WELLBUTRIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for WELLBUTRIN (WELLBUTRIN).
Bupropion is a relatively selective inhibitor of the neuronal reuptake of norepinephrine and dopamine. It does not inhibit monoamine oxidase or the reuptake of serotonin.
| Metabolism | Hepatic metabolism primarily by CYP2B6, with minor contributions from CYP1A2, CYP2C9, CYP2E1, and CYP3A4. Active metabolite hydroxybupropion formed via CYP2B6. |
| Excretion | Renal (87% as metabolites, 0.5% unchanged); fecal (10%) |
| Half-life | Terminal half-life: 21 ± 6 hours (hydroxybupropion 24 ± 6 h, threohydrobupropion 37 ± 13 h, erythrohydrobupropion 33 ± 10 h); requires 5-8 days to reach steady state |
| Protein binding | 82-88% bound to plasma proteins (mainly albumin); bupropion and its metabolites are extensively bound |
| Volume of Distribution | 19-30 L/kg (mean 27 L/kg); indicates extensive tissue distribution with accumulation in lungs, liver, and brain |
| Bioavailability | Oral: 5-20% (extensive first-pass metabolism by CYP2B6); sustained-release and extended-release formulations have similar bioavailability to immediate-release |
| Onset of Action | Oral: 2-4 weeks for therapeutic antidepressant effect; immediate-release peak plasma concentration at 2 hours, sustained-release at 3 hours, extended-release at 5 hours |
| Duration of Action | Dosing interval-dependent: immediate-release 6-8 hours (TID dosing), sustained-release 12-15 hours (BID), extended-release 24 hours (QD); clinical effect continuous with chronic dosing |
| Molecular Weight | 239.74 |
Immediate-release: 100 mg orally twice daily initially; after 3 days, increase to 100 mg 3 times daily. Sustained-release: 150 mg orally once daily initially; after 3 days, increase to 150 mg twice daily. Extended-release: 150 mg orally once daily initially; after 3 days, increase to 300 mg once daily.
| Dosage form | TABLET |
| Renal impairment | GFR 15-30 mL/min: reduce dose by 50% (maximum 150 mg/day). GFR <15 mL/min or on hemodialysis: use not recommended due to accumulation of metabolites. |
| Liver impairment | Child-Pugh A: reduce dose by 50% (maximum 150 mg/day). Child-Pugh B: reduce dose by 75% (maximum 100 mg/day). Child-Pugh C: contraindicated. |
| Pediatric use | For depression in adolescents (≥18 years): dose as per adult. For ADHD in children (6-12 years): immediate-release 3 mg/kg/day divided into 3 doses, starting at 1.5 mg/kg/day. For adolescents (12-18 years): immediate-release 2-3 mg/kg/day divided into 3 doses, maximum 300 mg/day. Extended-release not recommended under 18 years. |
| Geriatric use | Start at lowest dose (immediate-release 100 mg daily; sustained-release 150 mg daily; extended-release 150 mg daily). Titrate slowly due to increased risk of seizures and comorbidities. Maximum 300 mg/day in divided doses. |
| 1st trimester | Limited human data; animal studies show risk but not confirmed in humans. Use only if potential benefit justifies potential risk. Associated with increased risk of cardiovascular malformations in some studies. |
| 2nd trimester | Limited human data; no increased risk of major malformations reported. Monitor for emergence or worsening of depression. |
| 3rd trimester | May cause neonatal withdrawal symptoms or serotonin syndrome-like effects with late third-trimester exposure. Consider tapering near term. |
Clinical note
Comprehensive clinical and safety monograph for WELLBUTRIN (WELLBUTRIN).
| Placental transfer | Bupropion and its active metabolite hydroxybupropion cross the placenta; fetal concentrations are similar to maternal. |
| Breastfeeding | Bupropion and its metabolites are excreted into human milk. A case of seizure in a breastfed infant has been reported. Use with caution, especially in mothers with seizure risk or if infant has other risk factors. |
■ FDA Black Box Warning
Bupropion is associated with an increased risk of suicidal ideation and behavior in children, adolescents, and young adults taking antidepressants. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior.
| Serious Effects |
Seizure disorderCurrent or prior diagnosis of bulimia or anorexia nervosaAbrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugsConcomitant use with MAOIs or within 14 days of stopping MAOI
| Precautions | Seizure risk: Dose-dependent; higher risk with doses >450 mg/day, history of head trauma, CNS tumor, or concomitant use of drugs that lower seizure threshold., Neuropsychiatric adverse events including suicidal thoughts and behaviors., Hypertension, especially when used with nicotine replacement therapy., Activation of mania/hypomania in patients with bipolar disorder., Angle-closure glaucoma risk., Hepatotoxicity (rare). |
| Food/Dietary | Avoid alcohol due to increased seizure risk and CNS depression. No specific food restrictions, but high-fat meals may delay absorption. Grapefruit juice does not interact significantly. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Epidemiological studies have not established a consistent association between bupropion use and major congenital malformations, though some data suggest a small increased risk of cardiovascular defects, particularly ventricular septal defects, with first-trimester exposure. Second and third trimesters: Late pregnancy exposure may increase risk for neonatal seizures, respiratory distress, jitteriness, and irritability due to withdrawal or direct toxicity. Overall risk is low but not zero. |
| Fetal Monitoring | Monitor for maternal blood pressure elevation (bupropion can increase BP), seizures (especially in patients with seizure disorders or risk factors), and signs of serotonin syndrome if combined with other serotonergic agents. Fetal monitoring should include appropriate prenatal ultrasonography for growth and anatomy. Neonates exposed late in pregnancy should be observed for withdrawal symptoms and seizures. |
| Fertility Effects | Limited data. Bupropion may cause elevated prolactin levels, potentially leading to galactorrhea, amenorrhea, and ovulatory dysfunction. In men, case reports of erectile dysfunction and decreased libido. However, effects on fertility are not consistently observed and most studies show no significant impact on fertility. |
| Clinical Pearls | Wellbutrin (bupropion) is unique among antidepressants as it inhibits norepinephrine and dopamine reuptake with minimal serotonergic effects. It avoids sexual dysfunction and weight gain common with SSRIs. Contraindicated in patients with seizure disorders or eating disorders due to dose-dependent seizure risk. Also used for smoking cessation. May cause anxiety or insomnia; avoid dosing at bedtime. |
| Patient Advice | Take exactly as prescribed; do not crush or chew tablets as it increases seizure risk. · Common side effects include dry mouth, headache, insomnia, and anxiety; these often improve over time. · Report any unusual thoughts, suicidal ideation, or seizures immediately. · Do not take with other medications containing bupropion (e.g., smoking cessation aids). · Avoid alcohol completely while taking this medication. · This drug may cause a positive result on urine drug screens for amphetamines. |