Bupropion

Article Author:
Martin Huecker
Article Editor:
Abdolreza Saadabadi
Updated:
7/22/2018 10:43:26 PM
PubMed Link:
Bupropion

Indications

Bupropion is an antidepressant medication that is now also used in smoking cessation. Bupropion has been FDA-approved since 1985. The medication is FDA-approved for adult depression, seasonal affective disorder, and smoking cessation. Off-label, non-FDA approved uses include anti-depressant-induced sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), depression associated with bipolar disorder, and obesity. In the pediatric population, bupropion is used off-label for ADHD. 

Bupropion was first patented by Burroughs Wellcome (now part of GlaxoSmithKline) in 1974. Before 2000, the drug was referred to as amfebutamone. The sustained release formula was introduced in 1996. The extended-release formulation was marketed in 2003. The smoking cessation indication began in 1997. In 2012, GlaxoSmithKline paid a $3 billion fine for promoting the unapproved use of bupropion in weight loss and sexual dysfunction.

Mechanism of Action

Bupropion is listed as an aminoketone antidepressant with a mechanism that is not fully understood. Bupropion seems not to affect monoamine uptake but is known to inhibit reuptake of norepinephrine and dopamine weakly. The effects on norepinephrine and dopamine are thought to cause the clinical manifestations. Dopamine reuptake inhibition has been reported to be very high, while norepinephrine uptake is less potent. Bupropion also acts to a lesser degree on nicotinic and serotonin receptors.

The onset of therapeutic effect of bupropion usually occurs in the second week of taking the medication. The time to peak serum concentration is 2 hours for immediate release, 3 hours for sustained release, and 5 hours for extended release. The duration of action is 1 to 2 days. The gastrointestinal (GI) tract absorbs bupropion rapidly, with a volume of distribution of roughly 20 L/kg to 47 L/kg. Eighty-four percent of the drug will be protein bound.

Bupropion is metabolized in the liver by CYP2B6 to hydroxybupropion. Non-CYP metabolism follows to form erythrohydrobupropion and threohydroburpopion. These metabolites are active, with potency in the range of 20-50% of the parent compound. Finally, a glycinated conjugate is formed, and this is eliminated renally. Ten percent of the drug is eliminated in the feces, and 87% in the urine.

The half-life of bupropion is 3 to 4 hours distribution, but the half-life extends to about 21 hours when dosed chronically. 

Administration

Bupropion is administered orally as a hydrochloride. Tablets come in regular or extended-release forms. Extended-release forms include 12-hour formulations and 24-hour formulations (hydrobromide and hydrochloride forms). No route other than oral is used to administer bupropion.

The medication may be taken with or without meals. All of the tablets should be swallowed whole, with no crushing or dividing. Doses range from 75 mg up to the 522 mg Aplenzin.  

As of November 2017, the generic form of the drug costs just over $100 for a month supply. Brand names can exceed $1000 per month. The highest dose of Aplenzin exceeds $4000 for a month supply.

Adverse Effects

Bupropion has several adverse effects on significance. Many side effects occur in more than 10% of those taking the medication. These include:

  • Cardiovascular (tachycardia)
  • Respiratory (rhinitis, pharyngitis)
  • Central nervous system (Insomnia, headache, agitation, dizziness)
  • Dermatologic (diaphoresis)
  • Endocrine (weight loss)
  • Gastrointestinal (constipation, dry mouth, nausea)
  • Musculoskeletal (tremor)
  • Ophthalmologic (blurred vision).

The most serious adverse effects are lowered seizure threshold and potential worsening of suicidal ideation. 

The epileptic seizure occurrence was first noted in the 1980s, and bupropion was removed from the market from 1986 through 1989. The immediate-release preparation, especially in higher doses, appears to have the highest likelihood to cause seizures.

Of note, bupropion is one of the very few antidepressants that does not cause sexual dysfunction.

Contraindications

Hypersensitivity or allergy to bupropion or its constituents would preclude the use of the drug.

Seizure disorder is a major contraindication to use, in addition to any other factor predisposing to seizures: discontinuation of alcohol or sedatives, arteriovenous malformations, severe head injury, severe stroke, brain tumor, or other major central nervous system disease. 

Patients taking monoamine oxidase inhibitors should not take bupropion, nor should those taking linezolid or methylene blue. Canadian regulations prohibit use in patients taking thioridazine. 

Bupropion has had a United States boxed-warning related to suicidal thoughts and behavior in children, adolescents, and young adults. All patients who have depressive symptoms and begin any new medication should be monitored closely for suicidal symptoms. If symptoms worsen or overt suicidality ensues, the medication should be stopped.

In December 2016, a Safety Review was released. Data from a large clinical trial has convinced the FDA that the serious mood and behavior effects of bupropion is lower than prior represented. The U.S. boxed warning for bupropion for smoking cessation will change. The report notes that these reactions remain concerning, especially in patients with severe mood disorders or schizophrenia. This FDA report was specifically related to the use of bupropion in smoking cessation.

The doses and preparations of bupropion for depression demand higher caution.

Monitoring

Bupropion is not monitored with serum testing. There are no firmly established therapeutic levels of the drug. As with any medication, patients should be monitored clinically for serious adverse effects of this medication. Of note, some patients tolerate bupropion better at lower serum levels; therefore, lower initial doses should be attempted in all patients.

Bupropion, due to its metabolism by CYP enzymes, interacts with a diverse array of medications. Prior to prescribing, the provider should determine if any existing medications interact with bupropion. Common interactions include many antidepressants, clopidogrel, and other drugs that lower the seizure threshold. Alcohol intake should also be limited.

Bupropion is pregnancy class C and should be used with caution in breastfeeding individuals. The drug and its metabolites are secreted into breast milk.

Toxicity

Extensive data has been published related to bupropion overdose. The more serious exposures typically occur in an intentional overdose setting. With supportive care, unintentional overdoses usually lead to no major effects. Unintentional exposures in children appear quite rare; a 10 mg/kg threshold of safety has been proposed to reduce the use of healthcare resources.

In intentional overdoses, seizures are quite common. They occur in up to one-third of overdose exposures, though usually more in the range of 10% to 15%. Seizures usually occur within the first 6 hours after exposure, but one should exercise caution in extended-release preparations. In overdoses of the extended-release form, experts recommend an observation period of 24 hours due to the potential for delayed seizure onset. Though agitation and tremor often precede seizure, delayed seizures have been described with no preceding symptoms. 

Other effects include hallucinations, mental status changes, agitation, arrhythmias. Cardiovascular effects are uncommon after an overdose.

As in any overdose situation, the treating clinician should rule out the presence of coingestants. 

Bupropion abuse is rare but has been reported.