Bupropion hydrochloride

Uses and Indications

Bupropion hydrochloride is indicated for the treatment of major depressive disorder (MDD) and the prevention of seasonal affective disorder (SAD). The efficacy of bupropion in treating MDD has been established through multiple controlled trials, including two 4-week trials with inpatients and one 6-week trial with outpatients. A major depressive episode is characterized by a depressed mood or loss of interest or pleasure, along with at least five additional symptoms such as significant changes in weight or appetite, sleep disturbances, psychomotor agitation or retardation, fatigue, feelings of guilt or worthlessness, impaired concentration, or suicidal ideation.

Bupropion hydrochloride extended-release tablets (XL) are specifically indicated for both the treatment of MDD and the prevention of SAD. The efficacy for the prevention of seasonal major depressive episodes has been demonstrated in controlled trials involving adult outpatients with a history of MDD and a seasonal pattern.

Limitations of Use The long-term usefulness of bupropion should be periodically reevaluated for individual patients, particularly for those on extended treatment. The effectiveness of bupropion in long-term use beyond six weeks has not been systematically evaluated in controlled trials.

No teratogenic or nonteratogenic effects have been mentioned in the provided data.

Dosage and Administration

The recommended starting dose of bupropion hydrochloride is 150 mg once daily. For patients with Major Depressive Disorder and Seasonal Affective Disorder, the usual target dose is 300 mg once daily. After 4 days for Major Depressive Disorder or one week for Seasonal Affective Disorder, the dose may be increased to 300 mg once daily if tolerated.

For patients with moderate to severe hepatic impairment, the recommended dose is 150 mg every other day. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Similarly, for patients with renal impairment, a reduction in dose and/or frequency of dosing should be considered.

The maximum recommended dose is 400 mg per day, given as 200 mg twice daily, for patients who do not respond to 300 mg per day. In cases where a higher dose is required, the maximum dosage may be increased to 450 mg per day, administered as 150 mg three times daily, but only after careful consideration of the patient's clinical response and tolerance.

Bupropion should be administered whole; do not crush, divide, or chew the tablets. It may be taken without regard to meals. Gradual dose escalation is essential to minimize the risk of seizure, and periodic reassessment of the dose and the need for maintenance treatment is recommended.

Contraindications

Bupropion hydrochloride is contraindicated in patients with a seizure disorder due to an increased risk of seizures. It is also contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions are associated with a higher incidence of seizures when treated with bupropion.

The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may precipitate seizures. Additionally, the concurrent administration of bupropion with monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders is contraindicated. At least 14 days must elapse between discontinuation of an MAOI and initiation of bupropion therapy. Bupropion should not be started in patients who are being treated with linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of its components also constitutes a contraindication for its use.

Warnings and Precautions

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports indicate serious or clinically significant neuropsychiatric adverse events associated with bupropion hydrochloride, particularly during smoking cessation. These events may include changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Patients attempting to quit smoking should be closely monitored for these symptoms, and if they occur, bupropion should be discontinued, and a healthcare provider should be contacted.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, the daily dose should be limited to 450 mg, and the dose should be gradually increased. Bupropion should be discontinued if a seizure occurs.

Hypertension Bupropion hydrochloride can increase blood pressure. Blood pressure should be monitored before initiating treatment and periodically during treatment.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment, and symptoms of mania or hypomania should be monitored throughout the treatment.

Psychosis and Other Neuropsychiatric Reactions Patients are advised to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-Closure Glaucoma There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

WARNING: Suicidal Thoughts and Behaviors There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be monitored for the emergence of suicidal thoughts and behaviors, particularly during the initial months of treatment or during dose changes.

General Precautions

• All patients being treated with antidepressants should be monitored closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of treatment or at times of dose changes.

• Families and caregivers should be alerted to monitor for agitation, irritability, unusual changes in behavior, and the emergence of suicidality, reporting any such symptoms immediately to healthcare providers.

Laboratory Tests Blood pressure should be monitored before initiating treatment and periodically during treatment.

Get Emergency Medical Help Instructions Patients should be instructed to discontinue bupropion hydrochloride and contact a healthcare provider if they experience neuropsychiatric adverse events or if there are changes in behavior or thinking that are not typical for them.

Stop Taking and Call Your Doctor Instructions Patients should discontinue bupropion hydrochloride and consult a healthcare provider if they experience neuropsychiatric adverse events, seizures, or allergic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath).

Side Effects

Patients receiving bupropion hydrochloride may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common Adverse Reactions (incidence ≥5%; ≥2× placebo rate)

• Dry mouth

• Nausea

• Insomnia

• Dizziness

• Pharyngitis

• Abdominal pain

• Agitation

• Anxiety

• Tremor

• Palpitation

• Sweating

• Tinnitus

• Myalgia

• Anorexia

• Urinary frequency

• Rash

• Headache

• Constipation

Serious Adverse Reactions

Warnings

• WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

  • There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be monitored for worsening and emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation

• Serious or clinically significant neuropsychiatric adverse events have been reported, including:

  • Changes in mood (including depression and mania)

  • Psychosis

  • Hallucinations

  • Paranoia

  • Delusions

  • Homicidal ideation

  • Aggression

  • Hostility

  • Anxiety

  • Panic

  • Suicidal ideation

  • Suicide attempt

  • Completed suicide

Seizure Risk

• The risk of seizures is dose-related. It can be minimized by limiting the daily dose to 450 mg and gradually increasing the dose. Discontinue bupropion if a seizure occurs.

