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BuPROPion

Pronunciation

Pronunciation

(byoo PROE pee on)

Index Terms

  • Budeprion SR
  • Bupropion HCl
  • Bupropion Hydrobromide
  • Bupropion Hydrochloride

Dosage Forms

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

Tablet, Oral, as hydrochloride:

Wellbutrin: 75 mg [DSC], 100 mg [DSC]

Generic: 75 mg, 100 mg

Tablet Extended Release 12 Hour, Oral, as hydrochloride:

Budeprion SR: 100 mg [DSC] [contains tartrazine (fd&c yellow #5)]

Budeprion SR: 150 mg [DSC]

Buproban: 150 mg [DSC]

Wellbutrin SR: 100 mg, 150 mg, 200 mg

Zyban: 150 mg

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

Brand Names: U.S.

  • Aplenzin
  • Budeprion SR [DSC]
  • Buproban [DSC]
  • Forfivo XL
  • Wellbutrin SR
  • Wellbutrin XL
  • Wellbutrin [DSC]
  • Zyban

Pharmacologic Category

  • Antidepressant, Dopamine/Norepinephrine-Reuptake Inhibitor
  • Smoking Cessation Aid

Pharmacology

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.

Absorption

Rapid

Distribution

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

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.

Excretion

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

Onset of Action

1 to 2 weeks

Time to Peak

Bupropion: Immediate release: Within 2 hours; Sustained release: Within 3 hours; Extended release: ~5 hours (Forfivo XL: 5 hours [fasting]; 12 hours [fed])

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

Duration of Action

1 to 2 days

Half-Life Elimination

Distribution: 3 to 4 hours

Elimination: ~21 hours after chronic dosing (range: 12 to 30 hours); Metabolites (after a single dose): Hydroxybupropion: 20 ± 5 hours; Erythrohydrobupropion: 33 ± 10 hours; Threohydrobupropion: 37 ± 13 hours

Extended release (Aplenzin): 21 ± 7 hours; Metabolites: Hydroxybupropion: 24 ± 5 hours; Erythrohydrobupropion: 31 ± 8 hours; Threohydrobupropion: 51 ± 9 hours

Protein Binding

84%

Special Populations: Renal Function Impairment

Elimination of bupropion and/or major metabolites may be reduced.

Special Populations: 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.

Special Populations: Elderly

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

Special Populations: Gender

AUC was approximately 13% higher in men.

Use: Labeled Indications

Major depressive disorder (Aplenzin, Bupropion immediate release, Forfivo XL, Wellbutrin SR, Wellbutrin XL): Treatment of major depressive disorder (MDD).

Seasonal affective disorder (Aplenzin, Wellbutrin XL): Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD).

Smoking cessation (Zyban): As an aid to smoking cessation treatment.

Off Label Uses

Antidepressant-induced sexual dysfunction

Data from two randomized, double-blind, placebo-controlled trials supports the use of bupropion as an augmentation strategy for increasing sexual desire, arousal, lubrication, orgasm and satisfaction in patients with antidepressant-induced sexual dysfunction who have achieved remission on a serotonergic antidepressant.[Clayton 2004], [Safarinejad 2011] Additional trials may be necessary to further define the role of bupropion in this condition.

Based on the American Psychiatric Association practice guidelines for the treatment of patients with major depressive disorder, bupropion given for antidepressant-induced sexual dysfunction is recommended for the management of side effects of arousal, erectile dysfunction or orgasm dysfunction.

Attention deficit hyperactivity disorder (adults)

Data from a meta-analysis supports the use of bupropion in the treatment of ADHD in adults (Maneeton 2011). Additional trials may be necessary to further define the role of bupropion in this condition.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of mood disorders and co-morbid ADHD, bupropion is first-line in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. Additionally, these guidelines recommend bupropion is recommended first-line in patients with ADHD and comorbid major depressive episodes, either as monotherapy or as an adjunct to long-acting stimulant medications.

