Talk:Finasteride

Edit request on 2 January 2013

The line "This enzyme converts testosterone to dihydrotestosterone (DHT). " is wrong & is supposed to be "This enzyme PREVENTS conversion of..."

Hope you change it or allow me.

Zoeyetra (talk) 03:35, 2 January 2013 (UTC)

The enzyme 5α-reductase does the conversion. Finasteride inhibits the enzyme, thus preventing the conversion. I've reworded the lead for clarity. The wording is a bit awkward but it retains the highly relevant wikilinks. Adrian J. Hunter^{(talk•contribs)} 11:15, 2 January 2013 (UTC)

Edit request on 3 January 2013

Please add the following to the "History" section: Dr. Reddy’s Laboratories announced today that is has launched Finasteride Tablets (1 mg), a bioequivalent generic version of Propecia® (Finasteride) Tablets in the US market on January 02, 2013. Dr. Reddy’s ANDA for Finasteride 1 mg Tablets has been awarded a 180-day period of marketing exclusivity in the U.S. on 2 Jan, 2013.

Digitalpharmacist (talk) 14:36, 3 January 2013 (UTC)

Not done: mainly because the source provided is a wiki and a press release. Also the proposed text reads like a press release. Please provide reliable, third-party sources to support this claim and reword the proposed text to an encyclopedic tone and I might be willing to entertain this request. —KuyaBriBri^Talk 15:38, 3 January 2013 (UTC)

Jenny McCarthy

On the Howard Stern show Jenny McCarthy claimed that propecia has the side effcts of erectile disfunction. http://howardstern.com/ (go to wensday's show, March 13, 2013) I think its an interesting bit of information for the article, adding a cultural dimension. — Preceding unsigned comment added by 97.107.215.232 (talk) 08:01, 15 March 2013 (UTC)

It is already discussed in extenso. Jenny McCarthy is not a medical authority. JFW | T@lk 21:52, 17 March 2013 (UTC)

Edit request

Merck warned about persistent Finasteride side effects in the early 1990's on the Proscar label. This means they showed up in the clinical trials. The article as it currently is indicates that only Internet hysteria caused a wave of post-marketing case reports, mandating a label change. When in fact, side effects that persist after discontinuation was first on the label nearly two decades ago. The warning was only omitted on one Finasteride brand (Propecia). The Australian Financial Review mentioned this in a piece on finasteride. — Preceding unsigned comment added by Gilmour1201 (talk • contribs)

As I explained on your talk page, this cannot be discussed without a WP:MEDRS-compatible secondary source. JFW | T@lk 11:53, 20 February 2014 (UTC)

Both labels have been cited. The reader can verify the incongruity. — Preceding unsigned comment added by Gilmour1201 (talk • contribs) 08:28, 21 February 2014 (UTC)

JfdWolff, you can even read the label in your native tongue. See the Dutch label warning of persistent side effects here.

ETA: Copy and Paste if the linke won't work from Wikipedia.

http://www.dokteronline.com/pils/nl/patient_information_leaflet-760-proscar_5_mg,_filmomhulde_tabletten-nl.pdf-1326804181.pdf

"Als de verschijnselen bleven aanhouden, verdwenen ze meestal bij het stopzetten van de inname van PROSCAR."

Gilmour1201 The situation hasn't changed. You are engaging in investigative journalism rather than writing an encyclopedia. There is already a section that discusses very clearly the nature of sexual AEs and the fact that they might persist. You are now adding some weak sources (that definitely fail WP:MEDRS) to suggest that the package inserts didn't always discuss this side effect. The only benefit that I can see is an implied accusation of bad faith on behalf of the manufacturer. For such a claim you need very strong sources, quite the opposite of what you're doing. :::I really think you should have a look at dispute resolution rather than repeatedly adding the same stuff. Alternatively, you could try the reliable sources noticeboard to see whether the community has particular views on the quality of your sources. Good luck. JFW | T@lk 12:31, 21 February 2014 (UTC)

JDWolff , your latest post is so absurd I don't even know where to begin. You say, "there is already a section that discusses very clearly the nature of sexual AE's and the fact that they might persist." I already told you why an addendum is necessary. The article as is indicates that ONLY POST-MARKETING CASE REPORTS of persistent sexual AE's have been reported. But not only was persistent side effects warned about when Proscar hit the market, but persistent AE's were also picked up in the PLESS trials.

"You are now adding some weak sources (that definitely fail WP:MEDRS) to suggest that the package inserts didn't always discuss this side effect."

