The lost men – appendix

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This table summarizes cases of unresolved and severe adverse events from clinical trials of finasteride and dutasteride. It is an appendix to The lost men.

Go to The lost men

TrialCases in finasteride group
Proscar Phase I, spaced doses112 men took doses of finasteride up to 100 mg, which is 20x the dose later approved as Proscar. No safety information is reported.
Proscar Phase I, multiple doses2In Part 1, 30 healthy males, aged 19–46, were assigned to groups taking 25 mg, 50 mg and 100 mg finasteride per day for 11 days. The 100 mg dose is 20x higher than the dose later approved as Proscar, and 100x the dose of Propecia. The article reported “[n]o significant adverse experiences… The only symptoms reported that could possibly be related to drug were mild headache in two subjects in part 1 and one subject in part 2.” This omits adverse experiences the investigator did not consider drug-related. At this early stage of drug development, it is unclear how the investigator could determine which symptoms were and were not drug-related.
Proscar Phase II, one year3Among 15 dropouts, there were 2 deaths deemed unrelated to finasteride. Two patients dropped out reporting impotence and decreased libido, respectively. Five patients dropped out with no reason given for discontinuation.
There were 7 serious adverse experiences but the investigator reported that “none of these was considered to be drug-related.” Even though 10.4% of patients had serious adverse experiences and 22.4% discontinued the study, the authors noted, ”finasteride continues to demonstrate an excellent safety profile.”
Proscar Phase III4One suicide. One death. Seven men withdrew because of sexual dysfunction. It is unknown whether sexual dysfunction resolved in these men.
Proscar Long-term Efficacy and Safety Study (PLESS)5An estimated 28 men in the finasteride group (vs. 13 men in the placebo group) had a sexual adverse event that did not recover after withdrawal.
Propecia Phase II (5 mg)6In one case, drug-related ‘Impotence’ was unresolved 27 days after discontinuation. It is unknown whether it subsequently resolved.
Propecia Phase III, 4-year extension7In one man who left the trial because of sexual dysfunction, it was unresolved six months later. Sixteen men who stayed in the trial had sexual dysfunction which was not resolved at the end of the trial. It is unknown whether the adverse events resolved later.
Propecia Phase III, frontal hair loss8An unspecified number of men had sexual adverse events. Within this group, an unspecified number did not have resolution of the sexual adverse event(s) during the trial. It is unknown whether sexual adverse events resolved after they left the trial.
Finasteride – effect on semen parameters9One man had sexual dysfunction which did not resolve during the trial. No follow-up information is provided.
Dutasteride and finasteride – effects on semen parameters10In the dutasteride group, one man withdrew with impotence and decreased volume of ejaculate. Another withdrew with impotence and decreased libido.
In the finasteride group, three withdrew due to decreased libido, gynecomastia, and depression, respectively. The latter was regarded as a Serious Adverse Event.
In both treatment groups, sperm motility was reduced 6–12% from baseline 24 weeks (about 5.5 months) after the treatment ended.
In three men, 24 weeks after stopping finasteride or dutasteride, total sperm count was 19–33% of the level before starting treatment.
Prostate Cancer Prevention Trial (PCPT)11The dropout rate from the finasteride arm was greater than the placebo group over 7 years of the trial, and this was often due to sexual dysfunction side effects. Follow-up information on whether these side effects resolved is not available.
Japan trial, 2006–200912AEs occurred in 23 patients, but are only specified for 13 patients: decreased libido in 8 patients, liver disorder in 3 patients and enlarged breast in 2 patients.
Seven patients discontinued due to: decreased libido (3); hepatic functional disorder; ‘disturbance of memorization’; enlarged breast(s); and palpitations, fever and headache.
“Most” adverse events were described as mild; the number of non-mild adverse events is not specified. In men who stayed in the trial, adverse events which did not resolve were decreased libido with or without orchiatrophy (shrunken testicles). The number of men who had these adverse events is not provided. The status of men who discontinued with adverse events, and men who completed the trial with unresolved adverse events, is unknown.

References

  1. Rittmaster RS, Stoner E, Thompson DL, Nance D, Lasseter KC. Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men. J Androl. 1989. doi:10.1002/j.1939-4640.1989.tb00097.x • PubMed
  2. Gormley GJ, Stoner E, Rittmaster RS, et al. Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab. 1990. doi:10.1210/jcem-70-4-1136 • PubMed
  3. One-year experience in the treatment of benign prostatic hyperplasia with finasteride. The MK-906 (Finasteride) Study Group. J Androl. 1991. PubMed
  4. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med. 1992. doi:10.1056/NEJM199210223271701 • PubMed
  5. Wessells H, Roy J, Bannow J, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology. 2003. doi:10.1016/s0090-4295(02)02401-9 • PubMed
  6. Merck Research Laboratories. Drug Approval Package: Propecia NDA #020788; Trial 047. Drugs@FDA. December 19, 1997.
  7. Merck Research Laboratories Worldwide Product Safety. Periodic Safety Report for: Finasteride, 1 mg tablet and 0.2 mg tablet, MSD. November 30, 2006. View at pfsfoundation.org
  8. Leyden J, Dunlap F, Miller B, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999. doi:10.1016/s0190-9622(99)70081-2 • PubMed
  9. Overstreet JW, Fuh VL, Gould J, et al. Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol. 1999. PubMed
  10. Amory JK, Wang C, Swerdloff RS, et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men [published correction appears in J Clin Endocrinol Metab. 2007 Nov;92(11):4379]. J Clin Endocrinol Metab. 2007. doi:10.1210/jc.2006-2203 • PubMed
  11. Moinpour CM, Darke AK, Donaldson GW, et al. Longitudinal analysis of sexual function reported by men in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2007. doi:10.1093/jnci/djm023 • PubMed
  12. Sato A, Takeda A. Evaluation of efficacy and safety of finasteride 1 mg in 3177 Japanese men with androgenetic alopecia. J Dermatol. 2012. doi:10.1111/j.1346-8138.2011.01378.x • PubMed