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Bupropion: Drug information

Bupropion: Drug information
(For additional information see "Bupropion: Patient drug information" and see "Bupropion: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidality and antidepressant drugs:

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24; there was a reduction in risk with antidepressant use in subjects aged 65 and older.

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. Bupropion is not approved for use in pediatric patients.

Brand Names: US
  • Aplenzin;
  • Forfivo XL;
  • Wellbutrin SR;
  • Wellbutrin XL;
  • Zyban [DSC]
Brand Names: Canada
  • MYLAN-BuPROPion XL;
  • ODAN Bupropion SR;
  • PMS-BuPROPion SR;
  • RATIO-BuPROPion SR [DSC];
  • TARO-Bupropion XL;
  • TEVA-Bupropion XL;
  • Wellbutrin SR;
  • Wellbutrin XL;
  • Zyban
Pharmacologic Category
  • Antidepressant, Dopamine/Norepinephrine-Reuptake Inhibitor;
  • Smoking Cessation Aid
Dosing: Adult

Note: Bupropion is available as hydrochloride and hydrobromide salts. Doses are expressed in this monograph as hydrochloride salt except where noted as bupropion hydrobromide salt. Bupropion hydrochloride 150 mg is equivalent to about 174 mg of bupropion hydrobromide. Bupropion is available as immediate release, 12-hour extended release (sustained release), and 24-hour extended release tablets.

Attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (off-label use): Note: For patients with comorbid mood disorders or as an alternative agent for patients with substance use disorders (Brent 2019; CANMAT [Bond 2012]).

12-hour extended release (sustained release): Oral: Initial: 100 mg once daily in the morning; increase in 100 mg/day increments at intervals of 3 to 4 weeks based on response and tolerability up to 200 mg twice daily (Bukstein 2019; Reimherr 2005; Wilens 2001).

24-hour extended release: Oral: Initial: 150 mg once daily in the morning for 1 week; increase to 300 mg once daily for 3 weeks; may further increase dose based on response and tolerability up to 450 mg once daily (Wilens 2005).

Bipolar depression

Bipolar depression (off-label use): 12-hour extended release (sustained release): Oral: Initial: 100 mg once daily as an adjunct to mood stabilizer; increase based on response and tolerability at 2-week intervals up to 450 mg/day in 2 divided doses (average dose in clinical trials was 250 mg/day) (APA 2002; Grossman 1999; McIntyre 2002).

Major depressive disorder

Major depressive disorder (unipolar): Note: Treatment should be periodically evaluated at appropriate intervals to ensure lowest effective dose is used. Slower dose titrations may be indicated based on patient care setting, symptom severity, and concern for side effects. May also be used as an alternative agent for patients with SSRI-induced sexual dysfunction (APA 2010).

Immediate release: Oral: Initial: 100 mg twice daily; after 3 days may increase to the usual dose of 100 mg 3 times a day; if no clinical improvement after several weeks, may increase to a maximum dose of 450 mg/day in 3 or 4 divided doses; do not exceed 150 mg in a single dose.

12-hour extended release (sustained release): Oral: Initial: 150 mg daily in the morning; if tolerated, after 3 days, may increase to a target dose of 150 mg twice daily; if no clinical improvement after several weeks, may increase to a maximum dose of 200 mg twice daily; do not exceed 200 mg in a single dose.

24-hour extended release: Oral:

Hydrochloride salt: Initial: 150 mg once daily in the morning; if tolerated, may increase as early as day 4 of dosing to 300 mg once daily; if no clinical improvement after 2 weeks, may increase to 450 mg once daily.

Hydrobromide salt: Initial: 174 mg once daily in the morning; may increase as early as day 4 of dosing to 348 mg once daily (target dose).

Seasonal affective disorder

Seasonal affective disorder (SAD): 24-hour extended release: Oral:

Hydrochloride salt: Initial: 150 mg once daily in the morning; if tolerated, may increase after 7 days to 300 mg once daily in the morning.

Hydrobromide salt: Initial: 174 mg once daily in the morning; if tolerated, may increase after 7 days to 348 mg once daily in the morning.

Note: Prophylactic treatment should be reserved for patients with frequent depressive episodes and/or significant impairment. Initiate treatment in the autumn prior to symptom onset, and discontinue in early spring with dose tapering. Doses >300 mg daily (hydrochloride salt) or >348 mg daily (hydrobromide salt) have not been studied in SAD.

Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation

Selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction, augmentation (off-label use): 12-hour extended release (sustained release): Oral: Initial: 150 mg once daily for the first 3 days; increase to 150 mg twice daily, based on response and tolerability (Clayton 2004; Safarinejad 2011).

Smoking cessation

Smoking cessation: Note: May be used as monotherapy or in combination with nicotine replacement therapy (Siu 2015): 12-hour extended release (sustained release): Oral: Initial: 150 mg once daily for 3 days; increase to 150 mg twice daily (maximum dose: 300 mg/day). For patients who do not tolerate titration to the full dose, consider continuing 150 mg once daily; the lower dose has shown efficacy (Hughes 2014).

Note: Therapy should begin at least 1 week before target quit date. Target quit dates are generally in the second week of treatment. If patient successfully quits smoking, continue treatment for at least 12 weeks. May consider maintenance therapy based on individual patient risk:benefit; evidence suggests relapse prevention benefits with continuing therapy for up to 1 year. Conversely, if significant progress has not been made by the seventh week of therapy, success is unlikely; consider combination therapy, or discontinuation and use of an alternative agent (Leone 2020; manufacturer’s labeling).

