Bupropion hydrochloride

Description

Bupropion hydrochloride, USP, is an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its chemical structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2, with 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 extended-release tablets, USP (XL), are formulated for oral administration in dosages of 150 mg and 300 mg, presented as white to off-white extended-release tablets. Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including hydroxyl propyl methyl cellulose, microcrystalline cellulose, povidone, citric acid monohydrate, colloidal silicon dioxide, magnesium stearate, methacrylic acid copolymer, talc, titanium dioxide, colloidal anhydrous silica, sodium bicarbonate, sodium lauryl sulfate, and triethyl citrate. The formulation meets the USP Dissolution Test 18.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) 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 teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The dosage of the medication should be increased gradually to minimize the risk of seizures. Healthcare professionals are advised 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, with the option to increase the dose to 300 mg after 4 days if clinically indicated.

In the case of Seasonal Affective Disorder, treatment should be initiated in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a usual target dose of 300 mg once daily. After one week, the dose may be increased to 300 mg once daily, and treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe hepatic impairment should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of dosing.

In patients with renal impairment, it is recommended to consider a reduction in the dose and/or frequency of dosing based on the severity of the impairment.

Contraindications

Use of bupropion is contraindicated in the following situations:

• Patients with a seizure disorder, due to the increased risk of seizures.

• Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of adverse effects.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may precipitate seizures.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion. Additionally, bupropion should not be started in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the components of bupropion hydrochloride extended-release tablets (XL).

Warnings and Precautions

Increased risk of suicidal thinking and behavior has been observed in children, adolescents, and young adults taking antidepressants. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated serious or clinically significant neuropsychiatric adverse events associated with smoking cessation using bupropion. These events may include 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. Patients attempting to quit smoking should be observed for these symptoms, and they must be instructed to discontinue bupropion hydrochloride extended-release tablets and contact a healthcare provider if any of these adverse events occur.

Seizure Risk The risk of seizures is dose-related. 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, the medication should be discontinued immediately.

Hypertension Bupropion has the potential to increase blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

General Precautions Blood pressure should be monitored before starting treatment and periodically during the course of therapy. Additionally, screening for bipolar disorder and monitoring for symptoms of mania or hypomania is recommended.

Emergency Medical Help Instructions Patients must be advised to discontinue bupropion hydrochloride extended-release tablets and seek immediate medical attention if they experience any neuropsychiatric adverse events.

Stop Taking and Call Your Doctor Instructions Patients should discontinue the medication if a seizure occurs and should contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Side Effects

Patients may experience a range of adverse reactions while using this medication. Common adverse reactions include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions warrant particular attention. There is a WARNING: SUICIDAL THOUGHTS AND BEHAVIORS, indicating an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported during smoking cessation, including changes in mood (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 instructed to contact a healthcare professional immediately.

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

Activation of mania or hypomania has been observed, particularly in patients with a history of bipolar disorder, who should be screened and monitored for these symptoms. Angle-closure glaucoma has also been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion or within 14 days of stopping treatment with bupropion is contraindicated. Furthermore, bupropion should not be initiated in patients currently being treated with linezolid or intravenous methylene blue.

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

Drug Interactions

Coadministration of bupropion with certain drug classes may necessitate careful monitoring and potential dosage adjustments due to significant interactions.

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 required to maintain clinical efficacy. However, any dosage increase 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 Bupropion should be used with caution in patients taking other medications that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs Concomitant use of bupropion with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is advised.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion with MAOIs poses an increased risk of hypertensive reactions. Caution is warranted when these agents are used together.

Drug-Laboratory Test Interactions Bupropion may interfere with urine drug screening tests, potentially resulting in false-positive results for amphetamines. This should be considered when interpreting test results in patients receiving bupropion therapy.

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. When considering the use of bupropion in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need.

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 clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects in these studies. However, while clinical experience has not identified significant differences in responses between these age groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

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

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 hydrochloride extended release tablets during the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. In a prospective, longitudinal study, women with a history of major depressive disorder 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 hydrochloride extended release tablets were 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.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown. 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. Data from the international bupropion hydrochloride extended release tablets Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures, did not show an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall has been observed. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion hydrochloride extended release tablets in the first trimester was 1.3%, which is similar to the background rate of 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. 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 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, was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding 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 weighed against the mother's clinical need for bupropion hydrochloride extended-release tablets, USP (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 the patients, highlighting a significant risk associated with excessive intake.

Serious adverse reactions have been observed in individuals who overdosed on bupropion alone. These reactions include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances or arrhythmias. Additionally, when bupropion was part of multiple drug overdoses, symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure were reported.

While the majority of patients have recovered without lasting effects, there have been fatalities linked to overdoses of bupropion alone, particularly in those who ingested large quantities. In these severe cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

Healthcare professionals are advised to monitor patients closely for these symptoms and to initiate appropriate management procedures in the event of an overdose. Immediate medical intervention is crucial to address the potential complications associated with bupropion overdose.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with 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, which is approximately 2 to 7 times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. In contrast, 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 one of three 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 attempts 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, which contains essential information regarding the use of bupropion hydrochloride extended-release tablets (XL). It is important to inform patients, their families, and caregivers about the benefits and risks associated with this treatment and to counsel them on its appropriate use.

Patients should be instructed to read the Medication Guide thoroughly and healthcare providers should assist them in understanding its contents. Patients should be encouraged to discuss the information within the Medication Guide and to ask any questions they may have.

Healthcare providers should alert patients to the potential emergence of 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, particularly during the initial stages of treatment or when the dosage is adjusted. Families and caregivers should be advised to monitor patients closely 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 possible medication adjustments.

Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal ideation when attempting to quit smoking while taking bupropion. If patients experience such symptoms, they should discontinue bupropion hydrochloride extended-release tablets and contact a healthcare professional immediately.

Healthcare providers should educate patients about the signs of hypersensitivity and instruct them to discontinue bupropion if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking bupropion if they experience a seizure during treatment. It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

Patients should be made aware that bupropion 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 if necessary.

Healthcare providers should inform patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride.

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

Finally, healthcare providers should counsel patients to notify them if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs, affecting their metabolism.

Storage and Handling

Bupropion HCl extended-release tablets are supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It is essential to store the tablets at a controlled room temperature of 20° to 25°C (68°F to 77°F) to maintain their efficacy and stability. Proper storage conditions are crucial to ensure the integrity of the product throughout its shelf life.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets and seek immediate medical attention if they observe any signs of agitation, depressed mood, or atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients receiving antidepressants for major depressive disorder or other indications must be vigilant in monitoring for the emergence of agitation, irritability, and other concerning symptoms, reporting any such changes to healthcare providers promptly.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been documented, presenting with symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare reports of severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome, as well as symptoms indicative of delayed hypersensitivity, have also been associated with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)