Hypertension

• Bupropion hydrochloride can increase blood pressure. Blood pressure should be monitored before initiating treatment and periodically during treatment.

Activation of Mania/Hypomania

• Patients should be screened for bipolar disorder and monitored for symptoms of mania or hypomania.

Angle-Closure Glaucoma

• Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

Overdosage

• Seizures have been reported in approximately one-third of all cases of overdose. Other serious reactions associated with overdoses of bupropion alone include:

  • Hallucinations

  • Loss of consciousness

  • Mental status changes

  • Sinus tachycardia

  • ECG changes (including conduction disturbances or arrhythmias)

  • Clonus

  • Myoclonus

  • Hyperreflexia

  • Fever

  • Muscle rigidity

  • Rhabdomyolysis

  • Hypotension

  • Stupor

  • Coma

  • Respiratory failure

• Deaths associated with overdoses of bupropion alone have been reported, particularly in patients ingesting large doses. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were noted in these cases.

Additional Considerations

• Patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, or those undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs should use bupropion with caution.

• Monoamine Oxidase Inhibitors (MAOIs) should not be used in conjunction with bupropion or within 14 days of stopping treatment with either medication.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate a dose increase of bupropion when coadministered. However, this increase should not exceed the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to increased concentrations of various drugs metabolized by this enzyme. These include antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). When used in conjunction with these medications, a dose reduction of the concomitant drug should be considered.

Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) or sustained-release (SR) formulations to patients taking drugs that lower the seizure threshold, as this may increase the risk of seizures. Additionally, CNS toxicity may occur when bupropion is used with dopaminergic drugs such as levodopa and amantadine.

There is an increased risk of hypertensive reactions when bupropion is used concurrently with monoamine oxidase inhibitors (MAOIs). Therefore, this combination should be avoided.

Bupropion may also decrease plasma levels of digoxin; thus, monitoring of digoxin levels is recommended when these drugs are used together. Furthermore, bupropion can cause false-positive urine test results for amphetamines, which is important to consider in clinical settings.

In terms of pharmacokinetics, bupropion is primarily metabolized by the CYP2B6 isoenzyme, and coadministration with drugs that are substrates or inhibitors of this enzyme may affect its clinical activity. Drugs such as paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, ritonavir, and efavirenz have been shown to inhibit the hydroxylation of bupropion, although clinical studies to evaluate these interactions are limited.

Overall, careful consideration and monitoring are warranted when bupropion is prescribed alongside other medications, particularly those that interact with CYP2B6 and CYP2D6, as well as those that may lower seizure thresholds.

Pediatric Use

Safety and effectiveness of bupropion hydrochloride in the pediatric population have not been established. When considering the use of bupropion hydrochloride extended-release tablets (XL) in children or adolescents, healthcare providers must balance the potential risks with the clinical need.

Antidepressants, including bupropion, have been associated with an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults during short-term trials. It is essential to monitor all patients closely for worsening symptoms and the emergence of suicidal thoughts and behaviors, particularly when initiating antidepressant therapy. Families and caregivers should be advised to observe for signs of agitation, irritability, unusual changes in behavior, and suicidality, and to report any concerning symptoms to healthcare providers immediately.

No suicides occurred in pediatric trials of antidepressants, but pooled analyses of short-term placebo-controlled trials indicate a heightened risk of suicidal thinking and behavior in patients under 18 years of age.

Geriatric Use

In clinical trials involving approximately 6,000 patients treated with bupropion hydrochloride, 275 patients were aged 65 years or older, and 47 were aged 75 years or older. No significant differences in safety or effectiveness were observed between elderly patients and younger subjects. However, clinical experience suggests that some older individuals may exhibit greater sensitivity to the drug.

Bupropion is extensively metabolized in the liver to active metabolites, which are further processed and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, there is an increased risk of adverse reactions in this population, particularly in those with impaired renal function. Therefore, careful consideration should be given to dose selection in elderly patients, and it may be beneficial to monitor renal function during treatment.

Additionally, all patients, including those aged 65 and older, should be closely monitored for any clinical worsening, emergence of suicidal thoughts, or unusual changes in behavior, especially during the initial months of therapy or when doses are adjusted.

Pregnancy

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression during pregnancy.

When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. In contrast, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The study found that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued treatment. Therefore, healthcare providers should consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations.

No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3%, which is similar to the background rate of cardiovascular malformations (approximately 1%).

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow for definitive conclusions regarding a possible association. Similarly, findings on the risk for ventricular septal defect (VSD) are also inconsistent and do not permit conclusions regarding a possible association.

