Skip to main content
SpringerLink
Log in

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear.

Objective

The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS).

Methods

We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA®) queries (SMQs).

Results

Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders).

Conclusions

This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2002;29:10–4.

    Article  CAS  PubMed  Google Scholar 

  2. Thanigaimani S, Kichenadasse G, Mangoni AA. The emerging role of vascular endothelial growth factor (VEGF) in vascular homeostasis: lessons from recent trials with anti-VEGF drugs. Curr Vasc Pharmacol. 2011;9:358–80.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.

    Article  CAS  PubMed  Google Scholar 

  4. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–91.

    Article  CAS  PubMed  Google Scholar 

  5. European Medicines Agency. European public assessment report (EPAR) for Lucentis. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf. Accessed 6 Mar 2017.

  6. European Medicines Agency. European public assessment report (EPAR) for Macugen. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000620/WC500026218.pdf. Accessed 6 Mar 2017.

  7. European Medicines Agency. European public assessment report (EPAR) for Eylea. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002392/WC500135744.pdf. Accessed 6 Mar 2017.

  8. European Medicines Agency. European public assessment report (EPAR) for Avastin. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000582/WC500029262.pdf. Accessed 6 Mar 2017.

  9. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805–16.

    Article  CAS  PubMed  Google Scholar 

  10. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358:2606–17.

    Article  CAS  PubMed  Google Scholar 

  11. Kim H, Robinson SB, Csaky KG. FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis. 2009;15:2803–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287–97.

    Article  CAS  PubMed  Google Scholar 

  13. Campbell RJ, Gill SS, Bronskill SE, Paterson JM, Whitehead M, Bell CM. Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case–control study. BMJ. 2012;345:e4203.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Curtis LH, Hammill BG, Schulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128:1273–9.

    Article  PubMed  Google Scholar 

  15. Kemp A, Preen DB, Morlet N, Clark A, McAllister IL, Briffa T, et al. Myocardial infarction after intravitreal vascular endothelial growth factor inhibitors: a whole population study. Retina. 2013;33:920–7.

    Article  CAS  PubMed  Google Scholar 

  16. Pratt NL, Ramsay EN, Kemp A, Kalisch-Ellett LM, Shakib S, Caughey GE, et al. Ranibizumab and risk of hospitalisation for ischaemic stroke and myocardial infarction in patients with age-related macular degeneration: a self-controlled case-series analysis. Drug Saf. 2014;37:1021–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Micieli JA, Micieli A, Smith AF. Identifying systemic safety signals following intravitreal bevacizumab: systematic review of the literature and the Canadian Adverse Drug Reaction Database. Can J Ophthalmol. 2010;45:231–8.

    Article  PubMed  Google Scholar 

  18. Shamloo BK, Chhabra P, Freedman AN, Potosky A, Malin J, Weiss Smith S. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. Drug Saf. 2012;35:507–18.

    Article  CAS  PubMed  Google Scholar 

  19. European Medicines Agency, Heads of Medicines Agencies. Guideline on good pharmacovigilance practices (GVPs). Module IX - Signal Management. 2012 EMA/827661/2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129138.pdf. Accessed 6 Mar 2017.

  20. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The medical dictionary for regulatory activities (MedDRA®). Introductory guide for standardised MedDRA queries (SMQs) version 19.1. https://www.meddra.org/how-to-use/support-documentation. Accessed 6 Mar 2017.

  21. Agenzia Italiana del Farmaco (AIFA). Registri farmaci sottoposti a monitoraggio. http://www.agenziafarmaco.gov.it/content/registri-farmaci-sottoposti-monitoraggio. Accessed 6 Mar 2017.

  22. Parretta E, Rafaniello C, Magro L, Coggiola Pittoni A, Sportiello L, Ferrajolo C, et al. Improvement of patient adverse drug reaction reporting through a community pharmacist-based intervention in the Campania region of Italy. Expert Opin Drug Saf. 2014;13:S21–9.

    Article  PubMed  Google Scholar 

  23. Leone R, Moretti U, D’Incau P, Conforti A, Magro L, Lora R, Velo G. Effect of pharmacist involvement on patient reporting of adverse drug reactions: first Italian study. Drug Saf. 2013;36:267–76.

    Article  PubMed  Google Scholar 

  24. Ministero della Salute. Il farmacista di dipartimento quale strumento per prevenzione degli errori in terapia e l’implementazione delle politiche di governo clinico in ambito oncologico. 2011. http://www.salute.gov.it/imgs/C_17_pubblicazioni_1638_allegato.pdf. Accessed 2 May 2017.

  25. Van Wijngaarden P, Qureshi SH. Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age-related macular degeneration: a review of current practice. Clin Exp Optom. 2008;91:427–37.

    Article  PubMed  Google Scholar 

  26. Johnson D, Sharma S. Ocular and systemic safety of bevacizumab and ranibizumab in patients with neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2013;24:205–12.

    Article  PubMed  Google Scholar 

  27. Wong TY, Klein R, Sun C, Mitchell P, Couper DJ, Lai H, et al. Age-related macular degeneration and risk of stroke. Ann Intern Med. 2006;145(2):98–106.

