madman
Super Moderator
How routine pharmacovigilance failed to identify finasteride’s persistent sexual side effects (2021)
Michael S Irwig
The first warnings of persistent adverse sexual effects of finasteride (Propecia) by regulatory agencies were sounded in 2008 in Sweden and in 2009 in the United Kingdom. In 2011, two independent groups published peer-reviewed articles on the persistent adverse sexual effects of finasteride used for androgenetic alopecia.1,2 The term post finasteride syndrome was coined by some men to describe the persistent symptoms (sexual and non-sexual) that they developed in the setting of using or stopping finasteride. The most commonly reported symptoms to include low libido, erectile dysfunction, loss of penile and scrotal sensitivity, decreased ejaculatory force and volume, reduction in penile size, anhedonia, depressive symptoms, anxiety, decreased concentration, reduced muscle mass, and fatigue.3 Nonetheless, the existence of post-finasteride syndrome has been controversial among many in the medical community despite several human case series and animal studies that confirm adverse effects of finasteride.4 In July 2012, a 501(c)(3) nonprofit corporation was established in the United States called the Post-Finasteride Syndrome Foundation.
In January 2021, internal documents from Merck were made public thanks to a motion filed by Reuters in 2019, to unseal documents from litigation. These newly unsealed documents shed light on what Merck knew and when they knew it. One relevant document was the Risk Management Plan (Version Number 1.0 dated February 2009) that was discussed at a June 2009 meeting by Merck’s Risk Management Safety Team.5 This document identified three potential risks: persistent erectile dysfunction, male infertility, and depressive disorders. Using the Worldwide Adverse Experience System database, Merck officials identified 278 cases of erectile dysfunction that had not recovered. The report stated, “In the majority of these 278 cases critical data were not reported (i.e., time from discontinuation of finasteride to the time patient-reported as not recovered, concurrent medications, or medical history) limiting the values of these reports in assessing the relationship of finasteride therapy to the persistence of erectile dysfunction.” Nevertheless, the report also acknowledged and described several representative cases without evidence of confounding variables. The report also stated, “the ability to assess the overall trend in the time to recovery as well as overall outcome information relative to erectile dysfunction is limited, as longer-term outcome data are not available in the large majority of cases.”
In March 2011, the United States Food and Drug Administration (FDA) held a teleconference with Merck’s representatives to discuss post-marketing persistent sexual dysfunction. In that same month, the Center for Drug Evaluation and Research at the FDA approved Merck’s application to add to the product label “erectile dysfunction that continued after discontinuation of treatment.” The labeling changes to finasteride (Propecia and Proscar) took effect in April 2012. Of note, sexual adverse effects have also been reported in men who have taken finasteride for benign prostatic hypertrophy.6
Much of the controversy surrounding post-finasteride syndrome relates to the inherent limitations of post-marketing data. It is important to note that the randomized controlled trials of finasteride also had limitations as these trials were flawed in their ability to assess sexual adverse effects. According to a meta-analysis, these trials did not employ validated instruments to assess sexual function prior to and during medication use nor were they powered to detect an uncommon or rare (<1%) adverse effect.7 Merck’s phase III trials of finasteride 1 mg/day only included 3210 patients with a mean exposure of 749 days.5 In addition, the trials usually failed to disclose the specific details of the subjects who developed an adverse effect and/or withdrew from the studies.
The incidence of persistent sexual effects associated with finasteride is unknown. According to Merck’s Risk Management Plan, an estimated 4.6 million men had received finasteride 1 mg from 1998 to 2008.5 According to the public dashboard of the FDA’s Adverse Event Reporting System, as of June 2021, there were 10,295 serious adverse events for finasteride. It is well established that most adverse medication events are grossly underreported.8 Importantly, three of the four most common reaction types are related to sexual dysfunction: erectile dysfunction, sexual dysfunction, and decreased libido.
When confronted with data that their product could cause persistent erectile dysfunction, the Risk Management Safety Team at Merck, in 2009, had the opportunity to take further action to sort out the issue. Realizing that many adverse event reports lacked adequate information, the team could have recommended conducting additional rigorous prospective studies on finasteride to obtain needed information using validated instruments to assess sexual symptoms. Instead of seeking out the truth regarding a serious and life-altering adverse effect, the Risk Management Safety Team’s planned action was routine pharmacovigilance for another 2 years.5 It is difficult to justify this decision since routine pharmacovigilance was unable to provide adequate information on hundreds of cases from 1998 to 2008. The FDA also bears some responsibility as it did not advise or require Merck to conduct additional safety studies to adequately address the signal of persistent erectile dysfunction. Although we cannot turn back the clock to alter Merck’s approach and decision in 2009, prescribers of finasteride and male patients with androgenetic alopecia deserve to know how an opportunity was lost to seek the truth regarding this medication’s persistent sexual side effects.
