What are the considerations for off-label use of bupropion (Wellbutrin) in adult patients with a history of seizure disorders, eating disorders, or those taking interacting medications?

Off-Label Use of Bupropion in High-Risk Populations

Bupropion is absolutely contraindicated in patients with seizure disorders or eating disorders (anorexia nervosa/bulimia nervosa), and extreme caution is required when prescribing to patients on interacting medications that lower seizure threshold or are metabolized by CYP2D6. 1

Absolute Contraindications

Seizure Disorders

• Any current or prior seizure disorder or epilepsy is an absolute contraindication to bupropion use, regardless of formulation or indication 1
• The seizure risk with bupropion at therapeutic doses (≤300 mg/day) is approximately 0.1% (1 in 1,000) in patients without predisposing factors 2, 3
• If a seizure occurs while taking bupropion, the medication must be permanently discontinued 1
• Additional conditions that increase seizure risk and contraindicate bupropion include: brain tumors, head trauma, stroke, or any CNS pathology 4, 1

Eating Disorders

• Current or prior diagnosis of bulimia nervosa or anorexia nervosa is an absolute contraindication 1
• Patients with eating disorders have demonstrated severe abuse potential with bupropion XR, with documented cases of doses reaching 3,000-4,500 mg/day to control binge eating and suppress appetite 5
• This abuse pattern resulted in grand mal seizures, tachycardia, severe anxiety, and insomnia 5
• Clinicians must screen for eating disorder history before prescribing bupropion and consider bupropion abuse in eating disorder patients presenting with seizures 5

Abrupt Substance Discontinuation

• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is an absolute contraindication due to dramatically increased seizure risk 1
• This contraindication applies during the withdrawal period when seizure threshold is lowest 4

Critical Drug Interactions

MAOI Interactions

• Do not use bupropion with MAOIs or within 14 days of discontinuing an MAOI due to increased risk of hypertensive crisis 1
• This includes the antibiotic linezolid and intravenous methylene blue 1
• Do not start an MAOI within 14 days of stopping bupropion 1

CYP2D6 Substrates

• Bupropion is a potent CYP2D6 inhibitor and can significantly increase concentrations of drugs metabolized by this enzyme 1, 6
• High-risk medications requiring dose reduction when combined with bupropion include:
  • Antidepressants: venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline 1
  • Antipsychotics: haloperidol, risperidone, thioridazine 1
  • Beta-blockers: metoprolol 1
  • Type 1C antiarrhythmics: propafenone, flecainide 1
• Consider empiric dose reductions of 25-50% for CYP2D6 substrates when initiating bupropion 1

Medications That Lower Seizure Threshold

• Dose bupropion with extreme caution when combining with other drugs that lower seizure threshold 1
• This includes antipsychotics, other antidepressants, theophylline, systemic corticosteroids, and stimulants 1
• The maximum daily dose must never exceed 450 mg to maintain seizure risk at 0.1% 4, 2

Tamoxifen Interaction

• Bupropion is contraindicated in patients taking tamoxifen because bupropion inhibits CYP2D6, which is required to convert tamoxifen to its active metabolite 4

Opioid Interactions

• Naltrexone-bupropion combination products are absolutely contraindicated with any opioid therapy (including buprenorphine/naloxone) because naltrexone will precipitate severe opioid withdrawal 4
• Bupropion monotherapy does not have this contraindication and can be used cautiously in patients on stable opioid therapy 4

Dose Adjustments for Medical Comorbidities

Hepatic Impairment

• Moderate to severe hepatic impairment: Maximum dose is 150 mg every other day 4, 1
• Mild hepatic impairment: Reduce dose and/or frequency, though specific recommendations are not provided 4, 1
• Bupropion undergoes extensive hepatic metabolism (half-life ~21 hours), with accumulation risk in liver disease 6

Renal Impairment

• Moderate to severe renal impairment (GFR <90 mL/min): Reduce total daily dose by 50% 4
• End-stage renal disease: Avoid bupropion entirely 4
• Bupropion and its active metabolites are cleared renally and accumulate in renal dysfunction 4, 6

Additional High-Risk Situations

Uncontrolled Hypertension

• Uncontrolled hypertension is a contraindication to bupropion use 4, 1
• Bupropion can elevate blood pressure and heart rate, particularly when combined with nicotine replacement therapy 1
• Monitor blood pressure before initiating treatment and periodically during therapy, especially in the first 12 weeks 4, 1

Bipolar Disorder Risk

• Screen all patients for bipolar disorder before prescribing bupropion 1
• Bupropion can precipitate manic episodes, with evidence suggesting this may be dose-related (particularly at doses >450 mg/day) 7
• Monitor for symptoms including greatly increased energy, severe insomnia, racing thoughts, reckless behavior, and excessive happiness or irritability 1

Monitoring Requirements for High-Risk Patients

• Suicidal ideation monitoring: Particularly critical in patients <24 years old during the first 1-2 months of treatment 4, 1
• Neuropsychiatric symptoms: Monitor for delusions, hallucinations, paranoia, confusion, agitation, and behavioral changes 1
• Cardiovascular parameters: Blood pressure and heart rate monitoring, especially in first 12 weeks 4, 1
• Seizure risk factors: Continuously reassess for new conditions that lower seizure threshold 1

Clinical Decision Algorithm

Before prescribing bupropion, systematically exclude:

1. Current or past seizure disorder/epilepsy → Absolute contraindication 1
2. Current or past eating disorder → Absolute contraindication 1, 5
3. Active alcohol/benzodiazepine/barbiturate use with planned abrupt discontinuation → Absolute contraindication 1
4. Current MAOI use or use within past 14 days → Absolute contraindication 1
5. Uncontrolled hypertension → Absolute contraindication 4, 1
6. Tamoxifen therapy → Absolute contraindication 4
7. Opioid therapy (if considering naltrexone-bupropion) → Absolute contraindication 4

If prescribing despite interacting medications:

• Reduce doses of CYP2D6 substrates by 25-50% empirically 1
• Never exceed 450 mg/day total dose when combining with seizure threshold-lowering drugs 4, 2
• Implement intensive monitoring protocols 4, 1