid into the eye, leading to damage.[6] With dry AMD, there is a gradual breakdown of the light-sensing cells in the center of the retina, the cause of which is not clear.[7]

There is currently no effective treatment for dry AMD. Fortunately, vision loss usually progresses slowly with this form of the disease, allowing patients to live relatively normal, productive lives.[8]

In contrast, wet AMD often leads to much more rapid vision loss. One of the treatments that can help prevent or delay this debilitating outcome is ranibizumab, approved by the FDA in 2006. The drug works by neutralizing active forms of a small protein known as vascular endothelial growth factor (VEGF), which has been linked to abnormal blood vessel growth.[9] In clinical testing, subjects treated with monthly ranibizumab injections for a year experienced significantly less vision loss than those treated with placebo injections.[10] Even better, the drug actually improved vision for many subjects.[11]

In November 2011, the FDA approved aflibercept, another anti-VEGF drug that showed nearly identical effectiveness and safety compared with ranibizumab in clinical trials.[12],[13]

Since aflibercept offers no significant benefits over ranibizumab, Worst Pills, Best Pills News has applied our Seven-Year Rule, recommending against use of aflibercept until 2018. This is because research has shown that most cases in which a drug has received a black-box warning or been pulled from the market have occurred within seven years of approval.

Reduced dosing for cost and convenience

Most patients prefer not to receive eye injections every month. In addition to the unpleasantness of the injection itself, the procedure also carries side effects, including damage to the eye from the needle, increased pressure inside the eye and blood clots in arteries in other parts of the body, which can lead to strokes and heart attacks. [14],[15] Thus, researchers have been working on ways to give fewer injections while still maintaining effectiveness.

One approach researchers have studied is to adjust the dosing schedule based on how each person responds to treatment. With this method, patients still are monitored at monthly visits, but the number of injections is adjusted based on whether the ophthalmologist sees signs of returning AMD.[16],[17]

The largest and most rigorous trial testing this strategy found that while this method produced good results in many patients, those taking as-needed injections had slightly smaller average improvements in vision compared with those who had monthly injections.[18] On average, this meant seeing two and a half fewer letters on the eye chart after two years of treatment.[19] Since the difference is so small, some patients reasonably may choose as-needed treatment to avoid the difficulties of monthly injections.

Regeneron Pharmaceuticals Inc., the manufacturer of aflibercept, also has tested whether aflibercept — after an initial course of three monthly injections — can be effective when subsequently injected every two months instead of monthly.[20] The test was successful: Aflibercept injections every two months were just as effective at maintaining vision as monthly injections of either aflibercept or ranibizumab.

Does this mean aflibercept is effective for twice as long as ranibizumab? Not really. The two drugs never have been directly compared on a two-month dosing schedule. In fact, the best evidence suggests that the drugs work for about the same length of time. When ranibizumab and aflibercept were both taken as-needed in randomized trials, the number of injections needed was only slightly different. On average, subjects receiving ranibizumab needed an injection every nine weeks, while those taking aflibercept needed one every 10 to 11 weeks.

Also, in real-world use, patients tend to receive roughly the same number of injections regardless of whether they take ranibizumab or aflibercept, meaning neither drug is much more convenient than the other. The drugs also cost about the same, so choosing aflibercept would not save money.

Cost and risks with repackaged bevacizumab

Ranibizumab and aflibercept are extraordinarily expensive, with price tags of almost $2,000 for each injection. This can translate to hundreds of dollars or more in co-payments each month.[21]

To reduce costs, many ophthalmologists offer another drug: bevacizumab. This drug costs less than $50 per month, potentially saving patients, Medicare and private insurers tens of thousands of dollars per year per patient.

The FDA has approved bevacizumab as a cancer treatment, but not as a treatment for wet AMD. However, because, like ranibizumab, it blocks the activity of VEGF, it has been used to treat wet AMD for many years.[22] A recent large, publicly funded, randomized clinical trial showed that the drug’s effectiveness in treating wet AMD was very similar to that of ranibizumab.[23],[24]

However, by some measures, bevacizumab is slightly different in its effectiveness and safety: Patients who received bevacizumab had to get, on average, one more injection each year when treated as-needed and were more likely to have a serious adverse event, with gastrointestinal disorders more common among subjects receiving bevacizumab.[25] Also, further analysis showed that patients who experienced sustained vision loss were slightly more likely to have taken bevacizumab.[26]

Do these slight differences justify spending tens of thousands more on ranibizumab? Probably not, but there is an additional factor that should make patients think twice about using bevacizumab for this unapproved use.

