Bupropion hydrochloride

Description

Bupropion hydrochloride, USP is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.20, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride appears as a white powder and is soluble in water, 0.1 N Hydrochloric acid, and in alcohol.

Bupropion hydrochloride extended-release tablets USP (SR) are supplied for oral administration in strengths of 100 mg (red), 150 mg (green), and 200 mg (yellow). These are film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride USP along with inactive ingredients, which include colloidal silicon dioxide, diluted hydrochloric acid, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium stearyl fumarate, titanium dioxide, and edible black ink. The 100 mg tablet contains FD&C Red #40, the 150 mg tablet contains FD&C Blue #1 and D&C Yellow #10 Lake, and the 200 mg tablet contains D&C Yellow #10 Lake.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) 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 150 mg per day. To minimize the risk of seizures, the dose should be increased gradually. After an initial period of 3 days, the dose may be increased to 300 mg per day, administered as 150 mg twice daily, with an interval of at least 8 hours between doses. The usual target dose is 300 mg per day, maintained as 150 mg twice daily.

For patients who do not respond adequately to the 300 mg per day regimen, the maximum dose may be increased to 400 mg per day, given as 200 mg twice daily. It is essential to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, in patients with renal impairment, it is advisable to consider a reduction in dose and/or frequency of dosing based on individual patient needs.

Contraindications

Use of bupropion hydrochloride extended-release tablets (SR) 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 may precipitate seizures; therefore, bupropion should not be used in these circumstances.

The use of Monoamine Oxidase Inhibitors (MAOIs) is contraindicated in conjunction with bupropion hydrochloride extended-release tablets (SR) or within 14 days of discontinuing either treatment. This includes patients currently receiving linezolid or intravenous methylene blue.

Patients with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR) should not use this medication.

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 these patients for the emergence of such symptoms and instruct them to discontinue bupropion and seek immediate medical attention if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the daily dose to a maximum of 400 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) have been shown to potentially increase 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 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS associated with the use of antidepressants, including bupropion, particularly in children, adolescents, and young adults. Increased risk of suicidal thinking and behavior necessitates careful monitoring for any worsening or emergence of suicidal thoughts and behaviors in these populations.

To ensure patient safety, it is crucial to monitor blood pressure before starting treatment and periodically during therapy. Patients should be instructed to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events or if psychosis and other neuropsychiatric reactions occur.

Side Effects

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

Serious adverse reactions warranting caution include an increased risk of suicidal thoughts and behaviors, particularly 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 may also occur, 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.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride extended-release tablets (SR) can lead to increased blood pressure, necessitating monitoring of blood pressure before and during treatment.

Activation of mania or hypomania has been observed, particularly in patients with a history of bipolar disorder, and such patients should be screened and monitored for these symptoms. Patients are also advised to contact a healthcare professional if they experience any psychotic or other neuropsychiatric reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride extended-release tablets (SR) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either medication.

In cases of overdose, seizures have been reported in approximately one-third of cases, along with other serious reactions such as hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation), arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with overdoses of bupropion alone have been documented, 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, without exceeding the maximum recommended dose.

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). A dose reduction of these medications should be considered to mitigate potential adverse effects.

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 co-administered with drugs that lower the seizure threshold, as this may 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), and this combination should be approached with caution.

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. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

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 using the immediate-release formulation of bupropion for depression.