Dosing conversion:

Immediate-, 12-hour (sustained release), and 24-hour extended-release formulations (hydrochloride salt): Convert using same total daily dose (up to the maximum recommended dose for a given dosage form), but adjust frequency as indicated for immediate (3 to 4 times daily), 12-hour extended (sustained release) (twice daily), or 24-hour extended (once daily) release products.

Hydrochloride salt formulation (immediate release, 12-hour (sustained release), or 24-hour extended release) to hydrobromide salt formulation (extended release):

Bupropion hydrochloride 150 mg daily is equivalent to bupropion hydrobromide 174 mg once daily.

Bupropion hydrochloride 300 mg daily is equivalent to bupropion hydrobromide 348 mg once daily.

Bupropion hydrochloride 450 mg daily is equivalent to bupropion hydrobromide 522 mg once daily.

MAOI recommendations: Switching to or from an MAOI antidepressant:

Allow 14 days to elapse between discontinuing an MAOI intended to treat depression and initiation of bupropion.

Allow 14 days to elapse between discontinuing bupropion and initiation of an MAOI intended to treat depression.

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose (eg, over 2 to 4 weeks) to allow for the detection of reemerging symptoms. Withdrawal symptoms resulting from abrupt discontinuation are unlikely because bupropion has minimal serotonergic activity (APA 2010).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Limited pharmacokinetic data available for patients with kidney impairment. Accumulation of bupropion and its active metabolites are likely to occur if using unadjusted doses in patients with chronic kidney disease or end-stage kidney disease (Turpeinen 2007; Worrall 2004).

Altered kidney function:

CrCl >60 mL/minute: No dosage adjustment necessary (expert opinion).

CrCl 15 to 60 mL/minute: Use with caution; consider a maximum daily dose of 150 mg/day (Nagler 2012; Turpeinen 2007).

CrCl <15 mL/minute: Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours (expert opinion). Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day (Nagler 2012).

Hemodialysis, intermittent (thrice weekly): Minimally dialyzable (13%); major active metabolite (hydroxybupropion) is not dialyzable (Worrall 2004):

Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours (Worrall 2004; expert opinion). Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day (Nagler 2012).

Peritoneal dialysis: Not likely to be dialyzable (expert opinion):

Use of alternative agent may be preferred. Use with caution; to limit accumulation of active metabolites, initiate therapy at 100 mg every 48 hours or 150 mg every 72 hours (expert opinion). Titrate gradually based on tolerability and response to a maximum daily dose of 150 mg/day (Nagler 2012).

Dosing: Hepatic Impairment: Adult

Mild impairment (Child-Pugh score 5 to 6): Use with caution; manufacturer's labeling suggests a reduction in dose and/or frequency be considered but does not provide specific dosing recommendations. Some experts recommend decreasing the initial dose to 50% of usual dose and reducing dosing frequency (Mullish 2014). Use of the 450 mg ER tablet is not recommended (Forfivo XL is not available in a lower dose strength).

Moderate to severe impairment, including severe hepatic cirrhosis (Child-Pugh score 7 to 15): Use with extreme caution. Some experts recommend decreasing the initial dose to 50% of usual dose and reducing dosing frequency (Mullish 2014).

Hydrobromide salt: Maximum dose: 174 mg every other day.

Hydrochloride salt:

Immediate release: Maximum dose: 75 mg once daily.

12-hour extended release (sustained release): Maximum dose: 100 mg once daily or 150 mg every other day.

24-hour extended release: Maximum dose: 150 mg every other day.

Dosing: Pediatric

(For additional information see "Bupropion: Pediatric drug information")

Note: Use extra precaution with selection of dosage forms: Bupropion is available as either hydrochloride or hydrobromide (Aplenzin; not used in pediatric patients) salt formulations which are not interchangeable on a mg per mg basis; dosage expressed in terms of the salt formulation. Bupropion is available as immediate-release, 12-hour sustained-release, and 24-hour extended-release tablets. Patients must be able to swallow sustained- or extended-release products whole.

Attention-deficit/hyperactivity disorder (ADHD): Limited data available:

Note: Bupropion is not recommended as first-line therapy in the management of ADHD in pediatric patients (AACAP [Pliszka 2007]; AAP [Wolraich 2019]; NICE 2018). In comparative trials with methylphenidate, a small volume of evidence suggests bupropion may have similar efficacy (Jafarinia 2012; Ng 2017); however, the role of bupropion has not been defined.

Children ≥6 years and Adolescents: Oral:

Immediate release, hydrochloride salts: Initial: 1.5 to 3 mg/kg/day in 2 to 3 divided doses; maximum initial dose: 150 mg/day; titrate dose as needed to a maximum daily dose of 6 mg/kg/day or 300 mg/day with no single dose >150 mg (AACAP [Pliszka 2007]; Barrickman 1995; Conners 1996; Jafarinia 2012; Ng 2017). Note: When determining initial dose, assess available dosage forms (eg, 1/2 of 75 mg tablet may be lowest achievable dose).

12-hour sustained release (eg, Wellbutrin SR) and 24-hour extended release (eg, Wellbutrin XL), hydrochloride salts: In patients able to swallow tablets whole: May be used in place of regular tablets, once the daily dose is titrated using the immediate-release product and the titrated 12-hour dosage corresponds to a sustained-release tablet (Wellbutrin SR) or the 24-hour dosage range corresponds to an extended-release tablet size (Wellbutrin XL). In pediatric efficacy trials, mean final effective dose ranges for sustained-release formulations were similar to immediate release (Daviss 2001).

Depression, refractory: Limited data available:

Note: In the management of depression in children and adolescents, if pharmacotherapy deemed necessary with/without psychotherapeutic interventions, bupropion is not recommended as first-line therapy (AAP [Cheung 2018]; APA 2019; NICE 2019). Some suggest it may be beneficial in patients with comorbid ADHD (Daviss 2001). Treatment should be periodically evaluated at appropriate intervals to ensure lowest effective dose is used.