Bevacizumab is manufactured in large-dose vials suitable for cancer treatment. To treat wet AMD, the drug must be repackaged into smaller, single-dose syringes for eye injections.[27] The compounding pharmacies and repackaging facilities that typically carry out this task are not well monitored by the FDA and state agencies, and they sometimes engage in dangerous cost-cutting practices that lead to bacterial or fungal contamination. Contamination of bevacizumab has caused at least one large outbreak of eye infections in 2011 that led to permanent loss of vision in most affected patients.[28]

What You Can Do

People with wet or dry AMD might be able to increase their chances of maintaining good vision by eating lots of green, leafy vegetables and fish; exercising regularly; and not smoking.[29]

If your doctor diagnoses you with wet AMD and recommends injections, ranibizumab is the best choice, as this drug has been on the market for the longest time and is highly effective.

Start out with monthly injections. If your eyes respond well, talk with your doctor about switching to dosing as-needed to reduce the number of injections. Be aware that this dosing schedule may result in some loss of vision (or less improvement) compared with monthly injections, even with careful monitoring. Make sure you still see your ophthalmologist for monthly checkups, as vision can decline rapidly between visits.

Do not use aflibercept until 2018, because further safety information still may emerge about this relatively new product. Do not use bevacizumab to treat wet AMD, because the quality and sterility of repackaged bevacizumab cannot be guaranteed and because it is not FDA-approved to treat AMD.

The science for wet AMD treatment continues to evolve rapidly. By carefully selecting treatments based on the best evidence, most patients now can hope to maintain good long-term vision while avoiding the worst safety risks.

References

[1] Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. NEJM. 2006;355(14):1419-1431.

[2] National Eye Institute (NEI). Age-related macular degeneration (AMD). https://www.nei.nih.gov/health/maculardegen. Accessed April 1, 2014.

[3] Mayo Clinic. Dry macular degeneration: Symptoms. http://www.mayoclinic.org/diseases-conditions/macular-degeneration/basics/symptoms/con-20075882. Accessed April 1, 2015.

[4] Mayo Clinic. Wet macular degeneration: Symptoms. http://www.mayoclinic.org/diseases-conditions/wet-macular-degeneration/basics/symptoms/con-20043518. Accessed April 1, 2015.

[5] National Eye Institute (NEI). Facts about age-related macular degeneration. https://www.nei.nih.gov/health/maculardegen/armd_facts. Accessed April 1, 2014.

[6] Ibid.

[7] Ibid.

[8] Mayo Clinic. Dry macular degeneration: Treatments and drugs. November 20, 2012. http://www.mayoclinic.org/diseases-conditions/macular-degeneration/basics/treatment/con-20075882. Accessed April 1, 2015.

[9] Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. NEJM. 2006;355(14):1419-1431.

[10] Ibid.

[11] Ibid.

[12] Food and Drug Administration Center for Drug Evaluation and Research. Medical review: Application number 125387. November 18, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387Orig1s000MedR.pdf.

[13] Schmidt-Erfurth, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration. Opthalmology. 2014;121:193-201.

[14] DailyMed. Label: Eylea – aflibercept injection, solution. Updated March 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f96cfd69-da34-41ee-90a9-610a4655cd1c.

[15] DailyMed. Label: Lucentis – ranibizumab injection, solution. Updated February 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de4e66cc-ca05-4dc9-8262-e00e9b41c36d.

[16] Singer MA, Awh CC, Sadda S, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119:1175-1183.

[17] Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol. 2009;148:43-58.

[18] Comparison of age-related macular degeneration treatments trials (CATT) research group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology. 2012;119:1388-1198.

[19] Ibid.

[20] Schmidt-Erfurth, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration. Opthalmology. 2014;121:193-201.

[21] Department of Health and Human Services Office of the Inspector General. Medicare payments for drugs used to treat wet age-related macular degeneration. April 2012. OEI-03-10-00360. http://oig.hhs.gov/oei/reports/oei-03-10-00360.pdf. Accessed April 1, 2015.

[22] Comparison of age-related macular degeneration treatments trials (CATT) research group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology. 2012;119:1388-1198.

[23] Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The CATT Research Group. NEJM. 2011;364:1897-908.

[24] Comparison of age-related macular degeneration treatments trials (CATT) research group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology. 2012;119:1388-1198.

[25] Ibid.

[26] Ying G, Kim BJ, Maguire MG, et al. Sustained visual acuity loss in the comparison of age-related macular degeneration treatments trials. JAMA Ophthalmol. 2014;132(8):915-921.

[27] Department of Health and Human Services Office of the Inspector General. Medicare payments for drugs used to treat wet age-related macular degeneration. April 2012. OEI-03-10-00360. http://oig.hhs.gov/oei/reports/oei-03-10-00360.pdf. Accessed April 1, 2015.

[28] Goldberg RA, Flynn HW, Miller D, et al. Streptococcus Endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120(7):1448-53.

[29] National Eye Institute (NEI). Facts about age-related macular degeneration. https://www.nei.nih.gov/health/maculardegen/armd_facts. Accessed April 1, 2014.