I don't even know what you mean here. When discussing the package insert, how can you call citing the package insert itself a "weak source?" Please answer

"To suggest that package inserts didn't always discuss this side effect?" lol, WHAT? I said one of them discussed "this" side effect (side effects that persist after discontination) and the other omitted it

Proscar label: If side effects persist, they USUALLY resolve upon discontinuing 'Proscar'

Propecia label: These side effects went away in men who stopped taking PROPECIA

Clearly, one label indicates side effects can persist after discontinuing the drug, the other label indicates it cannot. This is information Wikipedia readers need to know about. Doctors look at these labels for information on how to treat patients.

ETA: These aren't the updated labels based on case reports. These were the original labels in the 1990's, as you would be easily able to verify in the sources I gave.

Adverse Events

I don't think it makes much sense to include information in the article about theoretical concerns about long term effects that were raised 17 years ago (BEFORE any long term safety data existed) and then exclude actual data about long term safety from two large, multi-year trials that were designed precisely to address long term safety questions. Whatever your feelings about adding data "from a single trial" (actually it was 2 and they were big stuides), data always outweighs theoretical concerns that were voiced before data was available.

I'd suggest deleting the theoretical concerns (as I did in the first place) and keeping the discussion focused on actual safety data. The actual data consists mainly of

• The results of the 5 year safety trials conducted post-approval. These are rigorous but not powered to detect rare side effects
• The case reports that formed the basis of regulatory warnings of long term sexual effects. These are less rigorous, but strongly suggestive of long term effects in a small minority of patients.

The latter of these is already incorporated in the article. The former should be too though its not a deal breaking issue from my point of view. What makes no sense is to raise the theoretical concerns from 1997 and then deliberately leave out the data from the trials that were designed to address those concerns.

I'm also modifying the language describing the AdCom meeting for now. In contrast to the current language stating that the panel "refused to approve" Propecia, both the official transcript of the meeting and a Chicago Sun article indicate that no vote was taken. Formerly 98 (talk) 14:38, 22 February 2014 (UTC)

Formerly 98 Why leave out the data from safety trials that show side effects can be persistent? As I stated before, this article as is indicates that the only evidence of persistent side effects is post-marketing case reports, when that isn't the case. Doctors can read this article and come to the conclusion that Finasteride cannot cause persisent side effects based on the omitted evidence. They may be unaware that Merck warned about a causal relationship between Proscar and persistent side effects when Proscar first hit the market*. The (pre-Wikipedia) paradigm only shifted when Propecia hit the market and the warning was "these side effects went away in men who stopped taking PROPECIA." Wikipedia shouldn't help to propagate this myth, when the data are right here. I agree with you 100%, let's not deliberately leave out any datum.

• Copy and paste for original label: mcs.open.ac.uk/nlg/old_projects/pills/corpus/pil/doc/proscar.doc

I don't fully agree with you since I feel there is a contradiction in your response. You mention the 5 year safety trials were deliberately designed to address those concerns but also mention that while these are rigorous they are not designed to detect rare side effects. On the contrary, this was an industry funded study and would have only been publicly released if it revealed data that was favorably to the manufacturer. This publishing phenomena has been well documented but really is part of another discussion.

I do agree that we should restructure the section on adverse side effects. As a compromise, I suggest we move mention of the advisory panel's discussion to the history section which talks about the drug discovery and approval process in more depth. The transcript of the advisory meeting does not include the outcome of the vote or the committee's recommendation but that is not the equivalent of saying it indicates no vote was taken. I do think it is worth including in the history section since as you probably know the FDA most often accepts the AdCom's suggestion especially when they do not suggest approval. I'll moderate the language about the committee's recommendation. So far, the news article I have provided is the only source to directly reference the committee's recommendation (or lack thereof). It would be appreciated if you would provide the Chicago Sun article for purposes of comparison since I was unable to locate this on my own. Thanks and I'm happy to discuss further if you feel these edits merit additional change. Doors22 (talk) 19:53, 22 February 2014 (UTC)

Hi Doors:

Thanks for your thoughtful response. I am aware that some of these issues have been discussed at great length, and I am not really the person to talk to about reversing decisions made previously. Frankly, I'm not that influential.

The language difference you note is intriguing, but I don't think it rises to the level of evidence required by WP:MEDRS. I do not know the detailed history of the package inserts, but I wonder if any of the following are relevant to your observation.

• Propecia is a 1 mg tablet and Proscar is 5 mg.
• The clinical trials were performed in different populations.

