Friday, December 9, 2016

Is The FDA Contraindication On Bupropion Wrong?






Since moving to a strictly outpatient consulting practice, I have been amazed at the number of women who are taking bupropion despite the above contraindication.  I have probable seen 50 women who were under my care in this situation.  In other words, I did not prescribe the bupropion and before seeing this would not have considered prescribing against an FDA contraindication.  The patients I see often have additional contraindications including a history of seizures, sedative hypnotic drug withdrawal, or alcohol withdrawal.  Seizures are the final common pathway for this subset of contraindications.  I have never really observed a seizure from bupropion and the vast majority of the patients with the contraindications have never had a seizure.  I have certainly observed and treated seizures in inpatient settings and understand that there is a low but significant risk of mortality with seizures.  I have also not observed a significant complication of seizures, but at the time I worked in an inpatient hospital environment with rapid access to nursing staff, medications, and experts.  None of the patients that I have initiated treatment on with bupropion have reported seizures, but I was strictly following the contraindication as listed in the FDA package insert.

My dilemma in this situation is always whether or not to continue the bupropion, especially when the patient tells me that it is the only medication that has been effective for them.  Patients who are seen in their late thirties or later generally have been tried on numerous antidepressants from several classes and that complicates the clinical picture.  Most of them have never seen a  psychiatrist and all of the medication trials have been done by primary care physicians.  It is common to see SSRI and bupropion combinations initiated by nonpsychiatrists.   In my current capacity, I am not treating any of these patients long term.  I see them anywhere from 1 to 3 months and at that time they return to see their personal physician or psychiatrist.  I try to contact their personal psychiatrist about the issue but communication among physicians is often difficult to complete.

As I began to see more and more of these patients my first question was a scientific one.  I was aware of the the trials that lead to the decision about eating disorders.  There were all based on immediate release preparations rather than the sustained release (SR) or extended release (XL) versions.  It certainly is possible that I am only seeing the success stories and that the patients with seizure related complications never come to my attention, but the practice of prescribing bupropion to a population that the FDA considers high risk seemed to be on the rise rather than decreasing.  Is it possible that all of the other prescribers had also not heard of this complication.  I knew that most of the patients were never apprised of the contraindication.  I know that because I had them read the contraindication section of the package insert for themselves.  Most would say that nobody have ever told them about this especially the part about any prior diagnosis of anorexia nervosa or bulimia.  It is difficult to tell a 45 year old woman who had bulimia nervosa in college and recovered that the bupropion that she has been taking for the last 10 years without any side effects needs to be stopped because of this contraindication.  The psychiatrists I talked with all minimized the wording in the warning.  They ignored the part about "prior diagnosis".  In fact some initiated treatment as the patient was completing treatment in a specialized eating disorders program.

I turned to the FDA web site for additional guidance on the agencies definition of contraindication.  Was it as relative as these psychiatrists were telling me?  It turns out the definitions used by the FDA in package inserts are defined in the Code of Federal Regulations (CFR).  The section defining contraindications follows (p. 6 of 18):

(5) 4 Contraindications. This section must describe any situations in which the drug should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs any possible therapeutic benefit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant therapy, disease state, or other condition, have a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk acceptable. Known hazards and not theoretical possibilities must be listed (e.g., if severe hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication). If no contraindications are known, this section must state "None."

People seem to think that there is room for interpreting this definition of contraindication and it does beyond the APA Ethics Committee.  I got the same opinion from an attorney.  I also consulted a national expert on eating disorders.  That expert opined that the contraindication was relative in both  a history of eating disorders and acute eating disorders.  The expert also had inside knowledge of why the FDA might have issued the contraindication in the context of scant evidence.

I have previously posted that the FDA seems to exhibit some biases when it comes to psychiatric disorders.  In some cases they seem to not consider the severity of the the disorder in considering contraindications.  There should be no question that eating disorders and depression are very serious conditions, serious enough that therapeutic options may include some risk.

In the meantime, I have decided to take some action.  The FDA web site is a wall with no way in for people like me with a legitimate problem.  I sent letters out to the US Senators from my state to try to find a way in.  My goal is to get this contraindication taken out so it reflects current clinical practice and the experience of depressed patients with both a past history of an eating disorder or an eating disorder.

If you are a person with that history or a psychiatrist who prescribes bupropion in the face of this contraindication, please join me in advocating for this change.    


George Dawson, MD, DFAPA


References:

1: Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry. 1998 Jul;59(7):366-73. PubMed PMID: 9714265.