Attention deficit hyperactivity disorder (children/adolescents)

Data from randomized, double-blind studies support the use of bupropion in the treatment of children and adolescents with ADHD (Barrickman 1995; Conners 1996; Jafarinia 2012). Additional trials may be necessary to further define the role of bupropion in this condition.

Based on the AACAP guidelines, bupropion is recommended as a second-line option in the management of ADHD in children and adolescents.

Depression associated with bipolar disorder

Data from a meta-analysis supports the use of bupropion in the treatment of depression associated with bipolar disorder. Despite demonstrating the efficacy of bupropion, the authors of this meta-analysis caution that there is a risk of switching from depression to mania when bupropion is used for this indication (Li 2016).

Based on the American Psychiatric Association (APA) guidelines, augmentation with bupropion is second-line for the management of depression associated with bipolar disorder that does not respond to lithium or lamotrigine. Due to inconsistencies in bupropion augmentation clinical trial results, the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend bupropion augmentation of lithium or valproic acid as an option in patients who are unresponsive to treatments with greater evidence.

Obesity

Data from a meta-analysis supports the use of bupropion for the promotion of modest weight loss in patients who are overweight or obese (Li 2005). Additional trials may be necessary to further define the role of bupropion in this condition.

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 antiepileptic 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

Aplenzin, Forfivo XL, Wellbutrin XL: Additional contraindications: Other conditions that increase seizure risk, including arteriovenous malformation, severe head injury, severe stroke, CNS tumor, CNS infection

Forfivo XL: Additional contraindications: Patients receiving other dosage forms of bupropion

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

Dosing: Adult

Depression: Oral: Note: Treatment should be periodically evaluated at appropriate intervals to ensure lowest effective dose is used.

Immediate release hydrochloride salt: 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

Sustained release hydrochloride salt: 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

Extended release:

Hydrochloride salt (Wellbutrin XL): Initial: 150 mg once daily in the morning; if tolerated, as early as day 4, may increase to 300 mg once daily (maximum dose: 300 mg/day; however, guidelines suggest up to 450 mg/day may be used [APA 2010]).

Hydrochloride salt (Forfivo XL): Switching from Wellbutrin immediate release, SR, or XL to Forfivo XL: Patients receiving 300 mg daily of bupropion hydrochloride for at least 2 weeks and requiring a dose increase or patients already taking 450 mg daily of bupropion hydrochloride may switch to Forfivo XL 450 mg once daily.

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

Switching from hydrochloride salt formulation (eg, Bupropion immediate release, SR, XL, or Forfivo XL) to hydrobromide salt formulation (Aplenzin):

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

Seasonal affective disorder (SAD): Initial: 150 mg once daily (Wellbutrin XL) or 174 mg once daily (Aplenzin) in the morning; if tolerated, may increase after 7 days to 300 mg once daily (Wellbutrin XL) or 348 mg once daily (Aplenzin) in the morning.

Note: Prophylactic treatment should be reserved for those 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 (Wellbutrin XL) or >348 mg daily (Aplenzin) have not been studied in SAD

Smoking cessation (Zyban): Initial: 150 mg once daily for 3 days; increase to 150 mg twice daily (maximum dose: 300 mg/day).

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 after 7 to 12 weeks, may consider ongoing maintenance therapy based on individual patient risk:benefit. Efficacy of maintenance therapy (300 mg daily) has been demonstrated for up to 6 months. Conversely, if significant progress has not been made by the seventh week of therapy, success is unlikely and treatment discontinuation should be considered.

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

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to allow for the detection of re-emerging symptoms. Withdrawal symptoms resulting from abrupt discontinuation are unlikely because bupropion has minimal serotonergic activity (APA 2010).

Manufacturer’s labeling:

Aplenzin: In patients receiving 348 mg once daily, taper dose down to 174 mg once daily prior to discontinuing.

Forfivo XL: Because the 450 mg tablet is the only available dose formulation, use another bupropion formulation for tapering the dose prior to discontinuation.

