Continuing Education Activity

Bupropion is an antidepressant medication that is now also used in smoking cessation. Bupropion has been FDA-approved since 1985. The drug 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. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of bupropion, pertinent for members of the interprofessional team for the treatment of patients with indications where bupropion has therapeutic value.

Objectives:

• Review the FDA-approved on-label indications of bupropion, as well as other off-label uses.
• Describe the mechanism of action of bupropion, including consequential interactions with other medications.
• Summarize the contraindications and risks associated with initiating bupropion.
• Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for the patient receiving treatment with bupropion.

Indications

Bupropion is an antidepressant medication that is now also used in smoking cessation. Bupropion was first patented by Burroughs Wellcome (now part of GlaxoSmithKline) in 1974. Before 2000, the drug was referred to as amfebutamone. Bupropion has been FDA-approved since 1985. The sustained release formula was introduced in 1996.[1], and the extended-release formulation was introduced in 2003.[2] In 1997, bupropion was introduced for the smoking cessation indication.[3] In 2012, GlaxoSmithKline paid a $3 billion fine for promoting the unapproved use of bupropion in weight loss and sexual dysfunction.

• The medication is FDA-approved for adult depression, seasonal affective disorder, and smoking cessation.[4][5][6]
• Off-label, non-FDA-approved uses include anti-depressant-induced sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), depression associated with bipolar disorder, and obesity.[7][8]
• In the pediatric population, bupropion is used off-label for ADHD.[9]

Mechanism of Action

Bupropion is an aminoketone antidepressant with a mechanism that is not fully understood.[10] 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. 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.[11]

Bupropion is metabolized in the liver by CYP2B6 to hydroxybupropion. Non-CYP metabolism follows to form erythrohydrobupropion and threohydrobupropion. These metabolites are active, with potency in 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.[12] 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 salt. Bupropion Tablets are available as regular or extended-release forms. There is no other route besides oral for bupropion administration.

• Immediate-release tablets are available in 75 mg and 100 mg strength.
• Extended-release forms of 12-hour hydrochloride salts formulations are available in 100 mg, 150 mg, and 200 mg tablets.
• Extended-release forms of 24-hour hydrobromide salts formulations are available in 174 mg, 348 mg, and 522 mg tablets.
• Extended-release forms of 24-hour hydrochloride salts formulations are available in 150 mg, 350 mg, and 450 mg tablets.  

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 522 mg for the once-daily dosage form. 150 mg of hydrochloride salt is equivalent to 174 mg of hydrobromide salt in tablet formulations.

For smoking cessation and depression, bupropion is usually started at the lowest dose of 150 mg daily and titrated carefully upwards to the maintenance dose of 300 mg per day. The maximum dose is 450 mg daily, given in divided doses.[13]

As of November 2017, the generic form of the drug costs just over $100 for a monthly supply. However, brand names can exceed $1000 per month. In addition, the highest dose of the 24-hour formulation exceeds $4000 for a month supply.

Adverse Effects

There are several significant adverse effects been reported for bupropion. Many of these side effects occur in more than 10% of patients.[14][15][16][17] These include:

• Cardiovascular (tachycardia)[18]
• Respiratory (rhinitis, pharyngitis)[19]
• Central nervous system (insomnia, headache, agitation, dizziness)[20]
• Dermatologic (diaphoresis)[21]
• Endocrine (weight loss)[22]
• Gastrointestinal (constipation, dry mouth, nausea)[23]
• Musculoskeletal (tremor)[24]
• Ophthalmologic (blurred vision)[24]

The most severe adverse effects are lowered seizure threshold and the potential of worsening suicidal ideation.[25]

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.[26] Of note, bupropion is one of the very few antidepressants that does not cause sexual dysfunction.[27]

Contraindications

• Patients who are hypersensitive or allergic to bupropion or its constituents should not use the medication.
• Seizure disorder is a major contraindication for bupropion therapy. In addition, bupropion is also contraindicated for any other factors predisposing to seizures, i.e., discontinuation of alcohol or sedatives, arteriovenous malformations, severe head injury, severe stroke, brain tumor, or other significant central nervous system disease.[28]
• Patients taking monoamine oxidase inhibitors should not take bupropion, nor should those taking linezolid or methylene blue. In addition, Canadian regulations prohibit use in patients taking thioridazine.[29][30]
• 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 signs. If symptoms worsen or overt suicidality ensues, the clinician should stop therapy with the drug.[31]
• 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. As a result, the U.S. boxed warning for bupropion for smoking cessation changed. However, the report notes that these reactions remain concerning, especially in patients with severe mood disorders or schizophrenia. This FDA report was explicitly related to the use of bupropion in smoking cessation.
• The doses and preparations of bupropion for depression demand higher levels of caution.[32]

Monitoring

• Bupropion does not require monitoring with serum testing. There are no firmly established therapeutic concentrations 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 concentrations; 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. Patients need to limit alcohol intake while on bupropion.[11]
• Bupropion is pregnancy class C and requires caution in breastfeeding individuals. The drug and its metabolites are secreted into breast milk.[33][34]

Toxicity

• There is extensive published data related to bupropion overdose.[35] The more serious exposures typically occur in an intentional overdose setting. With supportive care, unintentional overdoses usually lead to no significant effects. Accidental exposures in children appear quite rare; there is a proposed 10 mg/kg threshold of safety to reduce the use of healthcare resources.[36]
• In intentional overdoses, seizures are pretty common. They occur in up to one-third of overdose exposures, though usually more in the range of 10% to 15%. Seizures typically 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.[37]
• Other effects include hallucinations, mental status changes, agitation, arrhythmias. Cardiovascular effects are uncommon after an overdose.[38][18]
• As in any overdose situation, the treating clinician should rule out the presence of coingestants. 
• Bupropion abuse is rare, but reports do exist.[39]

Enhancing Healthcare Team Outcomes

Bupropion is a frequently prescribed medication by the primary care provider,s nurse practitioners, psychiatrists, and internists. However, all healthcare workers who prescribe this agent need to be familiar with its adverse effect profile, occurring in at least 10% of patients. The most serious adverse effects are lowered seizure threshold and potential worsening of suicidal ideation. Clinicians should perform a mental health assessment of patients at each visit and educate them on what to do if and when a seizure develops.[40] Pharmacists and nurses should also participate in these monitoring activities, perform medication reconciliation before drug administration, and inform the rest of the team if any concerns. This type of interprofessional collaboration can lead to more successful outcomes with bupropion therapy. [Level V]