Immediate release, hydrochloride salt: Children ≥8 years and Adolescents: Oral: Initial: 37.5 mg twice daily; titrate to response; titration intervals of every 1 to 2 weeks have been suggested (Mullen 2018); usual reported dosage range: 100 to 300 mg/day in divided doses; maximum reported daily dose: 400 mg/day (Dopheide 2006; Mullen 2018).

12-hour sustained release, hydrochloride salt (eg, Wellbutrin SR): Children ≥11 years and Adolescents: Oral: Initial: 2 mg/kg once daily up to 100 mg administered as a morning dose; may titrate as needed every 2 to 3 weeks using the following titration schedule: Step 2: Increase up to 3 mg/kg every morning; Step 3: Increase up to 3 mg/kg every morning and 2 mg/kg at 5 pm (17:00); Step 4: Increase up to 3 mg/kg/dose twice daily; maximum dose: 150 mg; reported mean effective dose: Morning: 2.2 mg/kg and afternoon: 1.7 mg/kg (Daviss 2001).

24-hour extended release, hydrochloride salt (eg, Wellbutrin XL): Children ≥12 years and Adolescents: Oral: Initial: 150 mg once daily; may titrate after 2 weeks to 300 mg once daily if adequate response not achieved; dosing based on a pharmacokinetic study in 8 patients with depression weighing ≥30 kg (Daviss 2006); doses as high as 400 mg/day have been reported (Dopheide 2006); may also be used once the daily dose is titrated using the immediate-release product and the 24-hour dosage range corresponds to an extended-release tablet size (Wellbutrin XL).

Smoking cessation: Limited data available: Adolescents ≥14 years and ≥40.5 kg: 12-hour sustained release, hydrochloride salt: Oral: Initial: 150 mg once daily for 3 days; increase to 150 mg twice daily; treatment should start while the patient is still smoking in order to allow drug to reach steady-state levels prior to smoking cessation; generally, patients should stop smoking during the second week of treatment; maximum daily dose: 300 mg/day; dosing based on a short-term efficacy trial of 104 adolescents who received therapy for 7 weeks with cessation counseling (Muramoto 2007); however, long-term efficacy (6-month abstinence data point) has not been reported (USPSTF 2020).

Dosing conversion between hydrochloride salt immediate release, 12-hour sustained release (eg, Wellbutrin SR), and 24-hour extended release (eg, Wellbutrin XL) products: Convert using same total daily dose (up to the maximum recommended dose for a given dosage form), but adjust frequency as indicated for 12-hour sustained (twice daily) or for 24-hour extended (once daily) release products.

Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing nonillness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Hathaway 2018). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Fenske 2009; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested; use with caution.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosing adjustment suggested.

Dosing: Older Adult

Refer to adult dosing; use with caution.

Discontinuation of therapy: Refer to adult dosing.

MAOI recommendations: Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Generic: 75 mg, 100 mg

Tablet Extended Release 12 Hour, Oral, as hydrochloride:

Wellbutrin SR: 100 mg, 150 mg, 200 mg

Zyban: 150 mg [DSC]

Generic: 100 mg, 150 mg, 200 mg

Tablet Extended Release 24 Hour, Oral, as hydrobromide:

Aplenzin: 174 mg, 348 mg, 522 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Forfivo XL: 450 mg

Wellbutrin XL: 150 mg, 300 mg

Generic: 150 mg, 300 mg, 450 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 12 Hour, Oral, as hydrochloride:

Wellbutrin SR: 150 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, polysorbate 80]

Zyban: 150 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Generic: 100 mg, 150 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Wellbutrin XL: 150 mg, 300 mg

Generic: 150 mg, 300 mg

Administration: Adult

Oral: May be taken without regard to meals. The manufacturer states that tablets should be swallowed whole; do not crush, chew, or divide. Chewing, crushing, injecting, or dividing long-acting products may increase seizure risk.

Immediate release: Administer 3 to 4 times daily with at least 6 hours between successive doses; do not exceed 150 mg in a single dose.

12-hour extended release (sustained release): Administer 2 times daily with at least 8 hours between successive doses; do not exceed 200 mg in a single dose.

24-hour extended release: Administer once daily with at least 24 hours between successive doses.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. Switch to IR bupropion. Of note, there is one publication that suggests tablet could be cut in half just prior to administration (Cochren 1999).

Administration: Pediatric

Oral: May be taken without regard to meals. The manufacturer states do not crush, chew, or divide sustained- or extended-release tablets (hydrochloride and hydrobromide salt formulations); swallow whole. Chewing, crushing, injecting, or dividing long-acting products may increase seizure risk. The insoluble shell of the extended-release tablet may remain intact during GI transit and is eliminated in the feces.

Immediate release: Administer with at least 6 hours between successive doses.

Sustained release: Typically administer 2 times daily with at least 8 hours between successive doses.

Extended release: Administer once daily with at least 24 hours between successive doses.

Use: Labeled Indications

Major depressive disorder (unipolar [excluding Zyban]): Treatment of major depressive disorder (MDD)

Seasonal affective disorder (24-hour extended release [Aplenzin, Wellbutrin XL]): Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD)

Smoking cessation (12-hour extended release [sustained release; Zyban]): As an aid to smoking cessation treatment

Use: Off-Label: Adult

Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation

Medication Safety Issues
Sound-alike/look-alike issues:

Aplenzin may be confused with Albenza, Relenza

BuPROPion may be confused with busPIRone

Forfivo XL may be confused with Forteo

Wellbutrin XL may be confused with Wellbutrin SR

Zyban may be confused with Diovan

Adverse Reactions (Significant): Considerations
Activation of mania or hypomania

Antidepressants (especially when used as monotherapy) may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients initially diagnosed with unipolar major depressive disorder (MDD) have been reported, as many cases of bipolar disorder initially present with a major depression episode (Ref). Some studies report a lower risk of manic switching with bupropion versus other antidepressants, but these studies have been small and lacked statistical power to determine true differences among agents (Ref).