In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats. In rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

Lactation

Data from published literature indicate that bupropion and its metabolites are present in human milk. In a lactation study involving ten women, the average daily infant exposure to bupropion and its active metabolites was estimated to be 2% of the maternal weight-adjusted dose, assuming a daily consumption of 150 mL/kg.

There are no available data regarding the effects of bupropion or its metabolites on milk production. Limited postmarketing reports have not established a clear association between bupropion exposure and adverse reactions in breastfed infants. However, there have been reports of seizures in breastfed infants, although the relationship between these seizures and bupropion exposure remains unclear.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for bupropion. Caution is advised when administering bupropion hydrochloride extended-release tablets to nursing mothers, and a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment may require dosage adjustments when using bupropion hydrochloride. It is recommended that renal function be monitored regularly, particularly prior to initiation and during treatment.

For patients with severe renal impairment, defined as a creatinine clearance of less than 30 mL/min, the use of bupropion is contraindicated. In cases of moderate renal impairment, where creatinine clearance ranges from 30 to 60 mL/min, a reduced dose should be considered to mitigate the risk of accumulation and potential adverse effects.

Additionally, for patients with a glomerular filtration rate (GFR) of less than 90 mL/min, careful consideration should be given to reducing the dose and/or frequency of administration, as bupropion and its metabolites are primarily cleared renally and may accumulate in these patients. Close monitoring for adverse reactions indicative of elevated bupropion or metabolite levels is advised.

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), it is recommended to consider reducing the dose and/or frequency of bupropion administration. For those with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride extended-release tablets should not exceed 150 mg every other day.

In patients with severe hepatic cirrhosis, bupropion should be used with extreme caution due to the potential for significantly increased peak levels and area under the curve (AUC) of the drug, leading to accumulation. In these patients, the dose should not exceed 100 mg once daily or 150 mg every other day, and a reduced frequency and/or dose is required to mitigate the risk of adverse effects.

Regular monitoring of liver function and clinical response is advisable in patients with hepatic impairment receiving bupropion therapy.

Overdosage

Overdoses of bupropion hydrochloride have been reported at doses of 30 grams or more, with seizures occurring in approximately one-third of cases. Serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, and respiratory failure, particularly in instances of multiple drug overdoses. Other symptoms may include sinus tachycardia, ECG changes such as conduction disturbances or arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure.

Deaths related to bupropion overdose have been documented, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest. Although many patients may recover without lasting effects, the potential for severe outcomes necessitates immediate medical attention.

There are no known antidotes for bupropion. In the event of an overdose, it is crucial to provide supportive care, which includes ensuring an adequate airway, oxygenation, and ventilation, as well as monitoring cardiac rhythm and vital signs. Induction of emesis is not recommended. Activated charcoal may be administered if appropriate, but there is no established experience with forced diuresis, dialysis, hemoperfusion, or exchange transfusion in managing bupropion overdoses.

Due to the dose-related risk of seizures, hospitalization following a suspected overdose should be considered. It is advisable to treat seizures with intravenous benzodiazepines and other supportive measures as necessary. Additionally, the possibility of multiple drug involvement should be taken into account. Consulting a Certified Poison Control Center for guidance in overdose situations is recommended; they can be reached at 1-800-222-1222 or through www.poison.org.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice at doses of bupropion hydrochloride up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m² basis); lower doses were not tested. The potential for these lesions to serve as precursors to neoplasms of the liver remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either species.

Bupropion hydrochloride demonstrated a positive response (2 to 3 times the control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, although it was negative in another assay. Additionally, an increase in chromosomal aberrations was reported in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Regarding fertility, a study in rats administered bupropion at doses up to 300 mg/kg/day revealed no evidence of impaired fertility. This included assessments of both male and female rats, with no adverse effects on fertility, reproduction, or the growth and development of offspring observed. However, doses of 200 mg/kg/day or greater were associated with transient ataxia or behavioral changes in adult female rats.

No teratogenic effects were reported in studies conducted in rats and rabbits, where bupropion was administered during the period of organogenesis. In rabbits, slight increases in fetal malformations and skeletal variations were noted at the lowest dose tested (25 mg/kg/day), with decreased fetal weights observed at doses of 50 mg/kg and higher. In rats, no adverse effects on offspring development were observed when administered bupropion at doses up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation.

Overall, the nonclinical toxicology data suggest that while bupropion hydrochloride may induce liver lesions in rats, it does not appear to significantly impair fertility or cause teratogenic effects at the tested doses.

Storage and Handling

Bupropion Hydrochloride is supplied in various forms, including tablets, extended-release tablets, and film-coated tablets. The product is available in multiple packaging configurations, including bottles and blister packs, with child-resistant closures as required.

The recommended storage conditions for Bupropion Hydrochloride are as follows:

• Store at controlled room temperature between 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) see USP Controlled Room Temperature.

• Protect from light and moisture.

• Preserve in well-closed, tight, light-resistant containers.

Specific packaging details include:

• Available in bottles containing 30, 60, 90, and 500 tablets.

• Dispensed in unit dose packaging for institutional use only.

• Blister packs containing 30 tablets.

It is essential to keep the product out of reach of children and ensure that containers are tightly closed to maintain product integrity.