I looked into this by digging into the FDA approval summary for Propecia http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/20788_PROPECIA%20TABLETS,%201MG_MEDR_P3.PDF My reasoning is as follows:

• The publications may not be reliable sources of AE information, but the FDA approval summaries probably are
  • The FDA requires submission of raw data from individual patients. One cannot simply omit data, it would be necessary to actively submit fraudulent data
  • This would put the individual responsible at high risk of jail time
  • There is reasonable evidence that these submissions are accurate. Most of the expose papers that revealed selective publication by pharma companies came from comparing published results to data obtained in Freedom of Information requests to FDA
• The Approval Summary for Propecia explicitly states: "Eleven patients (1.2%) on finasteride and 8 patients (0.9%) on placebo discontinued due to a drug related sexual adverse event. All of them had resolution of their sexual adverse events"

You are correct in that there is an intrinsic contradiction between doing a long term safety study and then stating that it was not powered to see an effect. But some side effects are just too rare to readily pick up in trials. The approval summary notes that only 1.2% patients discontinued due to sexual side effects. Assuming that 10% of those stopping due to sexual side effects find that they continue after stopping, that's only 0.1%. You'd need to do a trial in 10,000 patients (5,000 treatment, 5,000 placebo) to reliably see even one or two examples pre-approval. Based on the 700 spontaneous reports described by the FDA in their announcement, the usual assumption that only one in 10 to 20 unexpected adverse events is reported, and peak Finasteride sales of $1.2 billion, I think a rate of about 1 in a few thousand is probably a reasonable estimate of the actual rate. So there is no contradiction between saying that this was not seen in clinical trials but that it is probably a real effect of the drug.

As for a compromise:

• I've read a lot of these transcripts, and I disagree with your comment that a vote would not be shown. The transcript begins with the committee members introducing themselves and ends with adjournment of the meeting. The Chicago Tribune article specifically states that "The committee did not vote on Propeicia's safety or effectiveness".

• Generally I'd like to stick with the data and not with concerns voiced before data was available. Lets just state what the data shows.

• We know that the incidence of permanent sexual dysfunction is low (from the clinical trials), but it probably does occur (from the spontaneous reports and the FDA warning).

• Can we just state the above in the Sexual Side Effects section?

Also, I really don't want to go on record as recommending a rehash of anything that has been extensively discussed already. Please take any prior discussions of this issue into account.

Best Regards Formerly 98 (talk) 21:10, 22 February 2014 (UTC)

OK, after reading the Chicago Sun article it does change my understanding of the meeting. There is already mention of the persistent sexual side effects listed elsewhere in the article. The new interpretation of the AdCom meeting doesn't really make sense to include at the top of the side effects section so I think it makes sense to remove that whole paragraph entirely. Please let me know if you disagree.Doors22 (talk) 21:54, 22 February 2014 (UTC)

No objection here. Thanks for a good exchange of ideas. Formerly 98 (talk) 22:20, 22 February 2014 (UTC)

Formerly 98 You seem to be cherry-picking data. For the Propecia trials, you cite the following:

"Eleven patients (1.2%) on finasteride and 8 patients (0.9%) on placebo discontinued due to a drug related sexual adverse event. All of them had resolution of their sexual adverse events"

You call the 3040 Randomized Control Trial as rigorous, but fail to cite the results of persistent sexual Adverse Events

"Only 4% of finasteride and 2% of placebo patients discontinued the study because of sexual AEs. In men who discontinued with a sexual AE, 50% and 41% experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy, respectively."

Please note that the PLESS study was a double-blind, while the Propecia trial was not. The PLESS is more robust and more up-to-date than the Clinton era Propecia trial data. As you stated, let's stick with the data, giving favor to the most robust. The PLESS results of persistent sexual side effects deserves a place in the Sexual Side Effects section. They also corroborate post-marketing data. Once again, as the page currently is, the reader is led to believe that only the only evidence of persistent sexual side effects is case reports, and that isn't the case.

Also, it was me, not Doors, who was concerned about the incongruity of the two warning labels for the same drug. I'd like to discuss your points, but I think we should come to an agreement on the PLESS data first.

And your assumptions for your long-term Propecia side effects estimation are wrong, but more on that later.

Hi whoever wrote that. (You didn't sign your comment).

I found the reference for the PLESS Proscar results:"Only 4% of finasteride and 2% of placebo patients discontinued the study because of sexual AEs. In men who discontinued with a sexual AE, 50% and 41% experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy, respectively." I'm not deliberately cherry picking, but this study did not come up in a Pubmed search for phase 3 studies of finasteride. The difference is as you have reported it, and appears statistically significant. But the FDA reported in 2012 that "In controlled clinical trials, these side effects resolved in patients who stopped finasteride, as well as in most patients who continued therapy." I'd like to understand this a bit better, which will likely mean going to the library to see what was seen in the other trials.

I've provided the reference to my quote from the Propecia development program "Eleven patients (1.2%) on finasteride and 8 patients (0.9%) on placebo discontinued due to a drug related sexual adverse event. All of them had resolution of their sexual adverse events" above. Its on page 76 of the document I linked to above.

