Aflibercept Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:477243410
Tradename:Eylea, Zaltrap
Dailymedid:Aflibercept
Pregnancy Au:D
Pregnancy Au Comment:[1]
Pregnancy Category:Not recommended
Routes Of Administration:Intravenous, intravitreal injection
Atc Prefix:L01
Atc Suffix:XX44
Biosimilars:aflibercept-abzv, aflibercept-ayyh, aflibercept-jbvf,[2] aflibercept-mrbb, aflibercept-yszy,[3] Ahzantive, Enzeevu, Opuviz, Pavblu, Yesafili[4]
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:[5]
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[6]
Legal Eu:Rx-only
Legal Status:Rx-only
Cas Number:862111-32-8
Drugbank:DB08885
Chemspiderid:none
Unii:15C2VL427D
Kegg:D09574
Chembl:1742982
Synonyms:ziv-aflibercept
C:4318
H:6788
N:1164
O:1304
S:32

Aflibercept, sold under the brand names Eylea and Zaltrap among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer.[7] [8] It was developed by Regeneron Pharmaceuticals.

It is an inhibitor of vascular endothelial growth factor (VEGF).[9] [10]

Medical uses

Aflibercept (Eylea) is indicated for the treatment of people with neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and retinopathy of prematurity.

Aflibercept (Zaltrap), in combination with fluorouracil, leucovorin, and irinotecan (known as FOLFIRI), is indicated for the treatment of people with metastatic colorectal cancer that is resistant to, or has progressed following, an oxaliplatin-containing regimen.

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection, that is, into the eye.[11] For cancer treatment, it is given intravenously in combination with fluorouracil, leucovorin, and irinotecan.[12]

In July 2014, aflibercept (Eylea) was approved for the treatment of people with visual impairment due to diabetic macular edema[13] In May 2019, the US FDA expanded the indication for aflibercept to include all stages of diabetic retinopathy.[14]

In February 2023, the US FDA approved aflibercept (Eylea) as a treatment for retinopathy of prematurity.[15]

Contraindications

Aflibercept (Eylea) is contraindicated in people with infections or active inflammations of or near the eye, while aflibercept (Zaltrap) has no contraindications.

Adverse effects

Common adverse effects of the eye formulation include conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.

Aflibercept (Zaltrap) has adverse effects typical of anti-cancer drugs, such as reduced blood cell count (leukopenia, neutropenia, thrombocytopenia), gastrointestinal disorders like diarrhea and abdominal pain, and fatigue. Another common effect is hypertension (increased blood pressure).

Interactions

No interactions are described for either formulation.

Mechanism of action

In wet macular degeneration, abnormal blood vessels grow in the choriocapillaris, a layer of capillaries in the eye, leading to blood and protein leakage below the macula.

Aflibercept (Zaltrap) binds to circulating VEGFs and acts like a "VEGF trap".[16] It thereby inhibits the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as to placental growth factor (PGF), inhibiting the growth of new blood vessels in the choriocapillaris or the tumour, respectively. The aim of the cancer treatment, so to speak, is to starve the tumor.

Composition

Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin.

History

Regeneron commenced clinical testing of aflibercept in cancer in 2001.[17] In 2003, Regeneron signed a major deal with Aventis to develop aflibercept in the field of cancer.[18] In 2004 Regeneron started testing the compound, locally delivered, in proliferative eye diseases,[17] and in 2006 Regeneron and Bayer signed an agreement to develop the eye indications.[19]

Society and culture

Legal status

In November 2011, the US Food and Drug Administration (FDA) approved aflibercept for the treatment of wet macular degeneration.[20] [21]

In August 2012, the US FDA approved aflibercept (Zaltrap) for use in combination with 5-fluorouracil, folinic acid and irinotecan to treat adults with metastatic colorectal cancer that is resistant to, or has progressed following, an oxaliplatin‑containing regimen.[22] [23] [24] [25] To avoid confusion with the version that is injected into the eye, the FDA assigned a new name, ziv-aflibercept, to the active ingredient.[26]

In November 2012, the European Medicines Agency (EMA) approved aflibercept (Eylea) for the treatment of wet macular degeneration.[27]

In February 2013, the European Medicines Agency (EMA) approved aflibercept (Zaltrap) for the treatment of adults with metastatic colorectal cancer for whom treatment based on oxaliplatin has not worked or the cancer got worse.[28] Aflibercept (Zaltrap) is used with irinotecan, 5-fluorouracil, and folinic acid.