Wellbutrin XL: In patients receiving 300 mg once daily, taper dose down to 150 mg once daily prior to discontinuing.

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor antidepressant:

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

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

Antidepressant-induced sexual dysfunction (off-label use): Oral: Sustained release: 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).

Attention-deficit/hyperactivity disorder (off-label use): Oral:

Sustained release: Initial: 100 mg once daily in the morning; increase weekly in 100 mg/day increments based on response and tolerability up to 200 mg twice daily (Reimherr 2005; Wilens 2001)

Extended release: 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).

Depression associated with bipolar disorder (off-label use): Oral: Initial: 100 mg/day; increase based on response and tolerability at 2-week intervals up to 450 mg/day (average dose in clinical trials was 250 mg/day) (Grossman 1999; McIntyre 2002).

Obesity (off-label use): Oral: Sustained release: Initial: 150 mg once daily in the morning; increase to 150 mg twice daily after 3 days; may further increase dose after 2 weeks based on response and tolerability to 200 mg twice daily (dose-dependent responses were identified in one clinical trial) (Anderson 2002; Gadde 2001; Jain 2002).

Dosing: Geriatric

Refer to adult dosing; use with caution.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Pediatric

ADHD (off-label use): Children and Adolescents: Oral:

Immediate release: Initial: 3 mg/kg/day in 2 to 3 divided doses; maximum initial dose 150 mg/day; increase 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])

Sustained release and extended release: May use in place of immediate-release tablets, once the daily dose is increased using the immediate release product and the 12-hour dosage corresponds to a sustained-release tablet size or the 24-hour dosage corresponds to an extended release tablet size.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Renal Impairment

Use with caution; manufacturer’s labeling suggests a reduction in dose and/or frequency be considered but does not provide specific dosing recommendations. Aplenzin, Wellbutrin, Wellbutrin SR, Wellbutrin XL, and Zyban product labeling defines renal impairment as GFR <90 mL/minute.

Forfivo XL: Use is not recommended.

Dosing: Hepatic Impairment

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.

Forfivo XL: Use is not recommended.

Moderate to severe impairment, including severe hepatic cirrhosis (Child-Pugh score 7 to 15): Use with extreme caution; maximum dose:

Aplenzin: 174 mg every other day

Bupropion immediate release: 75 mg once daily

Forfivo XL: Use is not recommended.

Wellbutrin SR: 100 mg once daily or 150 mg every other day

Wellbutrin XL, Zyban: 150 mg every other day

Administration

May be taken without regard to meals. The manufacturer states that tablets should be swallowed whole; do not crush, chew, or divide.

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

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.

Sustained release: Administer 2 times daily with at least 8 hours between successive doses; do not exceed 200 mg in a single dose.

Storage

Store at 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Drug Interactions

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. 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. Consider therapy modification

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

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

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. 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. Consider therapy modification

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

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

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

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

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

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

Dipyrone: May decrease the serum concentration of BuPROPion. Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Efavirenz: May decrease the serum concentration of BuPROPion. Management: Monitor for decreased response to bupropion in patients treated with efavirenz. Increased bupropion doses may be required. Avoid the use of naltrexone/bupropion for weight management in patients receiving efavirenz. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

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

FLUoxetine: BuPROPion may enhance the adverse/toxic effect of FLUoxetine. BuPROPion may increase the serum concentration of FLUoxetine. Monitor therapy

FluvoxaMINE: BuPROPion may enhance the adverse/toxic effect of FluvoxaMINE. BuPROPion may increase the serum concentration of FluvoxaMINE. Monitor therapy

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy

Ioflupane I 123: BuPROPion may diminish the diagnostic effect of Ioflupane I 123. 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 anticonvulsants. 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 anticonvulsants. 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 anticonvulsants. Consider therapy modification

Isavuconazonium Sulfate: May decrease the serum concentration of BuPROPion. Monitor therapy

