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 reuptake 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. It possesses a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets (XL) USP for oral administration, available in dosages of 150 mg and 300 mg. Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including colloidal silicon dioxide, copovidone, ethyl cellulose, hydroxypropyl cellulose, glyceryl behenate, methacrylic acid copolymer, silicon dioxide, shellac glaze, and iron oxide black. The tablets are marked with edible black ink.

It is noteworthy that the insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is excreted in the feces. Additionally, the FDA-approved dissolution test specifications for this formulation differ from those established by the USP.

Uses and Indications

This drug is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

There are no specific teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily, which may be achieved after a period of 4 days, provided the patient tolerates the initial dose.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a typical target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily. It is recommended to continue this treatment regimen throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in the dose and/or frequency of administration.

In patients with renal impairment, a reduction in the dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in the following situations:

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

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.

The use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated with bupropion hydrochloride extended-release tablets (XL) or within 14 days of discontinuing either treatment. Additionally, bupropion hydrochloride extended-release tablets (XL) should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the components of bupropion hydrochloride extended-release tablets (XL) is a contraindication for use.

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including but not limited to mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Patients should be instructed to discontinue the medication and seek immediate medical advice if they experience any of these adverse events.

The risk of seizures associated with bupropion hydrochloride XL is dose-related. To minimize this risk, it is recommended that the daily dose be limited to 450 mg and that any increases in dosage be made gradually. Should a seizure occur, the medication must be discontinued immediately.

Bupropion hydrochloride XL has the potential to elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

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.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional if such reactions occur.

There is also a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion hydrochloride XL.

A critical warning exists regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Close monitoring for the worsening or emergence of suicidal thoughts and behaviors is essential in these populations.

To ensure patient safety, it is crucial to instruct patients to discontinue bupropion hydrochloride XL and contact a healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs. Regular monitoring of blood pressure is also recommended before and during treatment to mitigate potential risks.

Side Effects

Patients may experience a range of adverse reactions while taking bupropion hydrochloride extended-release tablets (XL). The most common adverse reactions reported include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious warnings associated with bupropion include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation during treatment.

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. Patients experiencing any of these symptoms should be advised to contact a healthcare professional immediately.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised.

Bupropion hydrochloride extended-release tablets (XL) may also lead to increased blood pressure; therefore, blood pressure should be monitored before and periodically during treatment. Additionally, there is a risk of activating mania or hypomania in patients with bipolar disorder, necessitating screening and monitoring for these symptoms.

Patients should be informed about the potential for psychosis and other neuropsychiatric reactions and should seek medical advice if such reactions occur. Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the presence of a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders, nor within 14 days of stopping treatment with either bupropion or an MAOI. Additionally, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue. Known hypersensitivity to bupropion or any of its components is also a contraindication for use.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (XL) with certain drug classes may lead to significant interactions that require careful consideration.

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 to achieve desired clinical exposure. However, any dosage adjustments should not exceed the maximum recommended dose.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6 and may elevate the 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 to mitigate the risk of adverse effects.

Drugs That Lower Seizure Threshold Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) in conjunction with other medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

Dopaminergic Drugs The concurrent use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic drugs such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion hydrochloride extended-release tablets (XL) with MAOIs poses an increased risk of hypertensive reactions. Caution is warranted, and monitoring for hypertensive symptoms should be implemented.

Drug-Laboratory Test Interactions It is important to note that bupropion hydrochloride extended-release tablets (XL) 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 for bupropion hydrochloride extended-release tablets (XL). When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need for treatment.

Geriatric Use

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

No overall differences in safety or effectiveness were observed between elderly patients and younger patients. 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 doses for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

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. A prospective, longitudinal study indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to 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.

Animal studies have shown that 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. Conversely, 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, with decreased fetal weights noted at doses twice the MRHD and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less in these studies.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; however, 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. All pregnancies have a background rate of birth defects, loss, or other adverse outcomes.

Data from an 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. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester 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) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. The United Healthcare database lacked sufficient power to evaluate these associations, while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, but the Slone Epidemiology case-control study did not find an increased risk for LVOTO. Similarly, the Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find an increased risk for any other cardiovascular malformations studied. Limitations in these studies include small numbers of exposed cases, inconsistent findings, and the potential for chance findings from multiple comparisons in case-control studies.

In summary, while data suggest that bupropion does not significantly increase the risk of congenital malformations overall, careful consideration of the risks associated with untreated depression and the potential fetal impacts is essential when managing treatment in pregnant patients.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten 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/kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

There are no data available on the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

The developmental and health benefits of breastfeeding should be considered alongside the mother’s clinical need for Bupropion Hydrochloride Extended-Release Tablets (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

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 are no established dosage adjustments, special monitoring requirements, or precautions outlined 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. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In these cases, seizures occurred in approximately one third of patients. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, alterations in mental status, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Neuromuscular symptoms such as clonus, myoclonus, and hyperreflexia have also been reported.

In situations where bupropion was part of a multiple drug overdose, additional severe reactions such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been observed. While most patients have recovered without lasting effects, there have been fatalities linked to bupropion overdose, 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.

In the event of a bupropion overdose, it is crucial to provide supportive care, which includes close medical supervision and monitoring of the patient. There are no known antidotes for bupropion, and healthcare professionals should consider the possibility of a multiple drug overdose. For up-to-date guidance and advice, it is recommended to consult a Certified Poison Control Center by calling 1-800-222-1222 or visiting www.poison.org.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of 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 of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, indicating a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide in individuals attempting to quit smoking while on bupropion therapy. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they are well-informed about their treatment. It is important to 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 changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly critical to monitor during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may indicate a need for immediate communication with the prescriber or healthcare professional, especially if the symptoms are severe or were not part of the patient's initial presentation. Such symptoms may be associated with 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, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, particularly when attempting to quit smoking while taking bupropion. They should be instructed to discontinue Bupropion Hydrochloride Extended-Release Tablets and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity is essential; patients should be made aware of the symptoms of severe allergic reactions and instructed to discontinue bupropion hydrochloride extended-release tablets if such reactions occur. Additionally, patients must be advised to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare providers should counsel patients regarding the risks associated with excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase the risk of seizures. Patients should be encouraged to minimize or avoid alcohol consumption.

Patients should also be informed that bupropion hydrochloride extended-release tablets can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. They may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure, such as an iridectomy, if indicated.

It is important to educate patients that bupropion hydrochloride extended-release tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that they should not be used in combination with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be advised that bupropion hydrochloride extended-release tablets may impair their ability to perform tasks requiring judgment, motor, and cognitive skills. Until they are certain that the medication does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Finally, patients should be counseled to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets may interact with other drugs, affecting their metabolism.

Storage and Handling

The product is supplied in a well-closed container to protect it from light. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity of the product.

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 Westminster Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)