Bupropion hydrochloride

Description

Bupropion Hydrochloride Tablets, USP, are classified as an antidepressant within the aminoketone class and are chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The chemical structure of bupropion hydrochloride 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 active pharmaceutical ingredient appears as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and inducing a sensation of local anesthesia on the oral mucosa.

Each tablet intended for oral administration contains either 75 mg or 100 mg of bupropion hydrochloride. The 75 mg tablet includes the following inactive ingredients: D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triacetin. The 100 mg tablet contains FD&C Red No. 40 Aluminum Lake along with hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triacetin.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD).

Limitations of Use: The available data does not indicate any teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride.

Dosage and Administration

The recommended starting dose for the medication is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, it is advised to increase the dose 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 important 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 the frequency of administration. Additionally, for patients with renal impairment, a reduction in dose and/or frequency may also 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.

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

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

Warnings and Precautions

Neuropsychiatric adverse events have been reported during smoking cessation treatment with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. Healthcare professionals should closely 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 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. If a seizure occurs, bupropion should be discontinued immediately.

Bupropion hydrochloride tablets may elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

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.

Psychosis and other neuropsychiatric reactions may occur; patients should be instructed to contact a healthcare professional if they experience such reactions.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

In summary, healthcare professionals should ensure that patients are monitored for the emergence of neuropsychiatric symptoms and suicidal thoughts. Blood pressure should be assessed before and during treatment to manage potential hypertension effectively. Patients should be advised to discontinue bupropion and seek immediate medical assistance if they experience any concerning neuropsychiatric events or symptoms.

Side Effects

Patients may experience a range of adverse reactions while using 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 adverse reactions warrant particular attention. A WARNING regarding the increased risk of suicidal thoughts and behaviors has been established, 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 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 can 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. Known hypersensitivity to bupropion or any of 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 (such as 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

Coadministration of bupropion with certain drug classes may lead to significant interactions that require careful consideration of dosage adjustments and monitoring.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, an increase in bupropion dosage may be necessary based on clinical response. However, the dosage should not exceed the maximum recommended limit.

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 medications should be considered when used concurrently with bupropion.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely in patients receiving this combination.

Drugs Lowering Seizure Threshold Caution is warranted when prescribing bupropion in conjunction with other medications that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs The 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 recommended.

Monoamine Oxidase Inhibitors (MAOIs) The use of bupropion in combination with MAOIs can heighten the risk of hypertensive reactions. Close monitoring is advised when these agents are used together.

Drug-Laboratory Test Interactions Bupropion hydrochloride tablets may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Therefore, caution is advised when considering the use of this medication in children, infants, and adolescents. Further studies are necessary to determine appropriate dosing and potential outcomes in these age groups.

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 some older individuals may exhibit greater sensitivity to the medication.

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 inherent risks to the mother associated with untreated depression during pregnancy. In animal studies, bupropion administered to pregnant rats during organogenesis did not show evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, when administered to pregnant rabbits during the same period, 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 general population is not well defined for the indicated population. However, it is acknowledged that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes, with the estimated background risk of major birth defects in clinically recognized pregnancies ranging from 2% to 4%, and the risk of miscarriage between 15% and 20%.

Clinical considerations indicate that a prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder revealed that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication. Therefore, healthcare providers should weigh the risks of untreated depression against the potential effects on the fetus when considering changes to antidepressant treatment 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 demonstrate an overall increased risk for malformations. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. The observed rate of cardiovascular malformations in pregnancies with first trimester exposure to bupropion was 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and specific cardiovascular defects, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), limit definitive conclusions. While the National Birth Defects Prevention Study (NBDPS) indicated an increased risk for LVOTO, the Slone Epidemiology case-control study did not find a similar association. For VSD, the Slone Epidemiology Study reported an increased risk, while other studies did not find a significant association. These findings are constrained by the small number of exposed cases and the potential for chance findings due to multiple comparisons.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during organogenesis at doses 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 doses starting from the lowest tested dose. 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. Additionally, a pre- and postnatal development study in pregnant rats showed no adverse effects on pup growth or development when bupropion was administered at doses up to 150 mg/kg/day from embryonic implantation through lactation.

Healthcare providers are encouraged to register patients exposed to any antidepressants during pregnancy in the independent pregnancy exposure registry by contacting 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. The relationship between bupropion exposure and these seizures remains unclear.

When considering the use of bupropion hydrochloride tablets in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for the medication and any potential adverse effects on the breastfed child from bupropion hydrochloride tablets or from the underlying maternal condition.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 approximately one-third of these cases, seizures were reported as a significant adverse effect. Other serious reactions associated with bupropion overdoses include hallucinations, loss of consciousness, alterations in mental status, and cardiovascular disturbances such as sinus tachycardia and ECG changes, which may manifest as conduction disturbances, including QRS prolongation or arrhythmias. Neurological symptoms such as clonus, myoclonus, and hyperreflexia have also been observed.

In cases where bupropion was part of a multiple drug overdose, additional severe symptoms were noted, including fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. While the majority of patients have recovered without lasting effects, there have been reports of fatalities associated with bupropion overdoses, particularly in individuals who ingested large quantities of the drug. In these cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were documented prior to death.

Healthcare professionals are advised to monitor patients closely for the aforementioned symptoms in the event of a suspected overdose. Immediate medical intervention may be necessary, and supportive care should be initiated as required.

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 to both male and female rats did not impact fertility. This dosage is approximately six times the maximum recommended human dose (MRHD) on a mg/m² basis. The 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, which is 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. These doses 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, which is 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, with 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.

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

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important for 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 (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 observe the patient on a day-to-day basis for any abrupt changes in behavior, as these may occur suddenly. Any severe or unexpected symptoms should be reported to the patient’s prescriber or healthcare professional promptly. Such symptoms may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential adjustments to the medication regimen.

Patients should be informed that some individuals have reported experiencing 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. If patients experience any of these symptoms, they should discontinue bupropion and contact a healthcare professional immediately.

Education on hypersensitivity symptoms is essential, and patients should 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.

Patients should be made aware 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. It is also important to inform patients that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. Patients may wish to undergo an examination to determine their susceptibility to angle closure and consider a prophylactic procedure, such as an iridectomy, if indicated.

Patients should be counseled that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in combination with ZYBAN or any other medications containing bupropion. Furthermore, patients should be advised that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks that require judgment or motor and cognitive skills. Until they are confident that bupropion hydrochloride tablets do not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

Lastly, patients should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride tablets and other drugs may interact and affect each other's metabolism.

Storage and Handling

The tablets are supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP), equipped with a child-resistant closure. It is essential to keep the container tightly closed to maintain the integrity of the product.

For optimal storage, the tablets should be kept at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F). Additionally, the tablets must be protected from light and moisture to ensure their efficacy and safety.

Additional Clinical Information

Patients receiving bupropion hydrochloride tablets for major depressive disorder (MDD) or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion and seek medical attention if they observe atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, patients should contact a healthcare professional if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion, or if they develop any allergic reactions, including skin rash or difficulty breathing.

Postmarketing data indicate that serious neuropsychiatric adverse events, including mood changes, psychosis, and suicidal ideation, have been reported in patients using bupropion for smoking cessation. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, as well as anaphylactic shock, have also been documented.

FDA Insert (PDF)

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

View full prescribing information (PDF)