Mechanism: Non-dose-related; idiosyncratic. Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref). The noradrenergic pharmacology of bupropion leading to stimulatory adverse reactions may play a role (Ref).

Onset: Varied; a systematic review observed that the risk of switching increased significantly within the initial 2 years of antidepressant treatment in patients with unipolar MDD receiving an antidepressant as monotherapy but not thereafter (up to 4.6 years) (Ref). Can present as new-onset mania or cycle acceleration of existing bipolar disorder (Ref).

Risk factors:

• Family history of bipolar disorder (Ref)

• Depressive episode with psychotic symptoms (Ref)

• Younger age at onset of depression (Ref)

• Antidepressant resistance (Ref)

CNS stimulation & neuropsychiatric effects

Bupropion can cause CNS stimulation in patients, including increased energy, insomnia, agitation, and nervousness, and, in more significant cases, anxiety or panic. On rare occasions, more significant neuropsychiatric effects, including abnormality in thinking, paranoid ideation, delusion, hallucination, psychosis, suicidal ideation, and homicidal ideation, may occur (Ref).

Mechanism: Dose-related; bupropion is chemically related to amphetamines. Inhibition of norepinephrine reuptake can lead to stimulatory effects and inhibition of dopamine reuptake can lead to alterations in thinking and perception (Ref). Bupropion also inhibits nicotinic acetylcholine receptors (Ref). In patients taking bupropion for smoking cessation, some cases occurred during treatment discontinuation and may reflect symptoms resulting from nicotine withdrawal.

Onset: Varied; may occur shortly after initiation or dose increases.

Risk factors:

• Concurrent substance use (especially stimulants) (Ref)

• Higher doses (Ref)

• History of psychiatric disease (possible risk factor) (Note: Cases have occurred in patients with and without preexisting psychiatric disease who are taking bupropion for smoking cessation)

• Misuse/overdose (Ref)

Ocular effects

Bupropion is associated with an increased risk of acute angle-closure glaucoma (AACG) in a case-controlled study, particularly in adults <50 years of age (Ref). AACG may cause symptoms, including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref). Of note, some studies suggest that bupropion may reduce the risk of open-angle glaucoma (Ref).

Mechanism: Unclear; hypothesized that bupropion may cause choroidal effusion and pupil dilation (Ref).

Risk factors:

Specific to bupropion:

• Adults <50 years of age (Ref)

Additional risk factors for AACG in general:

• Adults ≥50 years of age (slight increase) (Ref)

• Females (Ref)

• Hyperopia (slight increase) (Ref)

• Personal or family history of AACG (Ref)

• Concurrent use of medications that increase risk of AACG (eg, topiramate) (Ref)

• Asian or Inuit descent (Ref)

Seizure

Bupropion is associated with dose-related risk of seizure. Seizure risk with bupropion may be the greatest among antidepressants (Ref).

Mechanism: Dose-related; hypothesized to be related to increasing concentrations of sympathomimetic amines, causing activation of neuronal pathways in the hypothalamus (Ref).

Risk factors:

• Abrupt discontinuation of ethanol, benzodiazepines, barbiturates, or antiseizure drugs

• Concurrent electrolyte/metabolic disturbances (eg, hypoglycemia, hyponatremia, severe hepatic impairment, hypoxia)

• Concurrent use of drugs that lower the seizure threshold (eg, antipsychotics, antidepressants, theophylline, systemic corticosteroids, stimulants [including cocaine], anorexiants, hypoglycemic agents)

• Conditions with high seizure risk (eg, arteriovenous malformation, severe head injury, severe stroke, CNS tumor, CNS infection)

• Excessive use of ethanol, benzodiazepines, sedative/hypnotics, or opioids

• Higher doses/overdoses (especially >400 mg/day)

• History of anorexia or bulimia

• History of seizures

• Use of immediate-release formulations (Ref)

Suicidal thinking & behavior

Bupropion use is associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years of age) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults (≥65 years of age), a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs. Overdose with bupropion among adolescents was found to have more significant toxicological effects, including death, vs selective serotonin reuptake inhibitors (SSRI) overdoses (Ref).

Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses and another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).

Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).

Risk factors:

• Children and adolescents (Ref)

• Depression (risk of suicide is associated with major depression and may persist until remission occurs)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Tachycardia (11%)

Dermatologic: Diaphoresis (5% to 22%)

Endocrine & metabolic: Weight loss (14% to 28%)

Gastrointestinal: Constipation (8% to 26%), nausea (9% to 18%), nausea and vomiting (23%), xerostomia (10% to 28%)

Nervous system: Agitation (3% to 32% [placebo: 2% to 22%]), dizziness (6% to 22%), headache (≤34%), insomnia (11% to 40% [placebo: 6% to 21%]), migraine (≤26%)

Neuromuscular & skeletal: Tremor (1% to 21%)

Ophthalmic: Blurred vision (≤15%)

Respiratory: Nasopharyngitis (13%), pharyngitis (3% to 11%), rhinitis (12%)

1% to 10%:

