Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinguished by its chemical structure, which is unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Its chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO•HCl.

The compound appears as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is supplied in the form of film-coated tablets for oral administration, available in dosages of 75 mg (light orange) and 100 mg (light yellow). Each 75 mg tablet contains bupropion hydrochloride USP along with inactive ingredients including microcrystalline cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, titanium dioxide, ethyl cellulose, triacetin, iron oxide yellow, iron oxide red, and FD&C Red No. 40. The 100 mg tablet contains similar inactive ingredients, excluding FD&C Red No. 40.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD).

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The recommended starting dose is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, the dose should be increased gradually. After an initial period of 3 days, the dose may be escalated to 300 mg per day, given as 100 mg three times daily, ensuring that there is an interval of at least 6 hours between doses. The usual target dose is 300 mg per day, maintained as 100 mg three times daily.

The maximum allowable dose is 450 mg per day, which can be administered as 150 mg three times daily. It is essential for healthcare professionals to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

For patients with moderate to severe hepatic impairment, the recommended dose is 75 mg once daily. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or the frequency of administration. Similarly, for patients with renal impairment, a reduction in dose and/or frequency may be warranted.

Contraindications

Use of bupropion hydrochloride tablets is contraindicated in the following situations:

Patients with a seizure disorder are at increased risk of seizures when using bupropion.

Bupropion is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased seizure risk.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated, as it may elevate the risk of seizures.

Bupropion should not be used in conjunction with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders, or within 14 days of discontinuing such treatment. Additionally, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of its components contraindicates the use of bupropion hydrochloride tablets.

Warnings and Precautions

Neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and promptly contact a healthcare provider if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the daily dose to a maximum of 450 mg. If a seizure occurs, bupropion should be discontinued immediately.

Bupropion hydrochloride tablets may elevate blood pressure; therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Patients with a history of bipolar disorder should be screened prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is advised.

There is a potential risk of psychosis and other neuropsychiatric reactions. Patients should be instructed to contact a healthcare professional if they experience such reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

It is crucial to note the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including bupropion. Continuous monitoring for the worsening or emergence of suicidal thoughts and behaviors is necessary.

To ensure patient safety, healthcare providers should instruct patients to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms. Regular monitoring of blood pressure is also recommended before and during treatment.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride tablets. The most common adverse reactions reported include agitation, dry mouth, constipation, headache or migraine, nausea or vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbances.

Serious adverse reactions warrant particular attention. A boxed warning highlights the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, necessitating careful monitoring for the emergence or worsening of these symptoms. Neuropsychiatric adverse events have been observed during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. Discontinuation of treatment is advised if a seizure occurs. Additionally, bupropion hydrochloride tablets can elevate blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been reported, emphasizing the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Bupropion hydrochloride tablets should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI. Known hypersensitivity to bupropion or its ingredients is also a contraindication.

In cases of overdose, seizures were reported in approximately one-third of all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, ECG changes (such as conduction disturbances and arrhythmias), fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of bupropion with certain drug classes may lead to significant interactions that require careful consideration and monitoring.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, an increase in bupropion dosage may be necessary based on clinical response. However, the dosage should not exceed the maximum recommended limit.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6, which can lead to elevated plasma concentrations of drugs metabolized by this enzyme. This includes various 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). A dose reduction of these concomitant medications should be considered.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely when these medications are used together.

Drugs Lowering Seizure Threshold Caution is advised when prescribing bupropion hydrochloride tablets in conjunction with drugs that lower the seizure threshold, as this combination may increase the risk of seizures.

Dopaminergic Drugs Concomitant use of bupropion with dopaminergic medications such as levodopa and amantadine may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The use of bupropion alongside MAOIs can heighten the risk of hypertensive reactions. Close monitoring is warranted in such cases.

Drug-Laboratory Test Interactions Bupropion hydrochloride tablets may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for further information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 subjects, of which 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred subjects aged 65 years and older participated in trials using the immediate-release formulation of bupropion for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses, it is important to note that greater sensitivity in some older individuals cannot be ruled out.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies indicate that bupropion is classified as Pregnancy Category C. The risk summary suggests that exposure to bupropion during the first trimester does not appear to increase the overall risk of congenital malformations. It is important to note that all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. In reproductive developmental studies conducted in rats and rabbits, no clear evidence of teratogenic activity was observed; however, rabbits exhibited slightly increased incidences of fetal malformations and skeletal variations at doses approximately equal to the maximum recommended human dose (MRHD) and greater. Additionally, decreased fetal weights were noted at doses twice the MRHD and higher. Therefore, bupropion hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical considerations must include the risks associated with untreated depression when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum. Human data from the international bupropion Pregnancy Registry, which included 675 first-trimester exposures, and a retrospective cohort study utilizing the United Healthcare database with 1,213 first-trimester exposures, did not demonstrate an increased risk for malformations overall. Specifically, no increased risk for cardiovascular malformations was observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% in the Pregnancy Registry, comparable to the background rate of approximately 1%.