Michael S Irwig
The first warnings of persistent adverse sexual effects of finasteride (Propecia) by regulatory agencies were sounded in 2008 in Sweden and in 2009 in the United Kingdom. In 2011, two independent groups published peer-reviewed articles on the persistent adverse sexual effects of finasteride used for androgenetic alopecia.1,2 The term post finasteride syndrome was coined by some men to describe the persistent symptoms (sexual and non-sexual) that they developed in the setting of using or stopping finasteride. The most commonly reported symptoms to include low libido, erectile dysfunction, loss of penile and scrotal sensitivity, decreased ejaculatory force and volume, reduction in penile size, anhedonia, depressive symptoms, anxiety, decreased concentration, reduced muscle mass, and fatigue.3 Nonetheless, the existence of post-finasteride syndrome has been controversial among many in the medical community despite several human case series and animal studies that confirm adverse effects of finasteride.4 In July 2012, a 501(c)(3) nonprofit corporation was established in the United States called the Post-Finasteride Syndrome Foundation.
In January 2021, internal documents from Merck were made public thanks to a motion filed by Reuters in 2019, to unseal documents from litigation. These newly unsealed documents shed light on what Merck knew and when they knew it. One relevant document was the Risk Management Plan (Version Number 1.0 dated February 2009) that was discussed at a June 2009 meeting by Merck’s Risk Management Safety Team.5 This document identified three potential risks: persistent erectile dysfunction, male infertility, and depressive disorders. Using the Worldwide Adverse Experience System database, Merck officials identified 278 cases of erectile dysfunction that had not recovered. The report stated, “In the majority of these 278 cases critical data were not reported (i.e., time from discontinuation of finasteride to the time patient-reported as not recovered, concurrent medications, or medical history) limiting the values of these reports in assessing the relationship of finasteride therapy to the persistence of erectile dysfunction.” Nevertheless, the report also acknowledged and described several representative cases without evidence of confounding variables. The report also stated, “the ability to assess the overall trend in the time to recovery as well as overall outcome information relative to erectile dysfunction is limited, as longer-term outcome data are not available in the large majority of cases.”
In March 2011, the United States Food and Drug Administration (FDA) held a teleconference with Merck’s representatives to discuss post-marketing persistent sexual dysfunction. In that same month, the Center for Drug Evaluation and Research at the FDA approved Merck’s application to add to the product label “erectile dysfunction that continued after discontinuation of treatment.” The labeling changes to finasteride (Propecia and Proscar) took effect in April 2012. Of note, sexual adverse effects have also been reported in men who have taken finasteride for benign prostatic hypertrophy.6
Much of the controversy surrounding post-finasteride syndrome relates to the inherent limitations of post-marketing data. It is important to note that the randomized controlled trials of finasteride also had limitations as these trials were flawed in their ability to assess sexual adverse effects. According to a meta-analysis, these trials did not employ validated instruments to assess sexual function prior to and during medication use nor were they powered to detect an uncommon or rare (<1%) adverse effect.7 Merck’s phase III trials of finasteride 1 mg/day only included 3210 patients with a mean exposure of 749 days.5 In addition, the trials usually failed to disclose the specific details of the subjects who developed an adverse effect and/or withdrew from the studies.
The incidence of persistent sexual effects associated with finasteride is unknown. According to Merck’s Risk Management Plan, an estimated 4.6 million men had received finasteride 1 mg from 1998 to 2008.5 According to the public dashboard of the FDA’s Adverse Event Reporting System, as of June 2021, there were 10,295 serious adverse events for finasteride. It is well established that most adverse medication events are grossly underreported.8 Importantly, three of the four most common reaction types are related to sexual dysfunction: erectile dysfunction, sexual dysfunction, and decreased libido.
When confronted with data that their product could cause persistent erectile dysfunction, the Risk Management Safety Team at Merck, in 2009, had the opportunity to take further action to sort out the issue. Realizing that many adverse event reports lacked adequate information, the team could have recommended conducting additional rigorous prospective studies on finasteride to obtain needed information using validated instruments to assess sexual symptoms. Instead of seeking out the truth regarding a serious and life-altering adverse effect, the Risk Management Safety Team’s planned action was routine pharmacovigilance for another 2 years.5 It is difficult to justify this decision since routine pharmacovigilance was unable to provide adequate information on hundreds of cases from 1998 to 2008. The FDA also bears some responsibility as it did not advise or require Merck to conduct additional safety studies to adequately address the signal of persistent erectile dysfunction. Although we cannot turn back the clock to alter Merck’s approach and decision in 2009, prescribers of finasteride and male patients with androgenetic alopecia deserve to know how an opportunity was lost to seek the truth regarding this medication’s persistent sexual side effects.