    Article  PubMed  Google Scholar 

  28. Duan Y, Mo J, Klein R, Scott IU, Lin HM, Caulfield J, et al. Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans. Ophthalmology. 2007;114:732–7.

    Article  PubMed  Google Scholar 

  29. Tuñón J, Ruiz-Moreno JM, Martın-Ventura JL, Blanco-Colio LM, Lorenzo O, Egido J. Cardiovascular risk and antiangiogenic therapy for age-related macular degeneration. Surv Ophthalmol. 2009;54:339–48.

    Article  PubMed  Google Scholar 

  30. Bosnar D. Intravitreal bevacizumab and cardiovascular risk in patients with age-related macular degeneration: systematic review and meta-analysis of randomized controlled trials and observational studies. Drug Saf. 2016;39:517–41.

    Article  PubMed  Google Scholar 

  31. Semeraro F, Morescalchi F, Parmeggiani F, Arcidiacono B, Costagliola C. Systemic adverse drug reactions secondary to anti-VEGF intravitreal injection in patients with neovascular age-related macular degeneration. Curr Vasc Pharmacol. 2011;9:629–46.

    Article  CAS  PubMed  Google Scholar 

  32. Stewart MW. The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc. 2012;87:77–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina. doi:10.1097/IAE.0000000000001493. (epub 18 Jan 2017).

  34. Carneiro AM, Costa R, Falcão MS, Barthelmes D, Mendonça LS, Fonseca SL, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab. Acta Ophthalmol. 2012;90:e25–30.

    Article  CAS  PubMed  Google Scholar 

  35. Thulliez M, Angoulvant D, Le Lez ML, Jonville-Bera AP, Pisella PJ, Gueyffier F, Bejan-Angoulvant T. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132:1317–26.

    Article  PubMed  Google Scholar 

  36. European Medicines Agency. Eylea: EPAR - product information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002392/WC500135815.pdf. Accessed 6 Mar 2017.

  37. European Medicines Agency. Lucentis: EPAR - product information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000715/WC500043546.pdf. Accessed 6 Mar 2017.

  38. Zhang XY, Guo XF, Zhang SD, He JN, Sun CY, Zou Y, Bi HS, Qu Y. Comparison of bevacizumab and ranibizumab in age-related macular degeneration: a systematic review and meta-analysis. Int J Ophthalmol. 2014;7(2):355–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277–85.

    Article  CAS  PubMed  Google Scholar 

  40. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol. 2009;10:559–68.

    Article  CAS  PubMed  Google Scholar 

  41. Miles D. Management of toxicity in patients receiving therapy with bevacizumab. Eur J Cancer Suppl. 2008;6:29–39.

    Article  CAS  Google Scholar 

  42. Elice F, Rodegjiero F. Bleeding complications of antiangiogenic therapy: pathogenetic mechanisms and clinical impact. Thromb Res Suppl. 2010;125:S55–7.

    Article  Google Scholar 

  43. Qi WX, Tang LN, Yao Y. Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis. Clin Drug Investig. 2014;34:231–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sicilian Regional Pharmacovigilance Center, Messina, Italy

    Paola Maria Cutroneo

  2. Clinical Pharmacology Unit, University Hospital G. Martino, Messina, Italy

    Paola Maria Cutroneo, Claudia Giardina, Valentina Ientile & Gianluca Trifirò

  3. Pharmacovigilance Office, Italian Medicines Agency, Rome, Italy

    Simona Potenza & Laura Sottosanti

  4. Department of Experimental Medicine, Campania Regional Center of Pharmacovigilance and Pharmacoepidemiology, University of Campania, Naples, Italy

    Carmen Ferrajolo

  5. Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy

    Costantino J. Trombetta & Gianluca Trifirò

Authors
  1. Paola Maria Cutroneo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Giardina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentina Ientile
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simona Potenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura Sottosanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carmen Ferrajolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Costantino J. Trombetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gianluca Trifirò
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Maria Cutroneo.

Ethics declarations

Funding

This study was conducted as part of the multi-regional pharmacovigilance project “Short- and long-term monitoring of the benefit-risk profile of intravitreal use of anti-VEGF drugs through network of clinical and administrative data” funded by AIFA (CUP-H56D15000440005).

Ethical approval

The multi-regional pharmacovigilance project “Short- and long-term monitoring of the benefit-risk profile of intravitreal use of anti-VEGF drugs through network of clinical and administrative data” was notified to local ethical committees.

Conflict of interest

Paola M. Cutroneo, Claudia Giardina, Valentina Ientile, Simona Potenza, Laura Sottosanti, Carmen Ferrajolo, Costantino J Trombetta, Gianluca Trifirò have no conflicts of interest that are directly relevant to the content of this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 316 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cutroneo, P.M., Giardina, C., Ientile, V. et al. Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System. Drug Saf 40, 1131–1140 (2017). https://doi.org/10.1007/s40264-017-0553-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-017-0553-y

Search

Navigation