Inconsistent findings have been reported regarding the association between bupropion exposure during the first trimester and specific cardiovascular malformations, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). The United Healthcare database lacked sufficient power to evaluate the association with LVOTO, while the National Birth Defects Prevention Study (NBDPS) identified an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. For VSD, the Slone Epidemiology Study reported an increased risk following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5), while the NBDPS and United Healthcare database studies did not find an association. The limitations of these studies, including small sample sizes and inconsistent findings, should be considered when interpreting these results.

Animal studies have shown that bupropion, administered orally during the organogenesis period in rats and rabbits at doses up to 450 mg and 150 mg per kg per day, respectively, did not provide clear evidence of teratogenicity. However, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at the lowest tested dose (25 mg per kg per day, approximately equal to the MRHD on a mg per m² basis) and higher doses. Decreased fetal weights were observed at doses of 50 mg per kg and above. In rats, administration of bupropion at doses up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m² basis) prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

Lactation

Bupropion and its metabolites are present in human milk. In a lactation study involving 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL per kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

Exercise caution when administering bupropion hydrochloride tablets to lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there is no information available regarding dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population.

Overdosage

Overdoses of bupropion have been documented at doses of 30 grams or more, with significant clinical implications. In approximately one-third of these cases, seizures were reported, highlighting the potential for serious neurological effects. Other severe reactions associated with bupropion overdose include hallucinations, loss of consciousness, and cardiovascular disturbances such as sinus tachycardia and ECG changes, which may manifest as conduction disturbances, including QRS prolongation or arrhythmias.

In instances where bupropion was involved in multiple drug overdoses, additional severe symptoms have been observed. These include fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. While many patients have recovered without lasting effects, it is important to note that fatalities have been associated with bupropion overdoses, particularly in cases involving large doses. Reports indicate that patients who succumbed to overdose experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Healthcare professionals should be vigilant in monitoring patients for these symptoms following a suspected overdose. Immediate medical intervention is critical, and supportive care should be initiated as necessary. Continuous cardiac monitoring and seizure management may be required, along with symptomatic treatment for any additional complications that arise.

Nonclinical Toxicology

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

In terms of mutagenicity, bupropion elicited a positive response in the Ames bacterial mutagenicity assay, demonstrating a mutation rate that was 2 to 3 times higher than the control in 2 out of 5 strains tested. Additionally, an increase in chromosomal aberrations was reported in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg per kg per day indicated no evidence of impaired fertility. No information is available regarding teratogenic effects or additional animal pharmacology and toxicology data.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and homicidal ideation while using bupropion. Additional symptoms noted include aggression, hostility, agitation, anxiety, and panic. Instances of suicidal ideation and suicide have also been documented in patients attempting to quit smoking during treatment with bupropion. It is advised that patients discontinue bupropion and consult a healthcare professional if they encounter any of these symptoms.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with treatment using bupropion hydrochloride tablets. It is essential to inform patients, their families, and caregivers about the appropriate use of this medication and to assist them in comprehending the contents of the Medication Guide, which includes critical information regarding antidepressant medicines, depression, serious mental illnesses, and the potential for suicidal thoughts or actions.

Patients should be encouraged to discuss the Medication Guide's contents and to ask any questions they may have. Providers should instruct patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual behavioral changes, as well as worsening depression and suicidal ideation, particularly during the initial stages of treatment or when adjusting the dosage. Families and caregivers should monitor for these symptoms on a daily basis, as changes can occur abruptly. Any severe or sudden onset of these symptoms should be reported to the patient's prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal ideation when attempting to quit smoking while taking bupropion. They should be instructed to discontinue bupropion and contact a healthcare professional if they experience such symptoms.

Education on hypersensitivity symptoms is crucial, and patients should discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, patients must be advised to stop taking bupropion if they experience a seizure during treatment, as well as to avoid excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, which can increase the risk of seizures. Patients should minimize or avoid alcohol consumption.

It is important to inform patients that bupropion hydrochloride tablets may cause mild pupillary dilation, which can lead to angle-closure glaucoma in susceptible individuals. Patients should also be made aware that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in conjunction with ZYBAN or any other medications containing bupropion.

Healthcare providers should counsel patients that bupropion hydrochloride tablets, being a CNS-active drug, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until patients are confident that the medication does not adversely affect their performance, they should refrain from driving or operating complex machinery. Lastly, patients should be encouraged to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride tablets and other drugs.

Storage and Handling

The product is supplied in packaging that ensures its integrity and stability. It should be stored at a temperature range of 15° to 25°C (59° to 77°F). It is essential to protect the product from light and moisture to maintain its efficacy and safety. Proper handling and storage conditions are critical to preserving the quality of the product throughout its shelf life.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bupropion Hydrochloride as submitted by Alembic Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)