In August 2023, the FDA approved aflibercept (Eylea) for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy.[29]

Biosimilars

Yesafili was approved for medical use in the European Union in September 2023.[30]

In May 2024, aflibercept-jbvf (Yesafili) and aflibercept-yszy (Opuviz) were approved for medical use in the United States.[31] [32]

Aflibercept-mrbb (Ahzantive) was approved for medical use in the United States in June 2024.[33] [34] It is a biosimilar to Eylea.

In August 2024, aflibercept-abzv (Enzeevu) was approved for medical use in the United States.[35] [36] It is a biosimilar to Eylea.

In August 2024, aflibercept-ayyh (Pavblu) was approved for medical use in the United States.[37] [38] It is a biosimilar to Eylea.

In September 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Opuviz, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularization (myopic CNV). The applicant for this medicinal product is Samsung Bioepis NL B.V. Opuviz is a biosimilar medicinal product that is highly similar to the reference product Eylea (aflibercept), which was authorized in the EU in November 2012.[39]

In September 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Afqlir, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularization (myopic CNV). The applicant for this medicinal product is Sandoz GmbH. Afqlir is a biosimilar medicinal product that is highly similar to the reference product Eylea (aflibercept), which was authorized in the EU in November 2012.[40] Afqlir was authorized for use in the EU in November 2024.[41] [42]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ahzantive, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularisation (myopic CNV). The applicant for this medicinal product is Klinge Biopharma GmbH. Ahzantive is a biosimilar medicinal product that is highly similar to the reference product Eylea (aflibercept), which was authorized in the EU in November 2012.[43]

In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Baiama, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME) and visual impairment due to myopic choroidal neovascularisation (myopic CNV). The applicant for this medicinal product is Formycon AG. Baiama is a biosimilar medicinal product that is highly similar to the reference product Eylea (aflibercept), which was authorized in the EU in November 2012.[44] [45]

Economics

In March 2015, aflibercept was one of a group of drugs delisted from the UK Cancer Drugs Fund.[46] In 2017, injections of aflibercept (HCPCS code J0178) were responsible for the most billing to Medicare Part B, at .[47]

Research

In March 2011, aflibercept failed its primary endpoint of overall survival in the Vital phase III trial for second-line treatment of locally advanced or metastatic non-small cell lung cancer, although it improved the secondary endpoint of progression-free survival.[48]

In April 2011, aflibercept improved its primary endpoint of overall survival in the Velour phase III clinical trial for second-line treatment for metastatic colorectal cancer.[49]

Aflibercept was also in a phase III trial for hormone-refractory metastatic prostate cancer .[49]

A 2016 Cochrane Review examined outcomes comparing aflibercept versus ranibizumab injections in over 2400 people with neovascular AMD, from two randomized controlled trials. Both treatment options yielded similar improvements in visual acuity and morphological outcomes, though the authors note that the aflibercept treatment regimen has the potential to reduce treatment burden and risks from frequent injections.[50]

A 2017 review update studying the effects of anti-VEGF drugs on diabetic macular edema found that while all three studied treatments have advantages over laser therapy, there was moderate evidence that aflibercept is significantly favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year, longer term advantages were unclear.[51]