Lopinavir: May decrease the serum concentration of BuPROPion. Concentrations of the active metabolite, hydroxybupropion, may also be decreased. Management: Monitor bupropion response closely. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving lopinavir. Monitor therapy

Lorcaserin: BuPROPion may enhance the serotonergic effect of Lorcaserin. This could result in serotonin syndrome. Management: Seek alternatives to this combination when possible. Consider therapy modification

Lumacaftor: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypertensive effect of BuPROPion. Avoid combination

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

OCT2 Substrates: BuPROPion may increase the serum concentration of OCT2 Substrates. Monitor therapy

PARoxetine: BuPROPion may enhance the adverse/toxic effect of PARoxetine. BuPROPion may increase the serum concentration of PARoxetine. Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy

Ritonavir: May decrease the serum concentration of BuPROPion. Mixed effects on concentrations of the active hydroxybupropion metabolite have been reported. Management: Monitor for decreased bupropion effects. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving ritonavir. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Tricyclic Antidepressants: BuPROPion may decrease the metabolism of Tricyclic Antidepressants. Management: Seek alternatives when possible. Monitor patients receiving these combinations closely for increased serum concentrations (when testing is available) and toxic effects of the tricyclic antidepressant. Exceptions: Amoxapine; Protriptyline. Consider therapy modification

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. Consider therapy modification

Test Interactions

May interfere with urine detection of amphetamine/methamphetamine (false-positive). Decreased prolactin levels.

Adverse Reactions

>10%:

Cardiovascular: Tachycardia (≤11%)

Central nervous system: Insomnia (11% to 40%), headache (25% to 34%), agitation (2% to 32%), dizziness (6% to 22%)

Dermatologic: Diaphoresis (5% to 22%)

Endocrine & metabolic: Weight loss (14% to 23%)

Gastrointestinal: Xerostomia (10% to 28%), constipation (8% to 26%), nausea and vomiting (23%), nausea (1% to 18%)

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

Ophthalmic: Blurred vision (3% to 15%)

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

1% to 10%:

Cardiovascular: Palpitations (2% to 6%), cardiac arrhythmia (5%), chest pain (≤4%), flushing (≤4%), hypertension (1% to 4%; may be severe), hypotension (3%)

Central nervous system: Lack of concentration (9%), confusion (≤8%), anxiety (3% to 8%), hostility (≤6%), nervousness (4% to 5%), abnormal dreams (3% to 5%), sensory disturbance (4%), sleep disorder (4%), migraine (≤4%), irritability (3%), memory impairment (≤3%), drowsiness (2% to 3%), pain (3%), akathisia (≤2%), central nervous system stimulation (≤2%), paresthesia (≤2%), twitching (≤2%), dystonia (≥1%), abnormality in thinking (1%), depression

Dermatologic: Skin rash (1% to 8%), pruritus (2% to 4%), xeroderma (2%), urticaria (1% to 2%)

Endocrine & metabolic: Weight gain (9%), menstrual disease (2% to 5%), decreased libido (≤3%), hot flash (1% to 3%)

Gastrointestinal: Abdominal pain (2% to 9%), diarrhea (4% to 7%), flatulence (6%), anorexia (1% to 5%), dysgeusia (2% to 4%), increased appetite (2% to 4%), vomiting (≥1% to 4%), dyspepsia (3%), oral mucosa ulcer (2%), dysphagia (≤2%)

Genitourinary: Urinary frequency (≥1% to 5%), urinary urgency (≤2%), vaginal hemorrhage (≤2%), urinary tract infection (≤1%)

Hypersensitivity: Hypersensitivity reaction (1%)

Infection: Infection (8% to 9%)

Neuromuscular & skeletal: Myalgia (2% to 6%), arthralgia (4% to 5%), weakness (4%), neck pain (2%), arthritis (≤2%), dyskinesia (≥1%)

Otic: Tinnitus (1% to 6%), auditory disturbance (5%)