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

Data from epidemiological studies of pregnant women exposed to bupropion 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 during pregnancy. In animal studies, bupropion administered to pregnant rats during organogenesis showed no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, when administered 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 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. A prospective longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those 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 of untreated depression and potential effects on the fetus when making decisions about discontinuing or changing 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 overall increased risk for malformations. However, the Registry suggested a possible increase in cardiac malformations, with a prospectively observed rate of 1.3% for cardiovascular malformations in pregnancies exposed to bupropion during the first trimester, 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) are inconsistent, with some studies indicating an increased risk while others do not. The United Healthcare database lacked sufficient power to evaluate this association, while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO. Similarly, findings on the risk for ventricular septal defect (VSD) are inconsistent, with one study indicating an increased risk following first trimester exposure to bupropion, while other studies did not find increased risk for other cardiovascular malformations.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during organogenesis at doses of up to 450 mg/kg/day and 150 mg/kg/day, respectively. No fetal malformations were observed in rats, while rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose and greater. Decreased fetal weights were noted at doses of 50 mg/kg/day and higher, with no maternal toxicity evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered to pregnant rats at doses up to 150 mg/kg/day from embryonic implantation through lactation had no adverse effects on pup growth or development.

Healthcare providers are encouraged to register patients exposed to any antidepressants during pregnancy in the independent pregnancy exposure registry by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

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, 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 (SR) 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 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 can occur with significant clinical consequences. Reports indicate that overdoses of 30 grams or more have been documented, with seizures occurring in approximately one-third of these cases.

Clinical Manifestations 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 in cases of 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.

Management of Overdose 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, healthcare professionals should ensure that the patient has an adequate airway, oxygenation, and ventilation. Continuous monitoring of cardiac rhythm and vital signs is essential.

For further guidance in managing a bupropion overdose, it is recommended to consult a Certified Poison Control Center. This resource can provide valuable assistance in the assessment and management of the overdose situation.

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 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. 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 the 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 or female fertility were observed when rats were administered oral doses of bupropion up to 300 mg/kg/day, which is approximately 7 times the MRHD on a mg/m² basis. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males received the treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately 5 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. Additionally, suicidal ideation and suicide attempts have 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 in some individuals using bupropion for smoking cessation. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported among patients taking bupropion hydrochloride extended-release tablets (SR).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have been observed, with signs including 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.

The potential for seizures (convulsions) exists with bupropion hydrochloride extended-release tablets (SR), particularly in individuals with certain medical conditions or those taking specific medications. The risk of seizures may increase with higher doses of the medication.

Instances of high blood pressure, which can be severe, have been reported in some patients taking bupropion hydrochloride extended-release tablets (SR). The likelihood of developing high blood pressure may be elevated in individuals concurrently using nicotine replacement therapy for smoking cessation.

Some patients have experienced episodes of mania while on bupropion hydrochloride extended-release tablets (SR), characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech.

Visual disturbances, including eye pain, changes in vision, and swelling or redness in or around the eye, have also been reported.

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 early in the course 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 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, panic, and 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 extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients should be instructed to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare providers should counsel patients on 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 advised to minimize or avoid alcohol consumption.

During the initial titration phase, as the dose is increased above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures. Patients should also be made aware that taking bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

It is important to inform patients that bupropion hydrochloride extended-release tablets (SR) 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 bupropion-containing products.

Patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), 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 interactions may affect drug metabolism.

Patients must also inform their healthcare provider if they become pregnant or plan to become pregnant while on bupropion hydrochloride extended-release tablets (SR).

Storage instructions should be provided, advising patients to keep the tablets at room temperature, between 68° and 77°F (20° to 25°C), and to keep them dry and protected from light. Patients should be instructed to swallow the tablets whole, without chewing, dividing, or crushing them, to ensure the proper release rate of the medication. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next dose at the regular scheduled time, due to the dose-related risk of seizure.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. 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° to 30°C (59° 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

Families and caregivers of patients treated with antidepressants for major depressive disorder (MDD) or other indications should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop.

Additionally, patients should contact healthcare professionals if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion. In the event of an allergic reaction, characterized by symptoms like skin rash or shortness of breath, patients must stop the medication and consult a healthcare provider. Postmarketing reports indicate that serious neuropsychiatric adverse events, including mood changes and suicidal ideation, have occurred in patients using bupropion for smoking cessation. While many cases resolved after discontinuation, some patients required ongoing monitoring and supportive care until symptoms subsided.

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)