Sunday, May 4, 2014

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:

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.


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


  1. Occasional commenterMay 6, 2014 at 8:58 AM

    I wish there was a way to look at the contraindications while still in the doctor's office. My spouse was prescribed diabetes medication that was contraindicated for those with macular edema (given how common eye problems are with diabetes, a person has to wonder). I was given a pain medication prescription for a serious knee injury (didn't ask for any, ibuprofen was fine, but it was pushed on me) and I asked if it was safe for someone with bipolar and the PA said yes. Looked it up, it's an SNRI sort of (Ultram), called my psychiatrist who said don't take it. I guess I need to get an expensive iPhone. For now, I will google BEFORE I fill the prescriptions or ask at the pharmacy.

  2. For some sociocultural reason that I wish someone would define, I think physicians confuse the term "rare" with "never could happen."

    Many of the more than 1,000 case histories I have collected here contain accounts of obvious adverse effects seen fairly quickly from a psychiatric drug.

    The patient reports them and the doctor is unaware of them, even though they are clearly described in Medline Plus (which I consider a very weak source of patient education), the package insert, the PDR,, etc.

    Even black box warnings are disregarded. I've personally brought these to doctors to have them shrugged away.

    This happens with psychiatrists as well as non-psychiatrists. I recently spoke to a psychiatrist who is an administrator at UCSF Psychiatry and discussed this very issue. She dismissed the importance of black-box warnings and package insert info as CYA from the FDA and drug companies. She said "but the PDR lists everything."

    She also asserted that the FDA was collecting adverse event reports and that took care of post-marketing safety -- unaware that 1) the FDA doesn't do anything with that information and 2) doctors don't take it seriously.

    So, yeah, it's patients who need to practice defensive medicine -- by researching, very critically, any recommended drug or medical treatment. Of course, some will be unable to do this and continue to be poisoned.

    1. Black box warnings and contraindications can absolutely not be ignored. As a person who clearly practices at the other end of the spectrum, I can add that it is common for people to think that they should "get used to" side effects even when I explicitly and repeatedly tell them that my goal is to prescribe a medication so that there will be absolutely no side effects.

      The FDA does use post marketing surveillance to issue safety warning to physicians. The most recent example was the letter on prolonged QTc interval from citalopram.

      From my previous post:

      "A potentially useful regulatory measure is the number of medications that have been identified as problematic in post marketing surveillance and removed from the market for safety reasons. The best review I could find on that topic is reference 2. The paper looks at market withdrawals of new molecular entities (NMEs) approved by the FDA between the years 1980 and 2009. Of a total of 740 NMEs during that period, 118 (15.9%) were discontinued. Twenty six drugs out of 118 were withdrawn due to safety reasons or a total of 3.5% of the original approvals. Nervous system drugs represented a total 104/740 approved drugs and a total of 6.7% of the discontinuations as a percentage of the approvals. Safety withdrawals were a total of 3 drugs or 2.9% of the total approvals in this therapeutic class. The bottom line is that a total of 1 drug used for psychiatric indications out of 740 NMEs in the last 3 decades was a medication was withdrawn for safety reasons"

      Your perspective is clearly affected by your experience. The vast majority of people who have no inclination to do intensive research on medications are not poisoned. You also don't take into account the basic fact that nobody wants to take medications in the first place and that a lot of choices are affected by that fact.

  3. More about buproprion from Neil Sandson, MD author of Drug Interactions Casebook: The Cytochrome P450 System and Beyond. Washington, DC: American Psychiatric Publishing, Inc., 2003 (this is an interview from The Carlat Report):

    Dr. Sandson: The 2D6 inhibitors that we need to watch out for are Prozac, Paxil, high dose Zoloft, and Wellbutrin.

    TCR: Wellbutrin? That’s interesting, because people [psychiatrists] tend to think that Wellbutrin is completely clean.

    Dr. Sandson: Exactly, and it came off the “good” list in the year 2000, which is one of the few times we have a drug company to thank for being honest and forthright-the good folks at Glaxo cued us into that aspect of this drug. The most pertinent 2D6 substrates are beta-blockers, tricyclics, and a couple of analgesics, like hydrocodone (Vicodin and others) and Ultram (tramadol).

    TCR: So that’s the cast of characters. What’s the plot?

    Dr. Sandson: The plot is that when you add an inhibitor to a substrate, you will increase the blood level of the substrate significantly. There are numerous examples of clinicians adding Prozac to beta-blockers, causing people to become hypotensive, or someone being put on Paxil when they’re on tramadol and not achieving adequate analgesia, because tramadol has to be converted to M1 for adequate pain control.

    TCR: What should we do when we add an SSRI to a beta-blocker?

    Dr. Sandson: You either very carefully monitor pulse and blood pressure, or you instruct them to have their primary care doctor monitor this. You can also advise people that if they feel acutely dizzy to call you or their internist. Another option is for you to communicate with the internist before starting the SSRI and see if it makes sense to prospectively decrease the beta-blocker dose. Of course, one may also select a non-2D6 inhibiting SSRI, such as Celexa (citalopram) or Lexapro (escitalopram).

    and so forth, about many drug-drug interactions that psychiatrists at least "should really know cold, in terms of what you should commit to memory" but do not.

  4. Actually the CYP2D6 inhibitors that need to be watched are paroxetine, fluoxetine, bupropion, duloxetine, and sertraline. There is a good text written about these interactions:

    See my 2007 review at the bottom.

    Flockhart's web site is very good at looking at clinical relevance, but it takes a detailed consideration of the CYP variants and clinical monitoring to assure safe use of any medication.