External links

Notes and References

  1. Web site: 25 December 2019 . Ziv-aflibercept (Zaltrap) Use During Pregnancy . live . https://web.archive.org/web/20201129055243/https://www.drugs.com/pregnancy/ziv-aflibercept.html . 29 November 2020 . 12 March 2020 . Drugs.com.
  2. Web site: Yesafili (aflibercept-jbvf) injection, for intravitreal use . 19 August 2024 . U.S. Food and Drug Administration (FDA).
  3. Web site: Opuviz (aflibercept-yszy) injection, for intravitreal use . live . https://web.archive.org/web/20240521025155/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761350s000lbl.pdf . 21 May 2024 . 21 May 2024.
  4. Web site: 19 September 2023 . Yesafili Product information . live . https://web.archive.org/web/20231002061941/https://ec.europa.eu/health/documents/community-register/html/h1751.htm . 2 October 2023 . 2 October 2023 . Union Register of medicinal products.
  5. Web site: 2 February 2024 . Regulatory Decision Summary for Eylea HD . live . https://web.archive.org/web/20240402033640/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1708532368148 . 2 April 2024 . 2 April 2024 . Drug and Health Products Portal.
  6. Web site: 18 August 2023 . Eylea HD- aflibercept injection, solution . live . https://web.archive.org/web/20230829040233/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86d8848b-111b-4da9-8957-7cccef1b8f66 . 29 August 2023 . 28 August 2023 . DailyMed.
  7. Web site: 9 July 2019 . Eylea EPAR . live . https://web.archive.org/web/20201109043834/https://www.ema.europa.eu/en/medicines/human/EPAR/eylea . 9 November 2020 . 12 March 2020 . European Medicines Agency (EMA).
  8. Web site: 12 November 2019 . Zaltrap EPAR . live . https://web.archive.org/web/20201111223030/https://www.ema.europa.eu/en/medicines/human/EPAR/zaltrap . 11 November 2020 . 12 March 2020 . European Medicines Agency (EMA).
  9. Fraser HM, Wilson H, Silvestri A, Morris KD, Wiegand SJ . September 2008 . The role of vascular endothelial growth factor and estradiol in the regulation of endometrial angiogenesis and cell proliferation in the marmoset . live . Endocrinology . 149 . 9 . 4413–20 . 10.1210/en.2008-0325 . 18499749 . https://web.archive.org/web/20191208165552/http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=18499749 . 8 December 2019 . 3 July 2008 . free.
  10. Duncan WC, van den Driesche S, Fraser HM . July 2008 . Inhibition of vascular endothelial growth factor in the primate ovary up-regulates hypoxia-inducible factor-1alpha in the follicle and corpus luteum . Endocrinology . 149 . 7 . 3313–20 . 10.1210/en.2007-1649 . 18388198 . free.
  11. Web site: 12 August 2019 . Eylea- aflibercept injection, solution . live . https://web.archive.org/web/20210325013817/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f96cfd69-da34-41ee-90a9-610a4655cd1c . 25 March 2021 . 13 August 2020 . DailyMed.
  12. Web site: 10 June 2020 . Zaltrap- ziv-aflibercept solution, concentrate . live . https://web.archive.org/web/20200804175756/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d . 4 August 2020 . 13 August 2020 . DailyMed.
  13. Web site: 18 November 2011 . Eylea (aflibercept) FDA Approval History . live . https://web.archive.org/web/20240619093414/https://www.drugs.com/history/eylea.html . 19 June 2024 . 26 August 2024 . Drugs.com.
  14. FDA Approves Eylea (aflibercept) Injection for Diabetic Retinopathy . 13 May 2019 . 28 June 2023 . live . https://web.archive.org/web/20190514055732/https://investor.regeneron.com/news-releases/news-release-details/fda-approves-eylear-aflibercept-injection-diabetic-retinopathy . 14 May 2019 . Regeneron Pharmaceuticals Inc..
  15. Eylea (aflibercept) Injection Approved as the First Pharmacologic Treatment for Preterm Infants with Retinopathy of Prematurity (ROP) by the FDA . 8 February 2023 . 28 June 2023 . live . https://web.archive.org/web/20230628230201/https://investor.regeneron.com/news-releases/news-release-details/eylear-aflibercept-injection-approved-first-pharmacologic . 28 June 2023 . Regeneron Pharmaceuticals Inc..
  16. News: 7 February 2013 . Aflibercept Approved for Colorectal Cancer in Europe . live . https://web.archive.org/web/20130210084012/http://www.medscape.com/viewarticle/778918 . 10 February 2013.
  17. Web site: 1988 . Our History - A 25 year commitment to repeated innovation . live . https://web.archive.org/web/20170517181158/https://www.regeneron.com/history . 17 May 2017 . 7 May 2018 . www.regeneron.com.