Renal: Polyuria (≤1%)

Respiratory: Upper respiratory infection (9%), sinusitis (2% to 5%), cough (2% to 4%), increased cough (2% to 3%), epistaxis (2%), bronchitis (≤2%)

Miscellaneous: Accidental injury (2%), fever (1% to 2%)

Frequency not defined: Ophthalmic: Diplopia (≤3%)

<1% (Limited to important or life-threatening): Abnormal accommodation, abnormal stools, akinesia, alopecia, amnesia, anaphylactoid reaction, anemia, angioedema, angle-closure glaucoma, aphasia, ataxia, atrioventricular block, cerebrovascular accident, colitis, coma, complete atrioventricular block, cystitis, deafness, delayed hypersensitivity, delirium, delusions, depersonalization, derealization, drug-induced Parkinson disease, dry eye syndrome, dysarthria, dyspareunia, dysphoria, dysuria, ecchymoses, edema, EEG pattern changes, ejaculatory disorder, erythema multiforme, esophagitis, euphoria, exfoliative dermatitis, extrapyramidal reaction, extrasystoles, facial edema, gastric ulcer, gastroesophageal reflux disease, gastrointestinal hemorrhage, gingival hemorrhage, gingivitis, glossitis, glycosuria, gynecomastia, hallucination, hepatic injury, hepatic insufficiency, hepatitis, hirsutism, homicidal ideation, hyperglycemia, hyperkinesia, hypertonia, hypoglycemia, hypokinesia, hypomania, impotence, increased intraocular pressure, increased libido, inguinal hernia, intestinal perforation, jaundice, leg cramps, leukocytosis, leukopenia, lymphadenopathy, maculopapular rash, manic behavior, menopause, muscle rigidity, myasthenia, mydriasis, myocardial infarction, myoclonus, neuralgia, neuropathy, orthostatic hypotension, painful erection, pancreatitis, pancytopenia, panic, paranoia, peripheral edema, phlebitis, pneumonia, prostatic disease, psychosis, pulmonary embolism, restlessness, rhabdomyolysis, salpingitis, sciatica, seizure (dose-related), serum sickness-like reaction, SIADH, sialorrhea, skin photosensitivity, Stevens-Johnson syndrome, stomatitis, suicidal ideation, syncope, tardive dyskinesia, thrombocytopenia, tongue edema, urinary incontinence, urinary retention, vaginitis, vasodilatation, vertigo

ALERT: U.S. 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 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.

Warnings/Precautions

Major psychiatric warnings (use in treating psychiatric disorders):

• Suicidal thinking/behavior (use in treating psychiatric disorders): [US Boxed Warning]: 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 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, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); advise families and caregivers of the need for close observation and communication with the prescriber. A medication guide concerning the use of antidepressants should be dispensed with each prescription.

• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• CNS stimulation: May cause CNS stimulation (restlessness, anxiety, insomnia) or anorexia.

• 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).

• Hypersensitivity reactions: Anaphylactoid/anaphylactic reactions have occurred, with symptoms of pruritus, urticaria, angioedema, and dyspnea. Serious reactions have been (rarely) reported, including erythema multiforme, Stevens-Johnson syndrome and anaphylactic shock. Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity resembling serum sickness have been reported.

• Hypertension: May elevate blood pressure and cause hypertension. Events have been observed in patients with or without evidence of preexisting hypertension. The risk is increased when used concomitantly with monoamine oxidase inhibitors, nicotine replacement, or other drugs that increase dopaminergic or noradrenergic activity. Assess blood pressure before treatment and monitor periodically.

• Mania/hypomania: May precipitate a manic, mixed, or hypomanic episode; risk is increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Screen patients for a history of bipolar disorder and the presence of risk factors including a family history of bipolar disorder, suicide, or depression. Bupropion is not FDA approved for bipolar depression.