Cardiovascular: Cardiac arrhythmia (5%), cerebrovascular accident (≤1%), chest pain (3% to 4%), ECG abnormality (≤1%), edema, facial edema (≤1%), flushing (1% to 4%), hypertension (1% to 4%; may be severe hypertension), hypotension (3%), orthostatic hypotension (≤1%), palpitations (2% to 6%), peripheral edema (≤1%), syncope (1%), vasodilation (≤1%)

Dermatologic: Alopecia (≤1%), ecchymoses (≤1%), pruritus (2% to 4%), skin photosensitivity (≤1%), skin rash (3% to 8%), urticaria (1% to 2%), xeroderma (2%)

Endocrine & metabolic: Decreased libido (3%), gynecomastia (≤1%), hot flash (1% to 3%), increased libido, increased thirst (≤1%), menstrual disease (5%), weight gain (9%)

Gastrointestinal: Abdominal pain (2% to 9%), anorexia (1% to 5%), bruxism (≤1%), decreased appetite (4%), diarrhea (4% to 7%), dysgeusia (2% to 4%), dyspepsia (3%), dysphagia (2%), flatulence (6%), gastroesophageal reflux disease (≤1%), gingivitis (≤1%), increased appetite (2% to 4%), oral mucosa ulcer (2%), sialorrhea (≤1%), stomatitis, vomiting (4%)

Genitourinary: Dysmenorrhea (2%), impotence (≤1%), nocturia, painful erection (≤1%), prostatic disease (≤1%), testicular swelling (≤1%), urinary frequency (3% to 5%), urinary tract infection (1%), urinary urgency (2%), vaginal hemorrhage (2%)

Hepatic: Hepatic injury (≤1%), jaundice (≤1%)

Hypersensitivity: Hypersensitivity reaction (1%)

Infection: Infection (8% to 9%)

Nervous system: Abnormal dreams (3% to 5%), abnormal sensory symptoms (4%), abnormality in thinking (1% [placebo: 0%]), akathisia (2%), anxiety (3% to 8% [placebo: 1% to 6%]), ataxia, chills (≤1%), confusion (8%), decreased sexual activity, delayed ejaculation (≤1%), depersonalization (≤1%), depression, drowsiness (2% to 3%), dysarthria (≤1%), dysphoria (≤1%), dystonia, emotional lability (≤1%), euphoria (1%), formal thought disorder (≤1%), hallucination, hostility (6%), hypertonia (≤1%), hypoesthesia (≤1%), hypomania, irritability (3%), jitteriness (3%), lack of concentration (9%), mania, memory impairment (3%), myoclonus, nervousness (4% to 5% [placebo: 2% to 3%]), pain (3%), paranoid ideation (≤1%), paresthesia (1% to 2%), psychosis (≤1%) (Bailey 2008), seizure (dose-related), sleep disorder (4%), suicidal ideation (≤1%), twitching (1% to 2%), vertigo (≤1%)

Neuromuscular & skeletal: Arthralgia (4% to 5%), arthritis (2%), asthenia (4%), dyskinesia, hyperkinetic muscle activity (≤1%), limb pain (3%), lower limb cramp (≤1%), myalgia (2% to 6%), neck pain (2%)

Ophthalmic: Accommodation disturbance (≤1%), diplopia (≤3%), dry eye syndrome (≤1%), mydriasis (≤1%)

Otic: Auditory disturbance (5%), tinnitus (1% to 6%)

Renal: Polyuria (≤1%)

Respiratory: Bronchitis (2%), cough (2% to 4%), dyspnea (≤1%), epistaxis (2%), flu-like symptoms, sinusitis (2% to 5%), upper respiratory infection (9%)

Miscellaneous: Fever (≤2%)

<1%:

Cardiovascular: Acute myocardial infarction

Endocrine & metabolic: Glycosuria

Gastrointestinal: Intestinal perforation

Genitourinary: Urinary incontinence

Hypersensitivity: Tongue edema

Nervous system: Abnormal electroencephalogram, amnesia, derealization, disturbance in attention, malaise

Respiratory: Bronchospasm

Frequency not defined: Nervous system: Suicidal tendencies

Postmarketing:

Cardiovascular: Complete atrioventricular block, extrasystoles, phlebitis

Dermatologic: Cutaneous lupus erythematosus (Hannah 2018), erythema multiforme (Lineberry 2001), exfoliative dermatitis, maculopapular rash, Stevens-Johnson syndrome (Surovik 2010)

Endocrine & metabolic: Hirsutism, hyperglycemia, hypoglycemia, hyponatremia (Kim 2011), SIADH

Gastrointestinal: Abnormal stools, colitis, esophagitis, gastric ulcer, gastrointestinal hemorrhage, gingival hemorrhage, glossitis, pancreatitis

Genitourinary: Cystitis, dyspareunia, dysuria, ejaculatory disorder, salpingitis, urinary retention, vaginitis

Hematologic & oncologic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia

Hepatic: Hepatitis (Hu 2000)

Hypersensitivity: Anaphylactic shock, anaphylaxis, angioedema (Tackett 2008; Tuman 2016), nonimmune anaphylaxis, type IV hypersensitivity reaction

Immunologic: Serum sickness-like reaction (Davis 2001; McCollum 2000; Waibel 2004)

Nervous system: Aggressive behavior, aphasia, delirium (Dager 1990), delusion, extrapyramidal reaction, homicidal ideation, myasthenia, neuralgia, neuropathy, panic (Bailey 2008), parkinsonism (Grandas 2007; Jerome 2001), restlessness, tardive dyskinesia (Tuman 2017)

Neuromuscular & skeletal: Akinesia, hypokinesia, muscle rigidity, musculoskeletal chest pain, rhabdomyolysis (Bobe 2004; Miladi 2008), subacute cutaneous lupus erythematosus (Hannah 2018)

