Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets USP (SR) are 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 pharmaceutical ingredient, bupropion hydrochloride, is a white, crystalline powder that is highly soluble in water and has a bitter taste, producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration and are available in three strengths: 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each film-coated, sustained-release tablet contains the specified amount of bupropion hydrochloride, USP, along with inactive ingredients including cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide. The 100 mg tablet includes FD&C Blue No. 2 Lake, the 150 mg tablet contains both FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, while the 200 mg tablet incorporates Iron Oxide Red and Ferrosoferric Oxide. These tablets meet the USP Dissolution Test 7.

Uses and Indications

Bupropion hydrochloride extended-release (SR) tablets 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 to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release (SR) 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 associated with these conditions.

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 with bupropion is contraindicated. Bupropion 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 ingredients in bupropion hydrochloride extended-release (SR) tablets is a contraindication due to the risk of severe allergic reactions.

Warnings and Precautions

Serious neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicide. 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 daily dose to a maximum of 400 mg. If a seizure occurs, bupropion should be discontinued immediately.

Bupropion hydrochloride extended-release (SR) 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. In the event of psychosis or other neuropsychiatric reactions, patients should be instructed to contact a healthcare professional without delay.

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

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 of their condition or the emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion, healthcare professionals should implement the recommended monitoring parameters, including blood pressure assessments before and during treatment. Patients should be advised to discontinue bupropion and seek medical advice if they experience any neuropsychiatric adverse events or if they develop psychosis or other concerning symptoms.

Side Effects

Patients receiving bupropion hydrochloride extended-release (SR) tablets 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 the emergence or worsening of suicidal ideation and behaviors.

Neuropsychiatric adverse events have been observed during smoking cessation, including mood changes (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 can increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

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

Certain conditions and medications may increase the risk of adverse reactions. These include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, and the use of monoamine oxidase inhibitors (MAOIs). Bupropion should not be used in conjunction with MAOIs or within 14 days of stopping treatment with bupropion.

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), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with bupropion overdose have been documented, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

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

Pharmacokinetic Interactions

• 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, including 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.

Pharmacodynamic Interactions

• Drugs that Lower Seizure Threshold: Caution is advised when prescribing bupropion hydrochloride extended-release (SR) tablets in conjunction with other medications that may lower the seizure threshold.

• Digoxin: Bupropion may reduce plasma levels of digoxin. It is recommended to monitor digoxin levels closely in patients receiving both medications.

• Dopaminergic Drugs: The concurrent use of bupropion with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity.

• Monoamine Oxidase Inhibitors (MAOIs): There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release (SR) tablets are used with MAOIs.

Drug-Laboratory Test Interactions

Bupropion hydrochloride extended-release (SR) tablets may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to patients and healthcare providers to avoid misinterpretation of test results.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. 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 greater sensitivity to the medication 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 1-844-4056185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater, with decreased fetal weights noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical considerations suggest that women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue treatment. Therefore, it is essential to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

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 increased risk for malformations overall. However, the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, 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) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. The United Healthcare database lacked sufficient power to evaluate these associations, while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, and the Slone Epidemiology case-control study did not find an increased risk for LVOTO.

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

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

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

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 sinus tachycardia. Additionally, electrocardiogram (ECG) changes such as conduction disturbances, including QRS prolongation and arrhythmias, have been observed. Neuromuscular symptoms such as clonus, myoclonus, and hyperreflexia may also occur.

In more severe cases, particularly when bupropion is involved in multiple drug overdoses, additional complications such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported. While most patients have recovered without lasting effects, there have been fatalities associated with bupropion overdoses, particularly in those 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 these symptoms and to initiate appropriate management strategies, which may include supportive care and symptomatic treatment. Immediate medical attention is crucial in cases of suspected overdose to mitigate the risk of severe complications and improve patient outcomes.

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 rats, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, did not affect male or female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males were treated for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately five times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven and two times the MRHD on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, approximately two to seven 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, as well as psychosis, hallucinations, paranoia, delusions, and homicidal ideation while using bupropion. Additional symptoms noted include aggression, hostility, agitation, anxiety, panic, and suicidal ideation, particularly during attempts to quit smoking.

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 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 are particularly critical to monitor during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may indicate a need for immediate communication with the prescriber or healthcare professional, especially if the symptoms are severe or were not part of the patient’s initial presentation. Such symptoms may 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, particularly 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 is essential; patients should be made aware of the symptoms of severe allergic reactions and instructed to discontinue bupropion hydrochloride extended-release (SR) tablets if such reactions occur. Additionally, patients must be advised 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 encouraged to minimize or avoid alcohol consumption. During the initial titration phase, particularly when increasing the dose above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release (SR) tablets 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 (SR) tablets 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 indicated.

It is important to educate patients that bupropion hydrochloride extended-release (SR) tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used concurrently. Patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release (SR) tablets, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are confident that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

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

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at room temperature, ideally between 20°C and 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

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

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride and contact a healthcare provider immediately if they observe any agitation, depressed mood, or atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients receiving antidepressants for major depressive disorder (MDD) or other indications should be vigilant for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality, and report these symptoms to healthcare providers without delay.

Prescriptions for bupropion hydrochloride extended-release (SR) tablets should be limited to the smallest quantity necessary for effective patient management to minimize the risk of overdose. Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. While many patients reported symptom resolution after discontinuation of the medication, some experienced persistent symptoms, necessitating ongoing monitoring and supportive care until resolution occurs.

FDA Insert (PDF)

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

View full prescribing information (PDF)