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.

Dangerous Medication - Part 3 - A Risk-Averse Approach To Prescribing Bupropion

Bupropion is a widely prescribed antidepressant.  It is a safe and effective medication according to the FDA.  It can be safely prescribed with a high level of success.  It is probably more widely prescribed with the advent of guidelines suggesting that it is an augmenting agent for situations where antidepressant monotherapy is ineffective.  It may also end up being used with another antidepressant if a patient is interested in using it for smoking cessation and in an off label manner for attention deficit hyperactivity disorder and to treat sexual dysfunction associated with SSRI type antidepressants.  Bupropion does have a unique position in antidepressant pharmacotherapy.  With the increased focus on electrocardiogram abnormalities, it is probably the antidepressant that  is least likely to affect the QTc interval.

Bupropion is generally well tolerated, but there are some people who develop increased anxiety, agitation and insomnia.  This people generally need to stop taking the medication or reduce the dose.  A small number of people will develop mild to moderate hypertension and depending on the situation, the medication should be discontinued or the hypertension treated.  The largest problem I see with this medication is deciding when to stop and start it based on its contraindications.  The FDA package insert (from the FDA website using the brand name) on the matter is clear:

CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder. 
 WELLBUTRIN is contraindicated in patients treated with ZYBAN® 13 (bupropion hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion because the incidence of seizure is dose dependent. 
WELLBUTRIN is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). 
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients who have shown an allergic response to 
bupropion or the other ingredients that make up WELLBUTRIN Tablets

The package insert goes into some of the evidence for these contraindications, but the details seem fairly clear to me.  So why is it that the following happens?

1.  Patients who are not aware of the fact that bupropion can cause seizures.
2.  Patients who are prescribed this medication in spite of the contraindications.
3.  Patients with a past history or an active eating disorder taking this medication.
4.  Patients who are regularly drinking alcohol +/- sedative hypnotics taking this medication.
5.  Patients who have had generalized tonic clonic seizures taking this medication and the medicine is still prescribed.

I could go into much greater detail about some of the most extreme situations where this occurs, but I think it would be more instructive if I just cut to a few basic recommendations for the safe use of this medication:

1.  Do not prescribe it in the presence of contraindications.
2.  Do not prescribe it to anyone who has a known problem with alcohol or sedative abuse problems.  In fact, obtain a new history for those disorders at the time you are obtaining informed consent for the prescription and revisit the contraindications every time you increase the dose since the seizure risk increases with dose increases.
3.  Discontinue bupropion immediately if you are treating the patient for alcohol or sedative hypnotic withdrawal.  Have a serious conversation with that person about seizure risk an the FDA contraindications before restarting it.  People provided with that information quickly reassess the need for the medication and whether or not it has been helpful.
4. Discuss the warnings with the patient if they have medical comorbidity that is flagged in the package insert such as:

Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients.

and:

The risk of seizure is also related to patient factors, clinical situations, and concomitant 
medications, which must be considered in selection of patients for therapy with WELLBUTRIN. 
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold. 
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin. 
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold. 

5.  Seriously weigh the seizure risk of adding any medication that might lower the seizure threshold to any person who is stable on bupropion and keep that person involved of the possible seizure risk.  Do a detailed and individualized risk assessment for prescribing medications to any patients.
6.  Document the vital signs of any patient on bupropion and the trend.
7.  Do not prescribe bupropion again to anyone who has had a seizure while taking it.

I have seen bupropion prescribed in the context of all of the contraindications and warnings without seizures or other complications.  Risking a low frequency but serious complication is not the optimal way to prescribe it.  The other consideration is that the risk assessment needs to be done on an individualized basis.  A general number quoted as an average side effects from clinical trials obviously would not apply to a patient with multiple risk factors or a patient who reliably gets side effects every time he or she takes the drug.  Population based care sounds good when it is promoted by managed care companies or government agencies, but this is a good example of where that concept fails.  As I think about all of the high risk ways I have seen bupropion prescribed, I go back to the recent post on overprescriber biases and how that influences the process.  No physician trained in psychopharmacology would have these deficits on a purely cognitive level, but in the case of treatment resistant depression and a contraindication the situation may become higher risk.

That is an ideal time for consultation or referral rather than taking a chance.

If you are reading this from the patient perspective, I encourage reading the Medline Plus handout on any medication that you are taking. The FDA approved package insert is usually available on the Internet, even in the case of most generics.  I would exercise caution if you decide to study it.  In a previous post, I point out that a lot of people really don't want to know about detailed side effects in advance because they fear developing them by mere suggestion or they might avoid taking a useful medication entirely.  Some package inserts have specific "Information to the patient" that is usually designed to communicate important information.

George Dawson, MD, DFAPA