Cases of Ischemic Optic Neuropathy Associated With Phosphodiesterase-5 Inhibitor Use Reported to the Food and Drug Administration Adverse Event Reporting System

Letters to the Editor Cases of Ischemic Optic Neuropathy Associated With Phosphodiesterase-5 Inhibitor Use Reported to the Food and Drug Administration Adverse Event Reporting System T he use of phosphodiesterase 5 inhibitors (PDE5I) as a potential risk factor for anterior ischemic optic neuropathy (AION) has been reviewed (1) and debated (2) recently in the Journal. I thought it appropriate to add to the discussion by summarizing all cases reported to the Food and Drug Administration (FDA). Sildenafil was the first PDE5I approved by the FDA in March 1998, and was followed by vardenafil and tadalafil in 2003 and avanafil in 2012. All 4 medications are approved for treatment of erectile dysfunction. In addition, sildenafil and tadalafil are FDA approved for management of pulmonary hypertension. Reports of AION associated with PDE5I use were first published in the peer reviewed medical literature in 2000 (3). A recent review of the medical literature has identified a total of 39 case of AION associated with PDE5I use through 2014 (1). The FDA maintains a database of reported cases of patient complaints associated with medication use through its Adverse Event Reporting System (AERS). This database is a resource for documentation of new vision complaints that occurred after FDA approval that were not recognized during clinical trials. The FDA database denotes all cases as ischemic optic neuropathy (ION), which will be the term used here. In 2005, the FDA documented that a total of 43 cases of ION had been reported through AERS. The number of cases that have been reported to the FDA since 2005 has not been reviewed. Therefore, this study was undertaken to determine the number of the cases of ION in the FDA database for each of the PDE5I medications and to analyze the characteristics of the reported cases. An online request was made to the FDA through its Freedom of Information Act for a report of all documented adverse events for each of the PDE5I medications from the time of FDA approval through December 31, 2014. The terms "optic ischemic neuropathy" and "optic nerve infarction" were used to identify cases of ION. A reported diagnosis of optic atrophy, optic disc swelling, optic neuritis, optic pallor, or any other identifier indicative of a possible optic neuropathy such as visual field loss or color vision loss was discarded in this analysis, because it was not possible to confirm that the etiology for vision loss in these cases was not because of some other type of optic neuropathy. The number of cases, patient age, date of case Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 221-229 report, case report number, dose of medication, and any other reported details regarding frequency and duration of use were collected and analyzed. The number of cases of ION identified in the FDA database associated with sildenafil use between 1998 and 2014 was 443 (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A184). A small number of cases of ION associated with sildenafil use were reported to the FDA between 1999 and 2001. In 2002, ten cases were reported; however, 5 of those cases were reported to the FDA by this author and were the same as the 5 patients published as a case series in 2002 (4). In 2003, 14 cases associated with sildenafil use were documented, including 8 cases that were reported on the same day, the source of which could not be determined from the database. The only information listed for these same-day cases was that the patients used sildenafil; no information was reported on sildenafil dose, duration of use, sex, or age. In 2005, the year that the FDA mandated the inclusion of the warning about ION in the drug insert for PDE5I, eighty-eight ION cases associated with sildenafil use were reported, including 8 cases documented on March 28, 2005 and 4 cases on March 29, 2005. All cases from March 2005 documented the patient age, with most of the cases including the dose of sildenafil and frequency of use. In 2006, one hundred cases of ION were documented, including 6 cases reported on February 7, 2006, 8 cases on February 8, 2006, and 47 cases on June 14, 2006, with no details reported on the same-day cases other than male sex. In 2007, one hundred twenty cases of ION were reported in the database, including thirty cases listed on May 16, 2007 with only the patient age and sex documented, 9 cases on May 21, 2007 with most cases reporting only patient age and sex, and 12 cases on December 12, 2007 reporting the patient age and sex. In 2008 and 2009, 52 and 26 cases of ION associated with sildenafil use were reported respectively. Between 2010 and 2014, 2 to 7 cases per year were reported. Unique among the cases of ION associated with sildenafil use were 4 cases affecting individuals who were younger than 40 years of age. In 2007, 3 cases were reported, including 2 males who were 27 and 34 year old, and a 6 year old