• Neuropsychiatric effect (use in smoking cessation): Serious neuropsychiatric events have occurred in patients taking bupropion for smoking cessation, including changes in mood (eg, depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide. The majority occurred during bupropion treatment; some occurred during treatment discontinuation. A causal relationship is uncertain as depressed mood may be a symptom of nicotine withdrawal. Some cases also occurred in patients taking bupropion who continued to smoke. Neuropsychiatric effects occurred in patients with and without preexisting psychiatric disease; some patients experienced a worsening of their psychiatric illnesses. However, subsequent controlled trials in patients with or without psychiatric disorders have not identified significant differences in neuropsychiatric effects for patients taking bupropion, varenicline, nicotine patches, or placebo (Anthenelli 2016; Cinciripini 2013). Observe all patients taking bupropion for neuropsychiatric reactions. Instruct patients to stop taking bupropion and contact a health care provider if neuropsychiatric reactions occur.

• Ocular effects: May cause mild pupillary dilation, which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Psychosis: May cause delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion; most common in depressed patients and patients with a diagnosis of bipolar disorder. Symptoms may abate with dose reduction and/or withdrawal of treatment.

• Seizures: May cause a dose-related risk of seizures. Use is contraindicated in patients with a history of seizures or certain conditions with high seizure risk (eg, history of anorexia/bulimia or patients undergoing abrupt discontinuation of ethanol, benzodiazepines, barbiturates, or antiepileptic drugs). Aplenzin, Forfivo XL, and Wellbutrin XL are also contraindicated in patients with certain conditions with high seizure risk (eg, arteriovenous malformation, severe head injury, severe stroke, CNS tumor, and CNS infection). Use caution with concurrent use of antipsychotics, antidepressants, theophylline, systemic corticosteroids, stimulants (including cocaine), anorexiants, or hypoglycemic agents, or with excessive use of ethanol, benzodiazepines, sedative/hypnotics, or opioids. Use with caution in seizure-potentiating metabolic disorders (hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia). The dose-dependent risk of seizures may be reduced by gradual dose increases and by not exceeding the maximum daily dose. Do not coadminister with other bupropion-containing formulations; Forfivo XL is contraindicated in patients receiving other dosage forms of bupropion. Permanently discontinue if seizure occurs during therapy. Chewing, crushing, injecting, or dividing long-acting products may increase seizure risk.

• Sexual dysfunction: The incidence of sexual dysfunction with bupropion is generally lower than with SSRIs (Clayton 2004).

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

Disease-related concerns:

• ADHD (off-label use): All children diagnosed with ADHD who may be candidates for stimulant medications 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 with caution in patients with hepatic impairment; consider a reduction in dose and/or frequency; Forfivo XL is not recommended in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; consider a reduction in dose and/or frequency; Forfivo XL is not recommended in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

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

Dosage form specific issues:

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

Monitoring Parameters

Body weight; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; blood pressure (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).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Bupropion and its metabolites were found to cross the placenta in in vitro studies (Earhart 2012). An increased risk of congenital malformations has not been observed following maternal use of bupropion during pregnancy; however, data specific to cardiovascular malformations is inconsistent. The long-term effects on development and behavior have not been studied.

The ACOG recommends that antidepressant therapy during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (ACOG 2008; APA 2010; Yonkers 2009). There is insufficient information related to the use of bupropion to recommend use in pregnancy (ACOG 2010).

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 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, abdominal pain, tremors, nightmares, nausea, vomiting, constipation, dry mouth, insomnia, pharyngitis, sweating a lot, lack of appetite, or tablet shell in stool. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), confusion, seizures, anxiety, ideas of murder, forceful actions, psychosis, behavioral changes, hallucinations, irritability, panic attacks, mood changes, agitation, severe headache, severe dizziness, passing out, seizures, excessive weight gain or loss, angina, tachycardia, abnormal heartbeat, tinnitus, polyuria, enlarged lymph nodes, difficulty moving, severe joint pain, severe muscle pain, vision changes, eye pain, eye irritation, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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