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This Month's Question:

Given recent reports associating phosphodiesterase type 5 (PDE5) inhibitor therapy with hearing loss, please provide a context for and specific information about this adverse event. Has a causal relationship been established between PDE5 inhibitors and hearing loss?

Response by Louis Kuritzky, MD, Posted 03/15/08

Despite almost a decade of experience with tens of millions of men worldwide and a well-established safety record, occasional safety concerns regarding PDE5 inhibitors have periodically surfaced (eg, risks of myocardial infarction [MI], hypotension when co-administered with α-blockers, and nonarteritic anterior ischemic optic neuropathy [NAION]). To date, none of these safety concerns has resulted in significant long-term changes in prescribing practice by clinicians or utilization by the at-large population of men, because in each case, concerns about risk have been allayed or no confirmed causal association has been established. It is to be anticipated that any agent commonly administered to large populations of men at midlife or later might be associated periodically with what would otherwise be rare events. PDE5 inhibitors remain essentially pristine with regard to maintenance of their originally established contraindication and adverse event profiles. Nonetheless, it is wise to have a high level of vigilance when untoward events suggest even a potential link between a pharmacotherapy and adverse outcomes.

Original concerns about PDE5 inhibitors focused on cardiovascular safety issues, prompting an evaluation of whether sexual activity would precipitate a disproportionate incidence of cardiovascular events in men with cardiovascular disease who were taking PDE5 inhibitors.^1,2 Because most men who take PDE5 inhibitors are middle-aged and older, they share an epidemiologically disproportionate incidence of cardiovascular events at baseline. The notoriety of cases in which men who had suffered an MI in proximity to taking a PDE5 inhibitor prompted public as well as professional concern. Subsequently, a retrospective analysis of clinical trials demonstrated that use of a PDE5 inhibitor did not increase the rate of MI or cardiac mortality: The incidence was low and comparable to placebo.³ No increased cardiovascular risk was discernible among men taking PDE5 inhibitors, whether on-demand or daily.⁴ Current prescribing information contraindicates concomitant utilization with organic nitrates, and caution for patients receiving α-blockers remains appropriate.^5-7 With clinicians’ appropriate counseling and patient education and heightened awareness, patients with cardiovascular conditions can safely take PDE5 inhibitors.

In 2005, rare post-marketing case reports of sometimes irreversible vision loss occurring sporadically among patients receiving PDE5 inhibitors prompted US Food and Drug Administration (FDA) concern.⁸ Most of these cases were attributed to NAION, a condition that has been and remains rare but is seen in the general population of men and women who do not take PDE5 inhibitors. Nonetheless, the number of anecdotes of PDE5 inhibitor-associated NAION prompted a labeling change so that clinicians might heighten their vigilance for visual disturbance in patients taking PDE5 inhibitors, promptly discontinue medication, and refer for ophthalmologic consultation. Subsequently, a follow-up analysis of data from global clinical trials and European observational studies representing 52,000 patient-years of observation revealed that PDE5 inhibitor use was not associated with an increased incidence of NAION in a treated population when compared with the incidence within the general US population.⁹

In a similar manner, a wave of concern recently grew out of reports of hearing loss associated with PDE5 inhibitors. On October 18, 2007, the FDA approved an updated labeling precaution for all PDE5 inhibitors to reflect post-marketing reports of associated hearing loss.¹⁰ A case report published in the Journal of Laryngology and Otology describing a 44-year-old patient who experienced bilateral profound unremitting sensorineural hearing loss after 15 days of taking sildenafil 50 mg/day¹¹ prompted a review of the Adverse Events Reporting System that yielded 29 reports of sudden hearing loss (sometimes reversible) associated with PDE5 inhibitors.¹⁰ In these case reports, patients experienced unilateral partial to complete loss of hearing, with or without tinnitus or (rarely) vestibular symptoms (eg, vertigo, dizziness); approximately one third of these cases were temporary.¹⁰ Again, a causal relationship has not been established: It is not possible to determine whether these events are related directly to PDE5 inhibitors or to other factors. Clinicians should inform patients with ED that, if they experience these symptoms, they should immediately stop taking PDE5 inhibitors and seek medical care.^5-7,10

PDE5 inhibitors have an excellent safety profile and have been used by tens of millions of men worldwide. Labeling changes in 2008 (ie, approval of tadalafil 2.5 mg for once-daily use to treat erectile dysfunction [ED]) further support the safety of these agents. Although it is always wise to observe caution whenever clinical signals suggest a possible relationship, clinicians should remain confident that PDE5 inhibitors continue to maintain a consistently favorable safety record and remain the agents of choice for management of ED for the vast majority of patients.

References

1. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol. 2000;86:175-181.

2. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol. 2005;96:313-321.

3. Jackson G, Kloner RA, Costigan TM, Warner MR, Emmick JT. Update on clinical trials of tadalafil demonstrates no increased risk of cardiovascular adverse events. J Sex Med. 2004;1:161-167.

4. Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil: retrospective analysis of data from placebo-controlled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing. Am J Cardiol. 2006;97:1778-1784.

5. Cialis [package insert]. Indianapolis, IN: Eli Lilly and Company; 2008.

6. Levitra [package insert]. West Haven, CT: Bayer Pharmaceuticals Corporation; 2007.

7. Viagra [package insert]. New York, NY: Pfizer Inc; 2007.

8. US Food and Drug Administration. FDA updates labeling for Viagra, Cialis and Levitra for rare post-marketing reports of eye problems [press release]. http://www.fda.gov/bbs/topics/NEWS/2005/NEW01201.html. Accessed March 13, 2008.

9. Gorkin L, Hvidsten K, Sobel RE, Siegel R. Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy. Int J Clin Pract. 2006;60(4):500-503.

10. US Food and Drug Administration. FDA announces revisions to labels for Cialis, Levitra and Viagra: potential risk of sudden hearing loss with ED drugs to be displayed more prominently [press release]. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01730.html. Accessed March 13, 2008.

11. Mukherjee B, Shivakumar T. A case of sensorineural deafness following ingestion of sildenafil. J Laryngol Otol. 2007;121:395-397.