FDA quashed internal warning on suicidality linked to Propecia; changed course in 2022

KEY POINTS

In 2010, Merck requested to add ‘depression’ to adverse events in the Propecia label.
A safety group within FDA concurred, and also recommended adding ‘suicidal thoughts and behavior.’
FDA’s dermatology products group did not support adding a suicidality warning. Only ‘depression’ was added to the label in 2011.
Over a decade later, in 2022, FDA required the addition of ‘suicidal ideation and behavior’ to the Propecia label.
There have been discrepancies and delays in updating warnings across regions and countries.

It took over a decade for the U.S. Food and Drug Administration to come around to a recommendation of its own internal safety monitoring group. After declining to add a suicidality warning to the Propecia label in 2011, the Agency has required adding a nearly identical warning in 2022.

This turn of events begins with Merck’s 2010 request to add a ‘depression’ warning to the Propecia label in the United States. FDA’s dermatology products group asked an internal safety monitoring group to review reports of depression linked to Propecia. The group found support for adding a depression warning, and further recommended adding ‘suicidal thoughts and behavior.’

The dermatology division “opposed adding the suicide warning,” according to a recent memo by Judge Brian Cogan. In 2011, FDA announced that only ‘depression’ would be added to the label. In effect, FDA accepted Merck’s recommendation, but declined the recommendation of its own internal safety monitoring group.

A change of course in 2022

In its recent response to a Citizen Petition, FDA revisited links between finasteride and suicidality. Despite declining a similar recommendation in 2011, FDA has now required the addition of ‘suicidal ideation and behavior’ to the Propecia label. The new warning appeared in Propecia Prescribing Information in July 2022. FDA has not required that this warning appear in the patient package insert, nor in patient counseling information.

July 2022 update to Propecia Prescribing Information. ‘Suicidal ideation and behavior’ has been added; however, this is not required to be added to the patient package insert or patient counseling information.

The agency refused to say whether finasteride might be a cause of suicidal ideation and behavior. The label must include a disclaimer that “[t]he relationship between these pharmacodynamic activities and the mechanisms(s) by which Propecia exerts its clinical effect is unknown.”

Swedish regulator spurred Merck’s request to add depression to U.S. label

The catalyst for Merck’s request for a depression warning originated in Sweden. In 2007, the Swedish Medical Products Agency had called for Merck to discuss finasteride’s influence on depression. In 2010 the Swedish agency requested a “cumulative review of depression, including suicide related ADRs [adverse drug reactions].” Based on its review of adverse event reports, Merck could not exclude a possible link between Propecia and depressive events.

This link had implications for labeling in the U.S. Since FDA regulations require that drug warnings “remain adequate,” Merck submitted a request to FDA to add ‘depression’ to the U.S. label later that year.

Did Merck withhold other safety findings from U.S. label?

Merck was less responsive regarding warnings of persistent sexual dysfunction. After more than two years of wrangling between Merck and the Swedish regulator, a warning of persistent sexual dysfunction was added to the label in Europe in 2008. A similar warning on did not appear on the U.S. label until 2012. Was safety information in the U.S. label “adequate” during the approximately four years between label changes in Sweden and the U.S., as FDA regulations require?

A 2017 report from the European Medicines Agency recommended that ‘depression and suicidal ideation’ be added to the label of finasteride (5 mg) for prostate enlargement, but not the 1 mg dose for the treatment of hair loss. Now five years later, suicidal ideation has been added to the U.S. label for finasteride (1 mg).

In 2017, Health Canada required the addition of suicidal ideation to both Propecia and Proscar labels:

Health Canada’s review concluded that there may be a link between Proscar and Propecia (finasteride) and the risk of suicidal ideation. Health Canada has notified the manufacturer to update the Canadian product information on this potential safety issue.

During the 5-year delay between the addition of suicidal ideation in Canada and the United States, was safety information in the U.S. label “adequate”?

In 2018 the European Medicines Agency added ‘anxiety’ to the labels of both Proscar and Propecia. The U.S. label does not currently include a similar warning, even though this adverse event was among the most commonly reported events among younger men from 2018–2020.

Lengthy history of label changes since approval

Aside from international discrepancies, Propecia has a long history of label changes within the U.S. This raises questions about whether safety information in Merck’s New Drug Application was adequate. The following adverse events have been added since approval (see also a history of label changes):

2002: Testicular pain added
2004: Breast adverse events added
2010: Breast enlargement added
2011: First mention of depression; rare instances of breast cancer
2012: Added reports of sexual adverse events that “continued after stopping the medication” and “male infertility / poor quality of semen”
2014: Angioedema added to prescriber label
2021: Hematospermia added to prescriber label
2022: FDA requires 1) addition of suicidal ideation and behavior to postmarketing events; 2) addition of sexual adverse events to Patient Counseling Information

In summary, Merck has been slow to coordinate label changes across regions and countries as new safety information emerged. A long history of label changes—including the addition of persistent sexual dysfunction, semen and fertility concerns, depression and suicidality—suggests that safety reporting from the original clinical trials was wholly inadequate.

Appendix: Internal FDA assessment of suicidality reports

FDA’s 2011 letter requiring a label change includes an internal report from FDA’s Office of Surveillance and Epidemiology (OSE). Here, OSE assesses evidence of an association of finasteride with suicide-related adverse events (emphasis added):

We agree with the sponsor’s assessment to add depression to the Adverse Events, Postmarketing Experience section of the label. We also identified cases of suicide-related adverse events, which further support the potential association with finasteride. A relationship between finasteride exposure as a causal or contributory factor and depression-related and suicide-related events is difficult to assess based on the limited information provided in the cases and the presence of confounding factors (i.e. medical conditions associated with depression/suicide, use of medications labeled for depression/suicide); however, we identified cases of positive dechallenge and positive rechallenge that support a possible association. Whether these cases were marked by fluctuations in depression/suicidality or drug effects associated with finasteride is not certain.

Sources

Cogan B. Memorandum Decision and Order. Kelly S. Pfaff, et al., v. Merck & Co., Inc. Case 15-cv-3355; Document 97. Filed September 9, 2022.

FDA

U.S. Food and Drug Administration; Center for Drug Evaluation and Research. Approval package re: addition of depression to the post-marketing experience section of the label (NDA 20-788/S-017). March 11, 2011.

U.S. Food and Drug Administration; Center for Drug Evaluation and Research. Final Response Letter from FDA CDER to Post-Finasteride Syndrome Foundation. Page 43. Published June 8, 2022.

U.S. Food and Drug Administration. Highlights of Prescribing Information: PROPECIA (finasteride) tablets for oral use. Updated July 2022.

European Medicines Agency

European Medicines Agency; Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of the meeting on 3-6 April 2017. April 3–6, 2017.

European Medicines Agency; Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of the meeting on 09-12 April 2018. April 9–12, 2018.

European Medicines Agency; Pharmacovigilance Risk Assessment Committee (PRAC). Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s). April 2017.

European Medicines Agency; Pharmacovigilance Risk Assessment Committee (PRAC). Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s). April 2018.