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, and triacetin.

Uses and Indications

Bupropion hydrochloride tablets USP 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 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 either 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

Patients undergoing treatment with bupropion should be closely monitored for a range of potential neuropsychiatric adverse events associated with smoking cessation. 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, and panic. Additionally, there have been reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers 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 is dose-related; therefore, it is essential to minimize this risk by gradually increasing the dosage and limiting 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. It is recommended that blood pressure be monitored prior to initiating treatment and periodically throughout the course of therapy to ensure patient safety.

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 also a risk of psychosis and other neuropsychiatric reactions. Patients should be instructed to contact a healthcare professional if they experience such reactions during treatment.

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

A critical warning pertains to the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the worsening or emergence of suicidal thoughts and behaviors is essential.

To ensure safe use of bupropion, healthcare providers should implement the following laboratory tests: monitor blood pressure before initiating treatment and periodically during treatment.

Instruct patients to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms.

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.

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 or emergence of suicidal thoughts and behaviors during treatment.

Neuropsychiatric adverse events have been observed 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.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride tablets may increase 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. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is essential.

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 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. Furthermore, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue. 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, 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. 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

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate dose increases of the affected medication based on clinical response. However, these increases should not exceed the maximum recommended dose.

Bupropion is known to inhibit CYP2D6, which can lead to elevated concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone).

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

Caution is advised when prescribing bupropion hydrochloride tablets alongside medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

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

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

Lastly, it is important to note that bupropion hydrochloride tablets can lead to false-positive results in urine drug tests for amphetamines, which should be considered when interpreting test 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 additional 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.

Clinical considerations suggest that women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue treatment. Therefore, it is essential 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.

Human 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 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%, 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 data, careful consideration of the risks associated with untreated maternal depression is warranted.

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 weighed against 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 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, with instances involving doses of 30 grams or more. In approximately one-third of these cases, seizures have been reported. Healthcare professionals should be aware of the serious reactions that can arise from bupropion overdose, which may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as QRS prolongation.

Additional symptoms associated with bupropion overdose encompass sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. It is important to note that fatalities have been linked to bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac events often preceding death.

Currently, there are 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 also monitoring cardiac rhythm and vital signs closely.

Induction of emesis is not recommended for patients experiencing bupropion overdose. Healthcare providers should consult a Certified Poison Control Center for further guidance and management strategies in such situations.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day, which is approximately six times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male and female fertility in rats. This treatment was given 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 four 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 noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately six and two times the MRHD on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, approximately two to six 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, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, yielding a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies. No specific details were provided regarding animal pharmacology and toxicology in the available data.

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. Additionally, suicidal ideation and suicide attempts have been noted in individuals attempting to quit smoking while taking bupropion.

Reports indicate that new or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have occurred in some individuals using bupropion for smoking cessation. These symptoms appear to be more prevalent in patients with a prior history of mental health disorders compared to those without such a history.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been documented in patients taking bupropion hydrochloride tablets. In the event of a seizure while on this medication, patients are advised to discontinue use and contact their healthcare provider immediately.

Severe allergic reactions to bupropion hydrochloride tablets have been reported, which may include symptoms such as rash, itching, hives, fever, swollen lymph glands, 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 (Medication Guide) thoroughly. It is important to instruct patients, their families, and/or caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), 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 patients on a daily basis for any abrupt changes in behavior, as these may occur suddenly. Any severe, abrupt, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. Patients must be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Healthcare providers should inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should be advised to minimize or avoid alcohol consumption.

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

Patients should be counseled that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks that require judgment or motor and cognitive skills. They should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride tablets may interact with other drugs.

Patients must also inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with bupropion hydrochloride tablets.

In terms of storage, patients should be instructed to keep bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), ensuring that the tablets remain dry and protected from light.

Patients should take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, with doses 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. Furthermore, patients should be instructed that bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed, and that they can be taken 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 within the range of 15°C to 30°C (59°F to 86°F).

To ensure product integrity, it is essential to protect the product from light and moisture during storage and handling.

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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)