2: Horne RL, Ferguson JM, Pope HG Jr, Hudson JI, Lineberry CG, Ascher J, Cato A. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988 Jul;49(7):262-6. PubMed PMID: 3134343.




7 comments:

  1. Remember, the FDA regulates the marketing of treatments not the practice of medicine. I think that gives you wiggle room. I also think its irresponsible to take anyone off a treatment that's working. I remember how pissed I was when they went after Serzone, and Merital, if you're old enough to remember that one. And more recently, 23andme.com.

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    Replies
    1. I appreciate your perspective on that. I remember Serzone and Merital very well. I am still unclear about what happened with Merital - it disappeared in a hurry. I remember a huge study on Serzone +/- CBT that was published in the NEJM. My perspective has been that there are definitely higher risk medications out there with fewer restrictions that are used by other specialists. I can also cite ECT and the FDA's apparent continued effort to reclassify the devices and essentially remove the modality as a possibility. I conclude that is a definite step in regulating medical practice when there is nobody left to refer patients to for ECT.

      I think there rest of your post "23andme.com" was cut off and I am interested in the rest of that sentence.

      Delete
    2. Merital was yellow carded in 1986 for blood dyscrasias. The manufacturer stopped making it knowing FDA was going to come down. It was the original NDRI before Wellbutrin.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1340782/?page=1

      I was in residency and had several patients on it. They did not do as well on the substitutes.

      Certainly you are correct that the FDA is controlling practice by "chilling effect" though I don't think technically it's a blanket prohibition.

      The FDA shut down 23andme.com for medical information because it was afraid that women would use their BRCA status to just go out and get a mastectomy, as if any insurance company would approve of that. The statement from the FDA is just ludicrous:

      http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm376296.htm

      Since then the FDA has backed off a bit, allowing the kit to be used for some diseases.

      Getting a patient on a drug that works really well for them is often a challenge and I'm not fond of interference when things are going well.

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    3. Thanks for the clarification on both.

      I was also in residency when the Merital issue hit. I never prescribed it but remember it was heavily promoted.

      Agree on the 23andme issue. I am on it and it does allow you to search your genome for any potentially problematic gene. They do post 41 carrier states. The main difference being that there is no medical intervention. I would be interested in getting info on all of the potential correlations. They did large study that looked at depression in their customer base:

      https://www.ncbi.nlm.nih.gov/sites/myncbi/1-MAvBcofi/collections/51593799/public/

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    4. Certainly there is no problem with off-label if the evidence in the literature backs it up. Elsewhere we have talked about Prazosin for PTSD. I agree that it is a bit more intimidating when they say "contraindication". That's obviously more loaded than saying nothing at all. I've gone to many lectures featuring good psychopharmacologists who are willing to go over maximal permitted dosages in heroic cases.

      Fortunately I got on 23andme before the warning, and I got the complete package.

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  2. The joke here is that ALL antidepressants can lower the "seizure threshold" in people who are prone to seizures. I too have never seen a patient on Welbutrin with a history of an eating disorder have a seizure on it. Of course, even if a patient has full-on epilepsy, if they are stable on an anti-convulsant, they can take any psychiatric medication. Problem solved! Why Welbutrin was singled out is something I've always wondered about.

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  3. Update on the bupropion initiative. So far no response from either Senator Franken or Senator Klobuchar. I received this response from the FDA today. I guess that you can figure out how to send them an e-mail. They reserve the right to send this response indicating that you might not hear from them again. To me that means their "science" of writing this contraindication based on a very small clinical trial trumps my experience in seeing many fold more patients who safely took the drug. The other interesting point in their letter is that I have contacted the state Medical Board and they have also not responded.

    CDER DRUG INFO
    11:26 AM (1 hour ago)

    to me
    Dear Dr. Dawson,

    Thank you for writing the Division of Drug Information in the FDA's Center for Drug Evaluation and Research.

    Thank you for sharing your concerns and experiences with patients with the agency. Drug labeling is a summary of the essential scientific and medical information that is known about the drug and reflects the results obtained from clinical trials of the drug.

    We have forwarded your concern and comments to the division for consideration. You will not be contacted unless we require more information.

    Additionally, the FDA does not have regulatory authority over medical practice or healthcare providers, therefore, questions or concerns about medical practice should be directed to State Boards of Medicine.

    Best Regards,

    MM
    Drug Information Specialist
    Division of Drug Information | Center for Drug Evaluation and Research
    Food and Drug Administration

    For up-to-date drug information, follow the FDA's Division of Drug Information on Twitter @FDA_Drug_Info

    This communication is consistent with 21 CFR 10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.

    ReplyDelete