Erectile Dysfunction Drugs Increase Risk of Rare, Serious Adverse Ocular Events

The phosphodiesterase type 5 (PDE5) inhibitors are a family of commonly prescribed medications most often used to treat erectile dysfunction in men. There are currently four such drugs approved by the Food and Drug Administration (FDA) for this use: avanafil (STENDRA),[1] sildenafil (VIAGRA),[2] tadalafil (CIALIS)[3] and vardenafil (available in generic only).[4]

Sildenafil marketed under the brand name REVATIO[5] and tadalafil sold under the brand names ADCIRCA,[6] ALYQ[7] and TADLIQ[8] also are FDA-approved for treatment of pulmonary hypertension, a lung disorder that can cause heart failure. Finally, tadalafil is marketed in combination with finasteride under the brand name ENTADFI for treatment of benign prostate enlargement only.[9]

Public Citizen’s Health Research Group has designated the PDE5 inhibitors for treatment of erectile dysfunction as Limited Use and finasteride products as Do Not Use for any use.

For more than two decades, use of PDE5 inhibitors has been linked to an increased risk of rare, serious eye disorders — most often ischemic optic neuritis (insufficient blood flow to the optic nerve), which can lead to irreversible vision loss. A new study published in the May 2022 issue of the Journal of the American Medical Association (JAMA) Ophthalmology[10] provides the strongest evidence to date that PDE5 inhibitors increase the risk of arteritic ischemic optic neuritis, as well as the risks of two other serious adverse ocular events known as serous retinal detachment and retinal venous occlusion, both of which can lead to vision loss. This new evidence reinforces the need for patients using these drugs to vigilantly monitor for changes in their vision.

Prior evidence

Soon after the FDA approved the first PDE5 inhibitor, sildenafil, for treatment of erectile dysfunction in 1998, physicians started reporting cases of ischemic optic neuritis in patients taking the drug.[11],[12],[13],[14],[15] In many of these cases, the onset of vision problems occurred within minutes to hours after taking a dose of sildenafil.

In July 2005, the FDA approved revised product labeling for sildenafil, tadalafil and vardenafil — the three PDE5 inhibitors available in the U.S. at the time — that instructed physicians to advise patients using PDE5 inhibitors to stop the drugs and seek medical attention in the event of sudden loss of vision in one or both eyes.[16],[17],[18],[19] The updated labeling further noted that such symptoms may be a sign of ischemic optic neuritis.

In October 2005, based on an increasing number of published case reports of sildenafil-associated ischemic optic neuritis and an analysis of cases of ischemic optic neuritis reported to the FDA’s adverse-event reporting system, Public Citizen petitioned the FDA to add a black-box warning — the strongest warning that the FDA can require — regarding the risk of vision loss to the product labeling for sildenafil, tadalafil and vardenafil.[20] In 2011, the FDA denied the petition, claiming that the warnings about ischemic optic neuritis in the existing product labeling for these drugs were sufficient and a black-box warning was not warranted.[21]

Subsequently, a small number of observational studies found an increased risk of ischemic optic neuritis associated with use of PDE5 inhibitors. One such study published in 2015 analyzed data from 64 patients treated with a PDE5 inhibitor who had definite or possible ischemic optic neuritis.[22] The researchers for this 2015 study estimated that there was a twofold increased risk of acute ischemic optic neuritis during the immediate period following treatment with such drugs. The product labeling for all PDE5 inhibitors has since been updated to include data from the 2015 study and another similar study with comparable findings.[23],[24],[25],[26]

The new JAMA Ophthalmology study[27]

For the new study, researchers at the University of British Columbia in Canada analyzed data from a private health insurance claims database containing health information on more than 150 million people in the U.S. From this database, they accessed data pertaining to a random sample of 16.4 million people from 2006 to 2020 who had been enrolled in a private health insurance plan for at least one year.

From the selected sample, the researchers then identified a cohort of 213,033 men who were new users of sildenafil, tadalafil, vardenafil or avanafil. To be included in this study cohort, the men had to meet the following criteria: no use of a PDE5 inhibitor and no diagnosis of ischemic optic neuritis, serous retinal detachment or retinal venous occlusion in the year prior to the study period.

The new users of the PDE5 inhibitors were then followed to see whether they were diagnosed with any of the following serious eye disorders: ischemic optic neuritis, serous retinal detachment or retinal venous occlusion. Among the study cohort of new PDE5-inhibitor users, 1,146 were diagnosed with one of these conditions: ischemic optic neuritis, 240 patients; serous retinal detachment, 278 patients; and retinal venous occlusion, 628 patients.

The researchers compared the rates of occurrence of these adverse ocular events in regular users of PDE5 inhibitors — defined as patients who had at least one prescription for a PDE5 inhibitor every three months — with the rates of these events in non-users of PDE5 inhibitors.

After adjusting for differences between the two groups in risk factors for these eye disorders — including hypertension, coronary artery heart disease, smoking, diabetes and sleep apnea — the researchers found that the rate of occurrence of any of the three eye disorders combined was 1.9-fold greater in regular users of PDE5 inhibitors than in non-users.

For ischemic optic neuritis, the rate of occurrence was twofold greater in regular users of PDE5 inhibitors than in non-users. For serous retinal detachment and retinal venous occlusion, the rates of occurrence in regular users of these drugs were 2.6-fold and 1.4-fold higher, respectively, than in non-users.