  18. Web site: Hoffmann . Candace . 8 September 2003 . Aventis inks deal with Regeneron for collaboration on cancer therapy . dead . https://web.archive.org/web/20140414211959/http://www.firstwordpharma.com/node/215613 . 14 April 2014 . firstwordpharma.
  19. Web site: 19 October 2006 . Bayer HealthCare Signs On to Help Develop Regeneron's VEGF Trap-Eye . 17 September 2024 . GEN - Genetic Engineering and Biotechnology News.
  20. Web site: 18 November 2011 . Drug Approval Package: Eylea (aflibercept) NDA #125387 . live . https://web.archive.org/web/20231017030822/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387s0000toc.cfm . 17 October 2023 . 21 May 2024 . U.S. Food and Drug Administration (FDA).
  21. Web site: 19 November 2011 . FDA Approves Eylea for Macular Degeneration . live . https://web.archive.org/web/20130528151430/http://www.medpagetoday.com/Ophthalmology/GeneralOphthalmology/29811 . 28 May 2013 . 16 October 2013 . MedpageToday.com . Gever J.
  22. Web site: 6 September 2012 . Drug Approval Package: Zaltrap (ziv-aflibercept) NDA #125418 . live . https://web.archive.org/web/20220926220226/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125418_zaltrap_toc.cfm . 26 September 2022 . 21 May 2024 . U.S. Food and Drug Administration (FDA).
  23. Web site: 3 August 2012 . Ziv-Aflibercept . dead . https://web.archive.org/web/20131016041012/https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm . 16 October 2013 . 16 October 2013 . U.S. Food and Drug Administration (FDA).
  24. Web site: 17 December 2012 . 2012 Notifications . live . https://web.archive.org/web/20191226010037/https://www.fda.gov/drugs/resources-information-approved-drugs/2012-notifications . 26 December 2019 . 21 May 2024 . U.S. Food and Drug Administration (FDA).
  25. U.S. FDA Approves Zaltrap (ziv-aflibercept) After Priority Review for Previously Treated Metastatic Colorectal Cancer . 3 August 2012 . Sanofi and Regeneron . PR Newswire . 21 May 2024 . live . https://web.archive.org/web/20240521024356/https://www.prnewswire.com/news-releases/us-fda-approves-zaltrap-ziv-aflibercept-after-priority-review-for-previously-treated-metastatic-colorectal-cancer-164919796.html . 21 May 2024.
  26. Web site: Serebrov . Mari . GPhA: Common Name is Key to Biosimilar Competition . dead . https://web.archive.org/web/20131213045215/http://www.bioworld.com/content/gpha-common-name-key-biosimilar-competition-1 . 13 December 2013 . BioWorld.
  27. Web site: Aflibercept Injection Approved for the Treatment of Wet Age-Related Macular Degeneration in Europe . live . https://web.archive.org/web/20131125185521/http://www.amd-fruehdiagnose.de/eylea/eylea-aflibercept-injection-approved-treatment-of-wet-age-related-macular-degeneration-europe.htm . 25 November 2013 . 16 October 2013 . Amd-fruehdiagnose.de.
  28. Web site: Zaltrap : EPAR - Summary for the public . live . https://web.archive.org/web/20131016041239/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002532/WC500139486.pdf . 16 October 2013 . 1 July 2013.
  29. Eylea HD (aflibercept) Injection 8 mg Approved by FDA for Treatment of Wet Age-related Macular Degeneration (wAMD), Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) . 18 August 2023 . Regeneron Pharmaceuticals . GlobeNewswire . 26 August 2024 . live . https://web.archive.org/web/20230826191738/https://www.globenewswire.com/news-release/2023/08/18/2728276/0/en/EYLEA-HD-aflibercept-Injection-8-mg-Approved-by-FDA-for-Treatment-of-Wet-Age-related-Macular-Degeneration-wAMD-Diabetic-Macular-Edema-DME-and-Diabetic-Retinopathy-DR.html . 26 August 2023.
  30. Web site: 15 September 2023 . Yesafili EPAR . live . https://web.archive.org/web/20240217185524/https://www.ema.europa.eu/en/medicines/human/EPAR/yesafili . 17 February 2024 . 21 May 2024 . European Medicines Agency.
  31. FDA approves first interchangeable biosimilars to Eylea to treat macular degeneration and other eye conditions . 20 May 2024 . 21 May 2024 . live . https://web.archive.org/web/20240521025145/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-interchangeable-biosimilars-eylea-treat-macular-degeneration-and-other-eye . 21 May 2024 . U.S. Food and Drug Administration (FDA).
  32. Web site: 26 August 2024 . Biosimilar Drug Information . live . https://web.archive.org/web/20210828185647/https://www.fda.gov/drugs/biosimilars/biosimilar-product-information . 28 August 2021 . 26 August 2024 . U.S. Food and Drug Administration (FDA).