boy. In July 2014, ION was reported in a 213-day-old male infant. The 6-year-old and infant males were presumably being treated for pulmonary hypertension. The case report for the infant documents a daily dose of sildenafil of 0.6mg/kg/day; no dose is reported for the 6-year-old. These may be the same cases as those reported by Gaffuri et al in 2014 (5) and Sivaswamy and van Stavern in 2007 (6). Seventy-one cases of ION associated with tadalafil use are documented in the FDA database (see Supplemental Digital 221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor Content, Table E2, http://links.lww.com/WNO/A185). The number of annual cases ranged from 4 to 11. Unlike the sildenafil cases, there were no aggregated cases reported on a single day. Most of the cases reported the age, sex, and dose of tadalfil, but few cases reported the duration or frequency of use. In 2011, there were 2 reported cases of tadalafil-associated ION occurring in young men, ages 28 and 33. The 28-year-old used tadalafil at a dose of 10 mg twice a week, followed by 20 mg twice a day then 5mg/day for a total of 61 days, although it is not specified how many days he was taking each dose. This regimen was presumably for treatment of pulmonary hypertension. The 33-year-old used tadalafil at a dose of 10 mg, but no duration or frequency of use was documented. A total of 39 cases of ION associated with vardenafil use were found in the FDA database (see Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A186). Fourteen cases were reported in 2006 and 10 cases were reported in 2010. The annual number of cases reported in other years from 2005 through 2014 ranged from one to 4. The sex was reported for all cases. The age was documented in 30 cases. Thirteen cases had no data regarding either dose or frequency of vardenafil. All cases were over 40 years of age. In summary, a review of the FDA AERS for documented cases of ION with use of PDE5I, including sildenafil, tadalafil, and vardenafil, demonstrates that many additional cases have been reported since the FDA reported such cases in 2005. At that time, 38 and 4 cases were associated with sildenafil and tadalafil, respectively, and 1 associated with vardenafil. Those numbers as of the end of 2014 increased to 443, 71, and 39, respectively. Most of the cases were documented in men above the age of 40 years. The youngest case was a 7-month-old infant who was presumably being treated for pulmonary hypertension with sildenafil. Patient age as well as dose, duration, and frequency of PDE5I use were not consistently documented in the database. The number of cases reported here is 1 order of magnitude greater than the number of cases reported in the peer reviewed medical literature and may represent a more accurate representation of the actual number of cases associated with PDE5I use. However, given the large number of prescriptions for any of the PDE5I dispensed since their approval by the FDA, it has been enigmatic why the number of reported cases of PDE5I associated ION has not been even greater. The number of cases associated with PDE5I use is greater than the number of cases previously reported by 222 the FDA in 2005, and larger than the number of cases documented in the peer reviewed medical literature. The largest number of cases is associated with sildenafil use which is not surprising, given that sildenafil was the first PDE5I approved by the FDA and is likely most commonly prescribed among the PDE5I. There are no reported cases of ION associated with avanafil use. It is not possible to conclude a definitive association between PDE5I use and AION based on the information in the FDA database. However, it is still recommended that when AION is diagnosed, individuals should be asked about PDE5I use, and counseled about the potential consequences of continued use of PDE5I including vision loss. Howard D. Pomeranz, MD, PhD Department of Ophthalmology, North Shore Long Island Jewish Health System and Hofstra-North Shore LIJ School of Medicine, Great Neck, New York The author reports no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). REFERENCES 1. Pomeranz HD. The relationship between phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2016;36:193-196. 2. Lee MS, Vaphiades M. Are erectile dysfunction medications causally related to nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2016;36:202-207. 3. Egan R, Pomeranz H. Sildenafil (Viagra) associated anterior ischemic optic neuropathy. Arch Ophthalmol. 2000;118:291-292. 4. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafilassociated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002;109:584-587. 5. Gaffuri M, Cristofaletti A, Mansoldo C, Biban P. Acute onset of bilateral visual loss during sildenafil therapy in a young infant with congenital heart disease. BMJ Case Rep. 2014;2014. 6. Sivaswamy L, Van Stavern GP. Ischemic optic neuropathy in a child. Pediatr Neurol. 2007;37:371-372. Letters to the Editor: J Neuro-Ophthalmol 2016; 36: 221-229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.