Bupropion hydrochloride

Description

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

The active ingredient is presented as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and a local anesthetic effect on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration in strengths of 100 mg, 150 mg, and 200 mg. These tablets are white to off-white, film-coated, and designed for sustained release. Each tablet contains the specified amount of bupropion hydrochloride, USP, along with inactive ingredients including hydroxypropyl cellulose, saccharin, anhydrous lactose, colloidal silicon dioxide, talc, stearic acid, polyvinyl alcohol, titanium dioxide, and polyethylene glycol 3350.

The 100 mg strength meets USP dissolution test 7, while the 150 mg strength complies with USP dissolution test 2. The 200 mg strength has FDA-approved dissolution test specifications that differ from those of USP.

Uses and Indications

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

Limitations of Use: There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride as noted in the available data.

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 escalated 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 allowable dose is 400 mg per day, which should be 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 evaluate the need for dose and/or frequency adjustments.

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.

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, thus use is contraindicated in these circumstances.

The concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders with bupropion hydrochloride extended-release tablets (SR) is contraindicated. Additionally, bupropion hydrochloride extended-release tablets (SR) should not be initiated in patients currently receiving linezolid or intravenous methylene blue, nor should it be used within 14 days of stopping an MAOI.

Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR) is also a contraindication.

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 providers 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 that the dosage be gradually increased, with a maximum daily limit of 400 mg. Should a seizure occur, bupropion should 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 also recommended.

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 should be exercised in these patients.

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

To ensure patient safety, blood pressure should be monitored before starting treatment and periodically during treatment. 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 may experience a range of adverse reactions while using bupropion hydrochloride extended-release tablets (SR). 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 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. Patients experiencing any of these symptoms should be instructed to contact a healthcare professional immediately.

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 400 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion can increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Activation of mania or hypomania has been reported, necessitating screening for bipolar disorder and careful monitoring for these symptoms. Angle-closure glaucoma has also been noted in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnoses of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI.

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

Coadministration of bupropion hydrochloride extended-release tablets (SR) with certain drug classes may lead to significant interactions that require careful consideration.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and 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 concomitant medications should be considered.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely when these medications are used together.

Drugs Lowering Seizure Threshold Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (SR) in conjunction with drugs that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs Concomitant use of bupropion with dopaminergic medications 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 hydrochloride extended-release tablets (SR) with MAOIs can heighten the risk of hypertensive reactions. Caution is advised when these agents are used together.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (SR) 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 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 utilizing 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 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

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 involving 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. A prospective, longitudinal study indicated that women with a history of major depressive disorder 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 treatment decisions regarding antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, in pregnant rabbits, 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.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an overall increased risk for malformations. The registry was not specifically designed to evaluate individual defects but suggested a possible increase in cardiac malformations. The prospectively observed rate of cardiovascular malformations in pregnancies with first trimester exposure to bupropion was 1.3%, which is similar to the background rate of approximately 1%.

Findings regarding the risk of left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) following first trimester bupropion exposure are inconsistent. The NBDPS indicated an increased risk for LVOTO (adjusted OR = 2.6), while the Slone Epidemiology case-control study did not find an association. Similarly, the Slone Epidemiology Study found an increased risk for VSD (adjusted OR = 2.5) but did not find increased risk for other cardiovascular malformations, while the NBDPS and United Healthcare database studies did not establish an association with VSD.

In summary, while animal studies have shown no evidence of fetal malformations at certain doses, caution is warranted due to the potential risks associated with untreated maternal depression and the inconsistent findings regarding specific cardiac malformations. Healthcare providers should carefully weigh the benefits and risks when considering bupropion treatment in pregnant patients.

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 and any potential adverse effects on the breastfed child from bupropion or from the underlying maternal condition.

Renal Impairment

In patients with renal impairment, specifically those with a glomerular filtration rate (GFR) of less than 90 mL/min, consideration should be given to a reduced dose and/or dosing frequency of bupropion hydrochloride extended-release tablets (SR). Bupropion and its metabolites are primarily cleared renally, and in individuals with reduced kidney function, there is a potential for accumulation of the drug and its metabolites to a greater extent than usual.

Healthcare professionals should monitor these patients closely for adverse reactions that may suggest elevated levels of bupropion or its metabolites.

Hepatic Impairment

In patients with moderate to severe hepatic impairment, as defined by a Child-Pugh score of 7 to 15, the maximum recommended dose of bupropion hydrochloride extended-release tablets (SR) is 100 mg per day or 150 mg every other day.

For patients with mild hepatic impairment, indicated by a Child-Pugh score of 5 to 6, it is advisable to consider a reduction in the dose and/or frequency of dosing.

Close monitoring of liver function is recommended in patients with hepatic impairment to ensure safety and efficacy of treatment.

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, and alterations in mental status. Cardiovascular effects such as sinus tachycardia and electrocardiogram (ECG) changes, including conduction disturbances and arrhythmias (notably QRS prolongation), have also been observed. Neurological symptoms may manifest as clonus, myoclonus, and hyperreflexia.

In cases where bupropion was part of a multiple drug overdose, additional severe symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported.

While the majority of patients have recovered without lasting effects, there have been 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 noted 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

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 received oral doses of bupropion up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and during gestation or lactation. Males were treated for 60 days prior to and through mating without any noted fertility issues. However, doses of 200 mg/kg/day (approximately 5 times the MRHD on a mg/m² basis) or higher resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects on the fertility, reproduction, or 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, and homicidal ideation. Additional symptoms noted include aggression, hostility, agitation, anxiety, and panic. Instances of suicidal ideation and suicide have also been documented in patients attempting to quit smoking while taking bupropion.

Patients are advised to discontinue bupropion and consult a healthcare professional if they encounter any of these symptoms.

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 remain 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. Worsening of depression and suicidal ideation should also be closely monitored, particularly during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to observe patients on a daily basis for any abrupt changes in behavior, as these may indicate a need for immediate communication with the patient’s prescriber or healthcare professional. Such symptoms can be associated with an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

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, and panic when attempting to quit smoking while taking bupropion. They should 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 must be instructed to stop taking the medication and not to restart it 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. During the initial titration phase, particularly when increasing the dose above 150 mg/day, patients should 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 be made aware that taking bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. They may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure, such as an iridectomy, if necessary.

It is important to educate 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 in combination. Patients should also be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are certain that the medication does not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

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

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its integrity and efficacy.

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 they observe atypical changes in mood or behavior, or if suicidal ideation or behavior develops.

Patients are also instructed to contact healthcare professionals if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion. Additionally, any signs of allergic reactions, including skin rash or difficulty breathing, warrant immediate discontinuation of the medication and consultation with a healthcare provider. Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, including mood changes, psychosis, and suicidal behavior. Anaphylactoid and anaphylactic reactions have been reported, necessitating medical intervention, with rare cases of severe skin reactions and anaphylactic shock documented.

FDA Insert (PDF)

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

View full prescribing information (PDF)