Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.2, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride tablets USP are supplied for oral administration as 75 mg (light orange) and 100 mg (light yellow) film-coated tablets. Each 75 mg tablet contains microcrystalline cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, titanium dioxide, ethyl cellulose, triacetin, iron oxide yellow, and iron oxide red. Each 100 mg tablet contains microcrystalline cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, titanium dioxide, ethyl cellulose, triacetin, and iron oxide yellow.

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 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, 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 seizures.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

• Co-administration with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride tablets should not be used in conjunction with MAOIs or within 14 days of discontinuing either treatment. Additionally, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the other components of bupropion hydrochloride tablets.

Warnings and Precautions

Patients undergoing smoking cessation with bupropion should be closely monitored for neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including 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 for these symptoms and instruct them to discontinue bupropion and seek immediate medical attention if such adverse events arise.

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 maximum daily dose to 450 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride tablets have 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 they experience any such reactions.

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

There is a significant warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including bupropion. Continuous monitoring for the emergence or worsening of suicidal thoughts and behaviors is essential.

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

Side Effects

Patients may experience a range of adverse reactions while taking 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.

A significant warning associated with bupropion is the 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, anxiety, panic, and suicidal ideation. These events necessitate immediate communication with a healthcare professional if they occur.

The risk of seizures is dose-related, and it is recommended to gradually increase the dosage while limiting the daily dose to 450 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride tablets can elevate blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. There is also a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the contraindications for patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping such treatment. Furthermore, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

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

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion based on clinical response. However, the dosage should not exceed the maximum recommended limit.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). It is advisable to consider a dose reduction of these medications when used concurrently with bupropion.

Additionally, bupropion may reduce plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy.

Caution is warranted when bupropion is used alongside drugs that may lower the seizure threshold, as this combination could increase the risk of seizures.

The concomitant use of bupropion with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring of patients.

There is an increased risk of hypertensive reactions when bupropion is used in conjunction with monoamine oxidase inhibitors (MAOIs).

Lastly, it is important to note that bupropion can cause false-positive results in urine tests for amphetamines, which may lead to misinterpretation of drug screening results.

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 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 with the immediate-release formulation of bupropion.

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

There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any 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 https://womensmentalhealth.org/research/pregnancyregistry/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 during pregnancy. Animal studies indicate 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 higher.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. 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 during pregnancy at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their antidepressant treatment. Therefore, it is important to 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 with 1,213 first trimester exposures did not show an increased risk for malformations overall. Although the Registry was not designed or powered to evaluate specific defects, it 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% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of approximately 1%. However, 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 a possible association.

In summary, while bupropion exposure during the first trimester does not appear to significantly increase the risk of congenital malformations based on available human data, careful consideration of the risks associated with untreated maternal depression is essential.

Lactation

Data from published literature report the presence of bupropion and its metabolites 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/kg, to bupropion and its active metabolites 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 considered alongside the mother's clinical need for bupropion hydrochloride and any potential adverse effects on the breastfed child from bupropion hydrochloride or from the underlying maternal condition.

Renal Impairment

There is no information available regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as specific guidelines or recommendations are not provided.

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 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

In cases of bupropion overdose, significant clinical manifestations can occur, necessitating immediate medical intervention. Reports indicate that overdoses of 30 grams or more have been documented, with seizures occurring in approximately one-third of these instances.

Clinical Symptoms Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as conduction disturbances. Additional symptoms reported include sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Notably, fatalities have been linked to bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac failure often preceding death.

Management Recommendations There are currently no known antidotes for bupropion; therefore, supportive care and close medical supervision are critical in managing overdose cases. In the event of an overdose, it is essential to ensure an adequate airway, oxygenation, and ventilation, while continuously monitoring cardiac rhythm and vital signs. The induction of emesis is not recommended due to the potential for further complications.

Healthcare professionals are advised to consult a Certified Poison Control Center for guidance in managing bupropion overdose cases. Prompt and appropriate medical intervention is vital to mitigate the risks associated with overdose and to provide the best possible outcomes for affected patients.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered at doses up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 6 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 6 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. 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 the Ames bacterial mutagenicity assay, with a mutation rate 2 to 3 times higher than control in 2 of 5 strains tested. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

In terms of reproductive toxicity, no adverse effects on male and female fertility were observed when rats received oral doses of bupropion up to 300 mg/kg/day, approximately 6 times the MRHD on a mg/m² basis. This treatment was administered to females prior to mating and continued either through Day 13 of gestation or through lactation, while males were treated for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately 4 times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects on fertility, reproduction, or the growth and development of male or female offspring.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. These symptoms have been observed in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication. The incidence of these symptoms appears to be higher in individuals with a prior history of mental health disorders compared to those without such a history.

Patients experiencing a seizure while taking bupropion hydrochloride tablets are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride tablets is contraindicated in individuals who have had a seizure.

Severe hypertension has been reported in some patients taking bupropion hydrochloride tablets, with an increased risk noted in those concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been reported by some patients during treatment with bupropion hydrochloride tablets. Affected individuals are encouraged to contact their healthcare provider if these symptoms occur.

Severe allergic reactions have also been documented, with symptoms that may include rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

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 may occur, particularly during the initial stages of antidepressant treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can be significant. Any severe or sudden onset of such symptoms should be reported to the patient’s prescriber or healthcare professional promptly.

Patients should be educated about the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride tablets immediately if they experience a severe allergic reaction. Additionally, patients must be informed that if they experience a seizure while on treatment, they should discontinue and not restart bupropion hydrochloride tablets.

It is crucial to advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should minimize or avoid alcohol consumption. Patients should also be made aware that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be informed that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these tablets 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 that require 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.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride tablets may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Instruct patients to store bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), keeping them dry and protected from light. Patients should take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, ensuring that doses are separated by at least 6 hours to minimize the risk of seizure. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next tablet at the regular time due to the dose-related risk of seizure.

Finally, patients should be instructed to swallow bupropion hydrochloride tablets whole, without crushing, dividing, or chewing them, and they can take the tablets with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at room temperature, ideally between 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15°C and 30°C (59°F and 86°F) in accordance with USP Controlled Room Temperature guidelines.

To ensure product integrity, it is essential to protect the product from light and moisture during storage. Proper handling and storage conditions are critical to maintaining the quality and efficacy of the product.

Additional Clinical Information

The maximum recommended dose of bupropion hydrochloride tablets is 450 mg per day, administered as 150 mg three times daily, with a gradual titration to minimize the risk of seizure. Clinicians should counsel patients and caregivers to discontinue the medication 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. Patients should also be advised to report any neuropsychiatric symptoms such as delusions, hallucinations, or confusion, and to stop the medication if they experience allergic reactions, including skin rash or difficulty breathing.

Postmarketing surveillance has identified serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. Additionally, rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)