Importantly, these serious adverse ocular events are uncommon. For the three events combined, the rate of occurrence was 15.5 cases per 10,000 patients per year. For ischemic optic neuritis only, the rate was 3.2 cases per 10,000 patients per year. Thus, the overall absolute increase in risk of these adverse ocular events in regular users of PDE5 inhibitors was small.

What You Can Do

If you are taking a PDE5 inhibitor for erectile dysfunction or any other condition, you should discuss the possible risks of eye disorders with your ophthalmologist. If you experience any changes in your vision, you should be assessed by an ophthalmologist immediately, and if you are using the drug for erectile dysfunction, you should stop taking it until your eye symptoms have been fully assessed.

Report all serious adverse events related to any PDE5 inhibitor to the FDA’s MedWatch adverse-event reporting program by visiting www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Vivus LLC. Label: avanafil (STENDRA). May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d7127bb8-9e6b-4165-a0e2-2e99648427ce&type=display. Accessed October 7, 2022.

[2] Pfizer Inc. Label: sildenafil (VIAGRA). December 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020895s048lbl.pdf. Accessed October 7, 2022.

[3] Eli Lilly and Company. Label: tadalafil (CIALIS). April 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=bcd8f8ab-81a2-4891-83db-24a0b0e25895&type=display. Accessed October 7, 2022.

[4] Alembic Pharmaceuticals Inc. Label: vardenafil (generic only). October 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d2dce236-257e-44b6-93a9-9f0280257c6a&type=display. Accessed October 7, 2022.

[5] Pfizer Inc. Label: sildenafil (REVATIO). February 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f158fe10-d5dc-4432-b2c9-fc665401291b&type=display. Accessed October 7, 2022.

[6] Eli Lilly and Company. Label: tadalafil (ADCIRCA). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022332Orig1s011lbl.pdf. Accessed October 7, 2022.

[7] Teva Pharmaceuticals USA, Inc. Label: tadalafil (ALYQ). September 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3a404db2-7a7d-476f-81cf-979a67d37f66&type=display. Accessed October 7, 2022.

[8] CMP Pharma, Inc. Label: tadalafil (TADLIQ). June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214522s000lbl.pdf. Accessed October 7, 2022.

[9] Veru Inc. Label: finasteride and tadalafil (ENTADFI). December 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215423s000lbl.pdf. Accessed October 7, 2022.

[10] Etminan M, Sodhi M, Mikelberg FS, Maberley D. Risk of ocular adverse events associated with use of phosphodiesterase 5 inhibitors in men in the US. JAMA Ophthalmol. 2022;140(5):480-484.

[11] Egan R, Pomeranz H. Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch Ophthalmol. 2000;118(2):291-292.

[12] Cunningham AV, Smith KH. Anterior ischemic optic neuropathy associated with Viagra. J Neuroophthalmol. 2001;21(1):22-25.

[13] Boshier A, Pambakian N., Shakir SAW. A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil. Int J Clin Pharmacol Ther. 2002;40(9):422-423.

[14] Pomeranz HD, Smith KH, Hart WM, Egan RA. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002;109(3):584-587.

[15] Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmology. 2005;25(1):9-13.

[16] Pfizer Inc. Label: sildenafil (VIAGRA). June 2005. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020895s021lbl.pdf. Accessed October 7, 2022.

[17] Eli Lilly and Company. Label: tadalafil (CIALIS). July 2005. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021368s006lbl.pdf. Accessed October 7, 2022.

[18] Bayer Pharmaceuticals Corporation. Label: vardenafil (LEVITRA). July 2005. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021400s004lbl.pdf. Accessed October 7, 2022.

[19] Food and Drug Administration. Letter to Public Citizen regarding docket No. FDA-2005-P-0192. November 22, 2011. https://www.regulations.gov/document/FDA-2005-P-0192-0005. Accessed October 7, 2022.

[20] Public Citizen. Petition to require a black box warning for erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). October 20, 2005. https://www.citizen.org/article/petition-to-require-a-black-box-warning-for-erectile-dysfunction-drugs-sildenafil-viagra-tadalafil-cialis-and-vardenafil-levitra/. Accessed October 7, 2022.

[21] Food and Drug Administration. Letter to Public Citizen regarding docket No. FDA-2005-P-0192. November 22, 2011. https://www.regulations.gov/document/FDA-2005-P-0192-0005. Accessed October 7, 2022.

[22] Campbell UB, Walker AM, Gaffney M, et al. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015;12(1):139-151.

[23] Vivus LLC. Label: avanafil (STENDRA). May 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d7127bb8-9e6b-4165-a0e2-2e99648427ce&type=display. Accessed October 7, 2022.

[24] Pfizer Inc. Label: sildenafil (VIAGRA). December 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020895s048lbl.pdf. Accessed October 7, 2022.

[25] Eli Lilly and Company. Label: tadalafil (CIALIS). April 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=bcd8f8ab-81a2-4891-83db-24a0b0e25895&type=display. Accessed October 7, 2022.

[26] Alembic Pharmaceuticals Inc. Label: vardenafil (generic only). October 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d2dce236-257e-44b6-93a9-9f0280257c6a&type=display. Accessed October 7, 2022.

[27] Etminan M, Sodhi M, Mikelberg FS, Maberley D. Risk of Ocular Adverse Events Associated With Use of Phosphodiesterase 5 Inhibitors in Men in the US. JAMA Ophthalmol. 2022;140(5):480-484.