I disagree with your assessment that the PLESS trial is of higher quality than the Propecia trials. The FDA approval summary describes all of the Propecia trials as double blind, in contrast with your statement. The Propecia trials were performed in 1993-4, and the PLESS trial initiated around 1995-6 or so. The designs of the trials, which were set before the trials started and not when they ended, would presumably be of similar sophistication. Any difference in the results of the two trials is best attributed to the fact that they looked at drmatically different doses of finasteride.

What specifically about my assumptions do you think is are incorrect? The standard pharmacoepidemiology assumption is that 5-10% of unexpected adverse events of new drugs are reported. That would mean the 700 cases reported to the FDA corresponds to about 15,000 cases over 12 years, or a little over 1000 per year. Given that this was a billion dollar drug that sold for about $1000 for a year's therapy, one can calculate an incidence of about one per thousand patient years. This is a pretty good fit to the numbers I derived from the discontinuation rates in the FDA doc.

Thanks Formerly 98 (talk) 03:42, 23 February 2014 (UTC)

Hi Formerly 98. Can you please tell me the where exactly it states the Propecia trials were double-blind? Thanks.

I beg to differ that the different results were from "Dramatically different doses of Finasteride." Finasteride has a flat-dose response rate. 1mg of Finasteride inhibits nearly the same amount of DHT as 5mg. There was a study linked on this on the University of Pennsylvania website, but it was taken down late 2012. Suspicious. The dead link is here: http://www.physics.upenn.edu/facultyinfo/frankel/papers/propeciafda2/index.html

It's not that you're wrong regarding your estimation of what % of men experience persistent side effects, it's just that you weren't given the proper tools. The only information you are given on those who didn't experience persistent side effects are the patients who discontinued therapy. For those who finished the trial, there is a cutoff date when you are allowed to report an Adverse Event. So we have no measurement of the 900 other men who finished the trial. Going by case reports, the side effects start after quitting the drug. When disclosing to shareholders why they're being sued, Merck explained that patients experienced a range of sexual side effects upon cessation of Propecia.

As for going by case reports, we have no idea how many reports the FDA has received. They said they reviewed close to 700 reports, but it doesn't say how many they've received. Admittedly, the FDA doesn't review every report. Many of them are thrown out for a variety of reasons. So it's unreasonable to base an estimate on the case reports.

In the abstract of the paper I cited, it doesn't say how many men were in the Finasteride group. But if there were 1,500, 4% or 60 of them quit Finasteride due to a sexual AE. 50%, or 30, did not experience resolution of their sexual AE's. So that's 30 out of 1,500. And that's only measuring those who quit the trial. My estimation has it at 2%, yours at .01%. Either way, it's a moving target.

Also, I don't think the persistent sexual side effects in the PLESS trials was statistically significant. But I don't know if an ANOVA was done or they left it as is.

As for the FDA stating "In controlled clinical trials, these side effects resolved in patients who stopped finasteride, as well as in most patients who continued therapy," that's nothing but meaningless PR chatter. They don't like to admit that their studies fail to predict what is seen in the real-world. The evidence cited in this thread shows they're wrong. Like I've shown many times, the original Finasteride consumer label warned of persistent side effects. So the FDA was communicating nothing, just doing some face-saving PR vernacular. It's silly to think the FDA would admit the trials didn't properly screen for the withdrawal effect, admit patients weren't properly followed-up on after the trial was over, or cite a study that showed the label they approved was wrong the entire time. There's even more in the medical literature that say Finasteride side effects don't always resolve, but I'd like to finish with the PLESS and original Proscar label discussion before moving on.

Which label more accurately describes what's being seen in the real world?

Proscar label: If side effects persist, they USUALLY resolve upon discontinuing 'Proscar'

Propecia label: These side effects went away in men who stopped taking PROPECIA

Thanks for researching this important public health matter.

ETA: Formerly 98, if you're interested, there are people in forums. who claim they were involved in Finasteride clinical trials and experienced severe sexual problems after the trial concluded. Obviously, this would never make it to a Wikipedia page, but for academic reasons, if you're interested in hearing trial patients in their own words, here's one such patient:

"I signed up for the Prostate Cancer Prevention Trial at about the age of 50. Took Proscar 1mg daily for six years, followed by a prostate biopsy. When the test was unveiled, I was informed that I had been taking finasteride and not a placebo. Around the time the trial concluded, I began to notice ED problems, primarily loss of sensitivity. It became harder and harder to achieve an orgasm and ejaculate. After five years had elapsed, I was no longer able to achieve an intravaginal orgasm and had to masturbate. I was 60 years old by then. Since then, it has been a steadily downward slope. I no longer have morning erections and haven't been able to ejaculate for about a year."