Ophthalmic: Angle-closure glaucoma (Symes 2015), increased intraocular pressure

Otic: Deafness

Respiratory: Pneumonia

Contraindications

Hypersensitivity to bupropion or any component of the formulation; seizure disorder; history of anorexia/bulimia; patients undergoing abrupt discontinuation of ethanol or sedatives, including benzodiazepines, barbiturates, or antiseizure drugs; use of MAO inhibitors (concurrently or within 14 days of discontinuing either bupropion or the MAO inhibitor); initiation of bupropion in a patient receiving linezolid or intravenous methylene blue

24-hour extended release: Additional contraindications: Other conditions that increase seizure risk, including arteriovenous malformation, severe head injury, severe stroke, CNS tumor, CNS infection

Canadian labeling: Additional contraindications (not in US labeling): Concurrent use or use within 14 days of thioridazine; concurrent use with other dosage forms of bupropion

Warnings/Precautions

Concerns related to adverse effects:

• Cognitive impairment: May cause motor or cognitive impairment in some patients, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypertension: May elevate BP and cause hypertension. Events have been observed in patients with or without evidence of preexisting hypertension.

• Weight loss: May cause weight loss; use caution in patients where weight loss is not desirable.

Disease-related concerns:

• Attention-deficit/hyperactivity disorder (off-label use): All children diagnosed with attention-deficit/hyperactivity disorder who may be candidates for medication therapy, including bupropion, should have a thorough cardiovascular assessment to identify risk factors for sudden cardiac death prior to initiation of drug therapy.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease, history of hypertension, or coronary artery disease; treatment-emergent hypertension (including some severe cases) has been reported, both with bupropion alone and in combination with nicotine transdermal systems.

• Hepatic impairment: Use caution in patients with hepatic impairment and use extreme caution in patients with severe hepatic cirrhosis; plasma concentrations are increased. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mauri 2014; Mullish 2014). Consider a reduction in dose and/or frequency.

• Renal impairment: Use with caution in patients with renal impairment; consider a reduction in dose and/or frequency.

Special populations:

• Elderly: Use with caution in elderly patients; may be at greater risk of drug accumulation during chronic dosing. Consider a reduction in dose.

Dosage form specific issues:

• 24-hour ER tablet: Insoluble tablet shell may remain intact and be visible in the stool.

Other warnings/precautions:

• Abuse/misuse: Using doses higher than prescribed may result in increased motor activity, agitation/excitement and euphoria. Inhalation of crushed tablets or injection of dissolved bupropion has been reported, some resulting in seizures and death.

• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy (ECT); consider discontinuing, when possible, prior to ECT treatment (APA 2010).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (strong), OCT2

Drug Interactions

Agents With Seizure Threshold Lowering Potential: BuPROPion may enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of BuPROPion. Specifically, seizure threshold may be lowered. BuPROPion may enhance the adverse/toxic effect of Alcohol (Ethyl). Specifically, alcohol tolerance may decrease during treatment. Management: Patients receiving bupropion should be advised to minimize or avoid alcohol consumption due to possible lower alcohol tolerance, and lower seizure threshold associated with heavy alcohol consumption/abrupt discontinuation of heavy consumption. Risk D: Consider therapy modification

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Antihepaciviral Combination Products: May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): May enhance the adverse/toxic effect of BuPROPion. Risk C: Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Risk D: Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Risk D: Consider therapy modification

Benzhydrocodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Benzhydrocodone. Risk C: Monitor therapy

Brexanolone: BuPROPion may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brexpiprazole: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual dose with bupropion; reduce to 25% of usual if used with both bupropion and a strong or moderate CYP3A4 inhibitor. These recommendations do not apply if treating major depressive disorder. Monitor for seizures. Risk D: Consider therapy modification

Carvedilol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Risk C: Monitor therapy

Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Chlorpheniramine. Risk C: Monitor therapy

Citalopram: BuPROPion may enhance the adverse/toxic effect of Citalopram. BuPROPion may increase the serum concentration of Citalopram. Management: Initiate citalopram at the lower end of the normal dose range in patients receiving bupropion and consider limiting the maximum citalopram adult dose to 20 mg/day during concomitant bupropion treatment. Monitor for citalopram toxicities. Risk D: Consider therapy modification

CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2B6 Inducers (Moderate): May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

CYP2B6 Inducers (Weak): May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

CYP2B6 Inhibitors (Weak): May increase the serum concentration of BuPROPion. Risk C: Monitor therapy

Dapoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Risk C: Monitor therapy

Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg, with concurrent use of a strong CYP2D6 inhibitor. Risk D: Consider therapy modification

Dextromethorphan: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dextromethorphan. Risk C: Monitor therapy

Digoxin: BuPROPion may decrease the serum concentration of Digoxin. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Risk C: Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider therapy modification

Escitalopram: BuPROPion may enhance the adverse/toxic effect of Escitalopram. Risk C: Monitor therapy

Fesoterodine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Fexinidazole: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Management: Avoid concomitant use of fexinidazole and CYP2B6 substrates when possible. If combined, monitor for reduced efficacy of the CYP2B6 substrate. Risk D: Consider therapy modification

Flecainide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Flecainide. Risk C: Monitor therapy

FLUoxetine: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of FLUoxetine. Risk C: Monitor therapy

FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluPHENAZine. Risk C: Monitor therapy

FluvoxaMINE: BuPROPion may enhance the adverse/toxic effect of FluvoxaMINE. Risk C: Monitor therapy

Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Risk C: Monitor therapy

Gefitinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Risk C: Monitor therapy

Haloperidol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Haloperidol. Risk C: Monitor therapy

HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Risk C: Monitor therapy

Iloperidone: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. BuPROPion may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. BuPROPion may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with bupropion. Monitor for increased iloperidone toxicities, including QTc prolongation and arrhythmias. Additionally, monitor for increased risk of seizures when these agents are combined. Risk D: Consider therapy modification

Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: BuPROPion may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer bupropion until at least 7 days after each iobenguane dose. Risk X: Avoid combination

Ioflupane I 123: BuPROPion may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): BuPROPion may enhance the serotonergic effect of Lorcaserin (Withdrawn From US Market). This could result in serotonin syndrome. Management: Seek alternatives to this combination when possible. Lorcaserin prescribing information advises “extreme caution” when combining lorcaserin with bupropion, due to a proposed increased risk of serotonin toxicity. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy

Maprotiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Maprotiline. Risk C: Monitor therapy

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Risk X: Avoid combination

Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for EPS when combined. Risk D: Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of BuPROPion. Risk X: Avoid combination

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Risk C: Monitor therapy

Oliceridine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy

Ozanimod: May enhance the hypertensive effect of BuPROPion. Risk C: Monitor therapy

PARoxetine: BuPROPion may enhance the adverse/toxic effect of PARoxetine. Risk C: Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perhexiline. Risk C: Monitor therapy

Perphenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perphenazine. Risk C: Monitor therapy

Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Risk X: Avoid combination

Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Risk D: Consider therapy modification

Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Primaquine. Risk C: Monitor therapy

Propafenone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propafenone. Risk C: Monitor therapy

Propranolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propranolol. Risk C: Monitor therapy

RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification

Sertraline: BuPROPion may enhance the adverse/toxic effect of Sertraline. Risk C: Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Risk D: Consider therapy modification

Thioridazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Thioridazine. Risk X: Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Risk C: Monitor therapy

Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Systemic). Risk C: Monitor therapy

Tolterodine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Risk C: Monitor therapy

TraMADol: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Risk D: Consider therapy modification

Vilazodone: BuPROPion may enhance the adverse/toxic effect of Vilazodone. Risk C: Monitor therapy

Vortioxetine: BuPROPion may enhance the adverse/toxic effect of Vortioxetine. BuPROPion may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with bupropion. Following cessation of bupropion, the vortioxetine dose should be returned to the normal level. Risk D: Consider therapy modification

Zuclopenthixol: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Reproductive Considerations

Bupropion may be associated with less risk for sexual dysfunction than other antidepressants and may be considered as an alternative to or as adjunctive therapy with a selective serotonin reuptake inhibitor in patients with major depressive disorder experiencing sexual dysfunction (Jing 2016; Waldinger 2015).

Pregnancy Considerations

Bupropion and its metabolites cross the placenta (Fokina 2016a).

An increased risk of overall congenital malformations has not been observed following maternal use of bupropion during pregnancy; however, data specific to cardiovascular malformations is inconsistent.

The pharmacokinetics of bupropion are not significantly influenced by pregnancy; the overall maternal exposure to bupropion and the active metabolite hydroxybupropion are not significantly changed in pregnant patients (Fokina 2016b).

If treatment for major depressive disorder is initiated for the first time during pregnancy, agents other than bupropion are preferred (CANMAT [MacQueen 2016]). Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006).

Bupropion is also approved for use as an aid to smoking cessation. Adverse pregnancy outcomes are associated with maternal cigarette smoking (refer to Nicotine monograph for details). All pregnant patients should be screened for nicotine use, regardless of form (cigarettes, e-cigarettes, hookahs, snus, vaping products, as well as lozenges, patches, and gum). Cessation of intake is recommended, and interventions should be individualized (ACOG 2020). The benefit of tobacco smoking cessation for pregnant patients is well documented; behavioral interventions are effective and recommended. Information related to pharmacotherapy interventions in pregnancy is limited and insufficient to make specific recommendations (USPSTF [Krist 2021]). When behavioral counseling is insufficient, the severity of maternal tobacco dependance should be considered along with the known risks of smoking and possible risks of the pharmacologic intervention (ACOG 2020; USPSTF [Krist 2021]). Additional information is needed to show that bupropion is effective for the treatment of smoking cessation in pregnant patients (Claire 2020; Kranzler 2021).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 1-866-961-2388. Enrollment should be done as early in pregnancy as possible.

Breastfeeding Considerations

Bupropion and its active metabolites are present in breast milk.

The manufacturer reports the relative infant dose (RID) of bupropion and its active metabolites to be ~2% of a weight-adjusted maternal dose. In one report, the RID of bupropion ranged from 1.4% to 10.6% of the maternal dose when calculated using actual infant weights and maternal doses ranging from 150 to 300 mg/day (Davis 2009).

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

Bupropion and its active metabolites can be detected in the serum and urine of breastfeeding infants (Davis 2009; Neuman 2014).

Seizures and sleep disturbances have been reported in breastfeeding infants following bupropion exposure via breast milk (Chaudron 2004; Hale 2010; Neuman 2014). Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior, as well as growth and neurodevelopment (ABM [Sriraman 2015]; Sachs 2013; WFSBP [Bauer 2013]).

Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; however, antidepressant medication is recommended when psychotherapy is not an option or when symptoms are moderate to severe (ABM [Sriraman 2015]). When first initiating an antidepressant in a patient who is breastfeeding, agents other than bupropion are preferred (CANMAT [MacQueen 2016]); however, maternal use of bupropion is not considered a reason to discontinue breastfeeding (ABM [Sriraman 2015]). If treatment for smoking cessation is needed postpartum, agents other than bupropion are preferred (Sachs 2013). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Monitoring Parameters

Body weight; neuropsychiatric reactions; closely monitor patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (eg, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, social functioning), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); BP (baseline and periodically especially when used in conjunction with nicotine transdermal replacement); renal and hepatic function.

