Bupropion hydrochloride

Description

Bupropion hydrochloride, USP, is an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. Its chemical structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino 1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2, with a molecular formula of C13H18ClNO•HCl.

The compound appears as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is available in tablet form for oral administration, specifically as 75-mg (yellow) and 100-mg (red) film-coated tablets. Each tablet contains the specified amount of bupropion hydrochloride, USP, along with various inactive ingredients. The 75-mg tablet includes microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone, diluted HCl, colloidal silicon dioxide, stearic acid, magnesium stearate, talc, glycerol triacetate, D&C yellow no. 10 aluminum lake, titanium dioxide, and FD&C yellow no. 6. The 100-mg tablet comprises microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone, diluted HCl, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol triacetate, talc, titanium dioxide, FD&C Red no. 40, and FD&C yellow no. 6.

Uses and Indications

Bupropion hydrochloride is 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. Additionally, for patients with renal impairment, a reduction in dose and/or frequency should also be considered.

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.

Current or prior diagnoses of bulimia or anorexia nervosa are contraindicated due to the potential for increased seizure risk.

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs may precipitate seizures; therefore, bupropion should not be used in these circumstances.

The concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion should not be administered within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the ingredients in bupropion hydrochloride tablets is a contraindication due to the risk of severe allergic reactions.

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. Healthcare professionals are advised to observe these patients for the emergence of such symptoms and to 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 maximum daily dose to 450 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion has 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 necessary during treatment.

Additionally, there is a risk of psychosis and other neuropsychiatric reactions. Patients 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, including bupropion.

It is critical to note 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 patient safety, healthcare providers should instruct patients to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs. Regular monitoring of blood pressure is also recommended before and during treatment.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by seriousness and frequency.

Most common adverse reactions 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. These reactions are generally mild to moderate in severity.

Serious warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

There is a dose-related risk of seizures associated with this medication. 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.

Patients should be monitored for hypertension, as bupropion can increase blood pressure. Blood pressure should be assessed before initiating treatment and periodically during the course of therapy.

Activation of mania or hypomania has been observed, necessitating screening for bipolar disorder and careful monitoring for these symptoms in patients.

Psychosis and other neuropsychiatric reactions may occur; patients are advised to contact a healthcare professional if such reactions arise.

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

In cases of overdose, serious reactions such as seizures have been reported in approximately one-third of cases. Other serious adverse reactions may include hallucinations, loss of consciousness, changes in mental status, 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

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 alongside medications that lower the seizure threshold, as this may increase the risk of seizures.

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

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

Drug-Laboratory Test Interactions Bupropion 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. 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 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 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

Data from a pregnancy exposure registry indicates that there is ongoing monitoring of pregnancy outcomes in women exposed to antidepressants, including bupropion, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting the registry's website.

Epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not demonstrated an increased risk of congenital malformations overall. However, untreated depression during pregnancy poses risks to the mother and potentially to the fetus. Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, no fetal malformations were observed at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, in pregnant rabbits, non-dose-related increases in fetal malformations and skeletal variations were noted at doses approximately equal to the MRHD and higher, with decreased fetal weights observed at doses twice the MRHD and above.

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 ranging from 2% to 4% and miscarriage from 15% to 20% in clinically recognized pregnancies.

Clinical considerations suggest that women with a history of major depressive disorder who discontinue antidepressants during pregnancy are at a higher risk of experiencing a relapse compared to those who continue treatment. Therefore, it is crucial to weigh the risks of untreated depression against the potential effects on the fetus when considering changes to antidepressant therapy during pregnancy and postpartum.

Human data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study involving 1,213 first trimester exposures, did not indicate an overall increased risk for malformations. While the registry was not specifically designed to evaluate particular defects, it suggested a possible increase in cardiac malformations. However, the overall risk for cardiovascular malformations following first trimester exposure to bupropion was not found to be elevated, with a prospectively observed rate of 1.3% in pregnancies exposed to bupropion, which aligns with the background rate of approximately 1%.

Animal studies have shown that bupropion, administered orally to pregnant rats and rabbits during organogenesis, did not result in fetal malformations in rats at doses up to 450 mg per kg per day (approximately 10 times the MRHD). In rabbits, fetal malformations and skeletal variations were observed at doses starting from 25 mg per kg per day (approximately equal to the MRHD) and higher, with decreased fetal weights noted at doses of 50 mg per kg per day (approximately 2 times the MRHD). Importantly, no maternal toxicity was observed at doses of 50 mg per kg per day or less. Additionally, in a pre-and postnatal development study, bupropion did not adversely affect pup growth or development when administered to pregnant rats at doses up to 150 mg per kg per day (approximately 3 times the MRHD) from embryonic implantation through lactation.

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 per 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside the mother’s clinical need for bupropion tablets and any potential adverse effects on the breastfed child from bupropion tablets or from the underlying maternal condition.

Renal Impairment

There is no information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing to patients with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In 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, sinus tachycardia, and various ECG changes, such as conduction disturbances (including QRS prolongation) and arrhythmias. Additional symptoms may encompass clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in cases involving multiple drug overdoses.

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

Healthcare professionals are advised to monitor patients closely for the aforementioned symptoms and to initiate appropriate management strategies. Immediate medical intervention is critical in cases of suspected overdose, and supportive care should be provided as necessary.

Nonclinical Toxicology

There were no teratogenic effects observed in the studies conducted. Non-teratogenic effects were noted in a fertility assessment where oral administration of bupropion at doses up to 300 mg per kg per day did not adversely affect male and female fertility in rats. This dosage is approximately six times the maximum recommended human dose (MRHD) on a mg per m² basis. The treatment was administered 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 per kg per day or greater, which is approximately four times the MRHD on a mg per 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.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg per kg per day and 150 mg per kg per day, respectively. These doses correspond to approximately six and two times the MRHD on a mg per 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 per kg per day, which is approximately two to six times the MRHD on a mg per 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 observed 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, and homicidal ideation. Instances of aggression, hostility, agitation, anxiety, and panic have also been documented. Furthermore, there have been reports of suicidal ideation and suicide attempts occurring in patients attempting to quit smoking while on bupropion. 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, particularly during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should monitor patients closely for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional. Such symptoms may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential modifications to the treatment regimen.

Patients should be informed that some individuals have reported mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal thoughts and actions when attempting to quit smoking while using 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 cautioned 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. 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 assess their susceptibility to angle closure and consider a prophylactic procedure, such as an iridectomy, if indicated.

Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride tablets should not be used in conjunction with ZYBAN or any other medications containing bupropion.

Furthermore, patients should be advised 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 they are confident that bupropion hydrochloride tablets do not negatively impact their performance, patients should refrain from driving or operating complex, hazardous machinery.

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

Storage and Handling

The product is supplied in a tight container to ensure its integrity. It should be stored at room temperature, specifically between 20° to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its quality and efficacy.

Additional Clinical Information

The administration of bupropion hydrochloride tablets should not exceed a daily dose of 450 mg, ideally given as 150 mg three times daily, with a gradual titration to minimize the risk of seizure. Clinicians are advised to counsel patients and caregivers to discontinue the medication and seek immediate medical attention if any atypical changes in behavior, mood, or thinking occur, including signs of agitation, suicidal ideation, or suicidal behavior. Additionally, patients should be instructed to report any neuropsychiatric symptoms such as delusions, hallucinations, or confusion, as well as any allergic reactions, including skin rash or respiratory difficulties.

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

FDA Insert (PDF)

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

View full prescribing information (PDF)