  33. Web site: Ahzantive . 26 August 2024 . 5 October 2024 . https://web.archive.org/web/20241005181858/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761378s000lbl.pdf . live .
  34. Web site: Ahzantive Biologic License Application Approval . 26 August 2024 . 8 September 2024 . https://web.archive.org/web/20240908055807/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761378Orig1s000ltr.pdf . live .
  35. Web site: Enzeevu (aflibercept-abzv) injection, for intravitreal use . 26 August 2024 . 8 September 2024 . https://web.archive.org/web/20240908055807/https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761382s000lbl.pdf . live .
  36. Web site: Enzeevu Biologic License Application Approval . 26 August 2024 . 5 October 2024 . https://web.archive.org/web/20241005181859/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761382Orig1s000ltr.pdf . live .
  37. Web site: Pavblu- aflibercept-ayyh injection, solution . DailyMed . 28 October 2024 . 11 November 2024.
  38. Web site: Pavblu Biologic License Application Approval . 26 August 2024 . 8 September 2024 . https://web.archive.org/web/20240908060318/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/761298Orig1s000ltr.pdf . live .
  39. Web site: Pavblu EPAR . European Medicines Agency (EMA) . 19 September 2024 . 21 September 2024 . 21 September 2024 . https://web.archive.org/web/20240921040006/https://www.ema.europa.eu/en/medicines/human/EPAR/opuviz . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  40. Web site: Afqlir EPAR . European Medicines Agency (EMA) . 19 September 2024 . 21 September 2024 . 21 September 2024 . https://web.archive.org/web/20240921040639/https://www.ema.europa.eu/en/medicines/human/EPAR/afqlir . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  41. Web site: Afqlir PI . Union Register of medicinal products . 14 November 2024 . 20 November 2024.
  42. News: Sandoz receives European Commission approval for Afqlir (aflibercept), further strengthening leading biosimilar portfolio . Yahoo News.
  43. Web site: Ahzantive EPAR . European Medicines Agency (EMA) . 14 November 2024 . 16 November 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  44. Web site: Baiama EPAR . European Medicines Agency (EMA) . 14 November 2024 . 16 November 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  45. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024 . European Medicines Agency (EMA) . 15 November 2024 . 16 November 2024.
  46. Web site: 19 November 2015 . Cancer: Drugs:Written question - HL3340 . live . https://web.archive.org/web/20180402225615/https://www.parliament.uk/written-questions-answers-statements/written-question/lords/2015-11-05/HL3340 . 2 April 2018 . UK Parliament.
  47. Web site: Physician/Supplier National Data . live . https://web.archive.org/web/20180817194521/https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/MedicareFeeforSvcPartsAB/Downloads/LEVEL2CHARG17.pdf . 17 August 2018 . 11 June 2019 . Centers for Medicare & Medicaid Services.
  48. News: 11 March 2011 . Regeneron and Sanofi-Aventis Cancer Drug Misses Phase III Primary Endpoint but Meets Secondary Targets . live . https://web.archive.org/web/20120406205554/http://www.genengnews.com/gen-news-highlights/regeneron-and-sanofi-aventis-cancer-drug-misses-phase-iii-primary-endpoint-but-meets-secondary-targets/81244807/ . 6 April 2012.
  49. News: 27 April 2011 . Regeneron and Sanofi-Aventis Report Positive Phase III mCRC Trial Data . live . https://web.archive.org/web/20120202212928/http://www.genengnews.com/gen-news-highlights/regeneron-and-sanofi-aventis-report-positive-phase-iii-mcrc-trial-data/81245067 . 2 February 2012.
  50. Sarwar S, Clearfield E, Soliman MK, Sadiq MA, Baldwin AJ, Hanout M, Agarwal A, Sepah YJ, Do DV, Nguyen QD . February 2016 . Aflibercept for neovascular age-related macular degeneration . The Cochrane Database of Systematic Reviews . 2016 . 2 . CD011346 . 10.1002/14651858.CD011346.pub2 . 5030844 . 26857947.
  51. Virgili G, Curran K, Lucenteforte E, Peto T, Parravano M . June 2023 . Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis . The Cochrane Database of Systematic Reviews . 2023 . 6 . CD007419 . 10.1002/14651858.CD007419.pub7 . 10294542 . 38275741 . Cochrane Eyes and Vision Group.

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