When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (Vetter 2008).

Mechanism of Action

Aminoketone antidepressant structurally different from all other marketed antidepressants; like other antidepressants the mechanism of bupropion's activity is not fully understood. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of serotonin. Metabolite inhibits the reuptake of norepinephrine. The primary mechanism of action is thought to be dopaminergic and/or noradrenergic.

Pharmacokinetics

Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).

Duration of action: 1 to 2 days

Absorption: Rapid

Distribution: Vd: ~20 to 47 L/kg (Laizure 1985)

Protein binding: 84%

Metabolism: Extensively hepatic via CYP2B6 to hydroxybupropion; non-CYP-mediated metabolism to erythrohydrobupropion and threohydrobupropion. Metabolite activity ranges from 20% to 50% potency of bupropion. Bupropion also undergoes oxidation to form the glycine conjugate of meta-chlorobenzoic acid, the major urinary metabolite.

Half-life:

Distribution: 3 to 4 hours

Elimination:

Hydrochloride salt: ~21 hours after chronic dosing (± 9 hours); Metabolites (after a single dose): Hydroxybupropion: 20 ± 5 hours; Erythrohydrobupropion: 33 ± 10 hours; Threohydrobupropion: 37 ± 13 hours

Hydrobromide salt: 21 ± 7 hours; Metabolites: Hydroxybupropion: 24 ± 5 hours; Erythrohydrobupropion: 31 ± 8 hours; Threohydrobupropion: 51 ± 9 hours

Time to peak, serum:

Bupropion: Immediate release: Within 2 hours; 12-hour extended release (sustained release): Within 3 hours; 24-hour extended release: ~5 hours; 12 hours (fed)

Metabolite: Hydroxybupropion: Immediate release: ~3 hours; Extended release: ~6 to 7 hours

Excretion: Urine (87%, primarily as metabolites); feces (10%, primarily as metabolites)

Pharmacokinetics: Additional Considerations

Renal function impairment: Elimination of bupropion and/or major metabolites may be reduced.

Hepatic function impairment: Elimination of hydroxybupropion is reduced in patients with alcoholic liver disease. Bupropion Cmax increased 70%, AUC increased 3-fold, and mean half-life increased to 29 hours in patients with severe hepatic impairment. Mean half-life for active metabolites increased 2- to 5-fold in patients with severe hepatic impairment.

Geriatric: May be at risk of accumulation of bupropion and its metabolites.

Gender: AUC was approximately 13% higher in men.

Pricing: US

Tablet, 12-hour (buPROPion HCl ER (Smoking Det) Oral)

150 mg (per each): $1.94

Tablet, 12-hour (buPROPion HCl ER (SR) Oral)

100 mg (per each): $0.28 - $1.94

150 mg (per each): $0.30 - $1.94

200 mg (per each): $0.56 - $3.83

Tablet, 12-hour (Wellbutrin SR Oral)

100 mg (per each): $8.56

150 mg (per each): $9.17

200 mg (per each): $17.03

Tablet, 24-hour (Aplenzin Oral)

174 mg (per each): $69.33

348 mg (per each): $91.39

522 mg (per each): $207.98

Tablet, 24-hour (buPROPion HCl ER (XL) Oral)

150 mg (per each): $0.33 - $5.22

300 mg (per each): $0.55 - $19.33

450 mg (per each): $16.07 - $16.76

Tablet, 24-hour (Forfivo XL Oral)

450 mg (per each): $18.77

Tablet, 24-hour (Wellbutrin XL Oral)

150 mg (per each): $68.45

300 mg (per each): $90.35

Tablets (buPROPion HCl Oral)

75 mg (per each): $0.34 - $1.45

100 mg (per each): $0.44 - $1.97

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Abstain SR (EG);
  • Betetrim (TW);
  • Bupep SR (IN);
  • Buprotrin (TW);
  • Buxon (CL);
  • Carmubine (AT);
  • Deppreo (VN);
  • Elontril (DE, EE, ES, HU, IT, LT, NL, RO, SK);
  • Fumipan (EG);
  • Funnix (TW);
  • Inip (BR);
  • Le Fu Ting (CN);
  • Nicopion (KR);
  • Nicostop (VN);
  • Odranal (AR, CO);
  • Prewell (TW);
  • Prexaton (AU);
  • Quomen (TH);
  • Vixadep (EG);
  • Voxra (FI, SE);
  • Wekkbutrin (RU);
  • Wellbutrin (AT, BE, CH, IL, MX, NL, NO, PE, PY, TW, VE);
  • Wellbutrin Retard (IS, SK);
  • Wellbutrin SR (AR, BB, BM, BS, CL, EC, HK, HU, JM, KR, LV, MY, SG, UY);
  • Wellbutrin XL (BB, BH, BM, BS, CO, CR, DO, EC, GT, HK, HN, JM, KR, KW, NI, PA, PE, QA, SA, SV, TH, TW);
  • Wellbutrin XR (CY, HR, LU, MT, SI, TR);
  • Wellinta (EG);
  • Yue Ting (CN);
  • Zyban (AE, AT, BB, BE, BG, BM, BR, BS, BZ, CH, CY, CZ, DE, DK, FI, FR, GB, GR, GY, IE, IL, IN, IS, IT, JM, MT, NL, NO, NZ, PL, PR, PT, RO, SA, SE, SI, SR, TR, TT);
  • Zyban LP (FR);
  • Zyban SR (BH, KW, QA, SG);
  • Zyban Sustained Release (AU);
  • Zylexx SR (PK);
  • Zyntabac (ES)


For country abbreviations used in Lexicomp (show table)

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