Bupropion


Article Author:
Martin Huecker
Abbey Smiley


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
William Gossman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
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Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
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Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/8/2019 5:58:37 PM

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.[1][2][3] 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. [4]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. [5][6][7][8]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. 

Enhancing Healthcare Team Outcomes

Bupropion is a frequently prescribed medication by the primay 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 occur 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 be assessed and the patient should be educated on what to do if and when a seizure develops.[9] (Level V)


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Bupropion - Questions

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A male with a 15-year history of smoking has tried everything to quit smoking. He is also feeling down and depressed. What medication would treat both conditions?



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A 30-year-old woman with a 10-pack-year smoking history presents to her primary care provider to establish care and ask for advice in smoking cessation. She takes a multivitamin daily and is otherwise healthy. However, she admits she has had chronic difficulty sleeping for years and occasionally takes an antihistamine to help her fall asleep. She works as an elementary school teacher but admits that although she would like to find a romantic partner, she hasn't gone on a date in years because she feels unattractive and worthless and assumes that other people also think the same things about her. She admits she often feels bad about her life and wishes she could feel better. Which of the following mechanisms of action describes the drug most appropriate for treatment of the patient’s symptoms?



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Which of the following medications has been demonstrated to significantly increase the abstinence rate among patients attempting to quit smoking?



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A 25-year-old female is being admitted to a residential treatment facility for substance abuse. On admission, medication reconciliation is performed and it is discovered she is taking bupropion for smoking cessation, sertraline for depression, and ibuprofen as needed for headaches. Which of the following is the most appropriate recommendation regarding the patient's medications at this time?



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Which of the following is treated with bupropion?



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A 41-year-old female presents with complaints of new-onset sexual dysfunction 3 weeks after starting fluoxetine. She has a past medical history significant for anxiety, hypothyroidism, alcoholism, and anorexia in her teenage years. In the office, she has a heart rate of 56, blood pressure of 109/70, respiratory rate of 12, and temperature of 97.1 degrees. Her physical exam is notable for callouses on the dorsum of her hands. Which of the following medications is absolutely contraindicated to treat this patient?



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A patient was prescribed fluoxetine for depression recently. However, he is experiencing sexual side effects and does not want to continue taking this drug. Which of the following can treat his depression and is known to have a lower incidence of sexual side effects?



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A 29-year-old male recently became insured and is presenting to establish care with a new primary care clinician. He has no medical conditions but does admit to smoking 1 pack of cigarettes per day. He states that he recently lost his grandmother to lung cancer, and would like to quit smoking. He would like to use a nicotine-free smoking cessation aid, and his clinician suggests prescribing bupropion for the patient and explains the risks and benefits of the medication. The patient expresses concern when he learns that this drug may cause seizures. When prescribing this drug, which of the following practices is unsafe and is most likely to precipitate seizures in this patient?



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A 50-year-old female being treated as an inpatient for operative incision and drainage of a complicated skin abscess. Cultures are positive for VRE, and she is immediately started on the appropriate IV antibiotics. On the second day of hospital admission, she develops agitation and altered mental status. Her heart rate is 118, blood pressure is 160/120, and temperature is 101.4. On exam, she is confused and diaphoretic, with notable rigidity and hyperreflexia especially in her lower extremities. Medication reconciliation is rapidly performed, and it is discovered that the patient takes lisinopril for hypertension, and bupropion for depression. Which of the following is the most likely cause of the patient’s current symptoms?



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A 48-year-old male with a 20 pack-year smoking history presents with 5 weeks of insomnia after losing his father to lung cancer. He worries that he will die of cancer and he will not be able to provide for his family and feels that he is the cause of much of the hardships the family is experiencing. Often, he feels “slowed down” and spends the majority of his day in bed. He has lost 3 lbs over the past month. He denies any suicidal ideation and would like to quit smoking. His heart rate is 72, blood pressure is 130/75, respiratory rate is 14, and the temperature is 98.2. Which of the following medications is most appropriate for this patient?



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Bupropion - References

References

Hsieh MT,Tseng PT,Wu YC,Tu YK,Wu HC,Hsu CW,Lei WT,Stubbs B,Carvalho AF,Liang CS,Yeh TC,Chen TY,Chu CS,Li JC,Yu CL,Chen YW,Li DJ, Effects of different pharmacologic smoking cessation treatments on body weight changes and success rates in patients with nicotine dependence: A network meta-analysis. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2019 Feb 27;     [PubMed]
Hankosky ER,Bush HM,Dwoskin LP,Harris DR,Henderson DW,Zhang GQ,Freeman PR,Talbert JC, Retrospective analysis of health claims to evaluate pharmacotherapies with potential for repurposing: Association of bupropion and stimulant use disorder remission. AMIA ... Annual Symposium proceedings. AMIA Symposium. 2018;     [PubMed]
Livingstone-Banks J,Norris E,Hartmann-Boyce J,West R,Jarvis M,Hajek P, Relapse prevention interventions for smoking cessation. The Cochrane database of systematic reviews. 2019 Feb 13;     [PubMed]
Paccosi S,Cresci B,Pala L,Rotella CM,Parenti A, Obesity therapy: how and why? Current medicinal chemistry. 2019 Jan 24;     [PubMed]
Cohen JB,Gadde KM, Weight Loss Medications in the Treatment of Obesity and Hypertension. Current hypertension reports. 2019 Feb 12;     [PubMed]
Pi-Sunyer X,Apovian CM,McElroy SL,Dunayevich E,Acevedo LM,Greenway FL, Psychiatric adverse events and effects on mood with prolonged-release naltrexone/bupropion combination therapy: a pooled analysis. International journal of obesity (2005). 2019 Jan 21;     [PubMed]
Correia MS,Whitehead E,Cantrell FL,Lasoff DR,Minns AB, A 10-year review of single medication double-dose ingestions in the nation's largest poison control system. Clinical toxicology (Philadelphia, Pa.). 2019 Jan;     [PubMed]
Dagan Y,Yager J, Severe bupropion XR abuse in a patient with long-standing bulimia nervosa and complex PTSD. The International journal of eating disorders. 2018 Oct;     [PubMed]
Yang YC,Yeh TC,Liang CS, A case of recurrent seizures: Drug-drug interaction between low-dose clozapine and extended-release bupropion. The Australian and New Zealand journal of psychiatry. 2019 Feb;     [PubMed]

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