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.
Bupropion is an aminoketone antidepressant with a mechanism that is not fully understood. Bupropion seems not to affect monoamine uptake but is known to inhibit the reuptake of norepinephrine and dopamine weakly. The effects on norepinephrine and dopamine appear to lead to its clinical manifestations. Dopamine reuptake inhibition is reportedly very high, while norepinephrine uptake is less potent. Bupropion also acts to a lesser degree on nicotinic and serotonin receptors.
The onset of the 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 to 50% of the parent compound. Finally, a glycinated conjugate forms, and this undergoes renal elimination. Ten percent of the drug's elimination is 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.
Bupropion is administered orally as a hydrochloride salt. Tablets come in regular or extended-release forms. Extended-release forms include 12-hour formulations and 24-hour formulations (hydrobromide and hydrochloride forms). There is no other route besides oral for bupropion administration.
Patients may take the medication 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 for the once-daily dosage form.
As of November 2017, the generic form of the drug costs just over $100 for a monthly supply. Brand names can exceed $1000 per month. The highest dose of the 24-hour formulation exceeds $4000 for a month supply.
The most serious adverse effects are lowered seizure threshold and potential worsening of suicidal ideation.
Clinicians and researchers first noted the epileptic seizure occurrence 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 of causing seizures.
Of note, bupropion is one of the very few antidepressants that does not cause sexual dysfunction.
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 significant 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 clinician should stop therapy with the drug.
In December 2016, researchers released a safety review. Data from a large clinical trial has convinced the FDA that the serious mood and behavior effects of bupropion are lower than previously 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 levels of caution.
Bupropion does not require monitoring 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, clinicians should attempt lower initial doses in all patients.
Bupropion, due to its metabolism by CYP enzymes, interacts with a diverse array of medications. Before 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 requires caution in breastfeeding individuals. The drug and its metabolites are secreted into breast milk.
There is extensive published data related to bupropion overdose. The more serious exposures typically occur in an intentional overdose setting. With supportive care, unintentional overdoses usually lead to no significant effects. Unintentional exposures in children appear quite rare; there is a proposed 10 mg/kg threshold of safety 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 seizures, there are cases of delayed seizures described with no prior 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 reports do exist.
Bupropion is a frequently prescribed medication by the primary care provider, nurse practitioner, psychiatrist, and an internist. However, all healthcare workers who prescribe this agent need to be familiar with its adverse effect profile, which occurs in at least 10% of patients. The most serious adverse effects are lowered seizure threshold and potential worsening of suicidal ideation. At each visit, the patient's mental health status should undergo assessment, and the patient should receive education on what to do if and when a seizure develops. Pharmacists and nurses should also participate in these monitoring activities, informing the rest of the team if there is any cause for concern. This type of interprofessional collaboration can lead to more successful outcomes with bupropion therapy. [Level V]
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