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 antidepressants. 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 criteria.

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. Similarly, in patients with renal impairment, a reduction in dose and/or frequency may be warranted.

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 this medication.

Bupropion is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the heightened risk of seizures associated with these conditions.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is also a contraindication, as it may increase the risk of seizures.

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

Additionally, bupropion is contraindicated in individuals with known hypersensitivity to bupropion or any of the other ingredients in the formulation.

Warnings and Precautions

The use of bupropion hydrochloride extended-release (SR) tablets necessitates careful consideration of several warnings and precautions to ensure patient safety.

Increased Risk of Suicidal Thoughts and Behaviors Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including bupropion. It is essential to monitor these patients closely for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients undergoing smoking cessation with bupropion may experience serious neuropsychiatric adverse events. These can include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Patients should be observed for these symptoms, and if they occur, they must be instructed to discontinue bupropion and contact a healthcare provider immediately.

Seizure Risk 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 400 mg. If a seizure occurs, bupropion should be discontinued.

Hypertension Bupropion can elevate blood pressure; therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

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

Monitoring Parameters Regular monitoring of blood pressure is essential before and during treatment with bupropion. Additionally, screening for bipolar disorder and monitoring for symptoms of mania or hypomania should be conducted.

Emergency Instructions Patients must be advised to seek emergency medical help if they experience any neuropsychiatric reactions.

Discontinuation Instructions Patients should be instructed to discontinue bupropion and contact their healthcare provider if they experience any neuropsychiatric adverse events.

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. Patients should be advised to contact a healthcare professional if they experience any of these reactions.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion can increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been reported, particularly in patients with a history of bipolar disorder, and these patients should be screened and monitored accordingly. Angle-closure glaucoma has also been noted in patients with untreated anatomically narrow angles who are treated with antidepressants.

Patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, or those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs should exercise caution. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion is contraindicated, as is the use of bupropion within 14 days of stopping an MAOI intended for psychiatric disorders.

In cases of overdose, seizures were reported in approximately one-third of 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 (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

• Seizure Threshold: Caution is advised when prescribing bupropion hydrochloride extended-release (SR) tablets to patients taking other medications that may lower the seizure threshold, as this could increase the risk of seizures.

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

• 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 advised.

• Monoamine Oxidase Inhibitors (MAOIs): The combination of bupropion with MAOIs can heighten the risk of hypertensive reactions. Caution is warranted when these agents are used together.

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 considered when interpreting 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 needed 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 with 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 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 doses 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 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. A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks of untreated depression and potential effects on the fetus when discontinuing or changing treatment with 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. In contrast, 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 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 increased risk for malformations overall. Although the Registry was not designed or powered to evaluate specific defects, it suggested a possible increase in cardiac malformations. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which is similar to the background rate of approximately 1%. However, study findings regarding bupropion exposure 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 a possible association.

In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) from embryonic implantation through lactation 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, was found to be 2% of the maternal weight-adjusted dose.

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

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for bupropion hydrochloride extended-release (SR) tablets, as well as 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 data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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

In cases of bupropion overdosage, significant clinical manifestations can occur, particularly with doses of 30 grams or more. Seizures have been reported in approximately one-third of these cases. Other serious adverse reactions associated with bupropion overdose 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 instances of multiple drug overdoses.

While most patients tend to recover without lasting effects, there have been reports of fatalities linked to bupropion overdose, especially in individuals who ingested large quantities. In these cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for the most current guidance and recommendations. Healthcare professionals can reach the Poison Control Center at 1-800-222-1222 or visit www.poison.org for further assistance.

There are currently no known antidotes for bupropion. Management of an overdose should focus on supportive care, which includes close medical supervision and monitoring. It is essential to consider the possibility of a multiple drug overdose. Ensuring an adequate airway, oxygenation, and ventilation is critical, along with continuous monitoring of cardiac rhythm and vital signs. Induction of emesis is not recommended in these situations.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of oral doses of bupropion 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 of 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, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, instances of suicidal ideation and suicide have been noted in individuals attempting to quit smoking while taking bupropion. It is advised that patients discontinue bupropion and consult a healthcare professional if they encounter any of these symptoms.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. Healthcare providers should 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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly important 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. If such symptoms arise, especially if they are severe, sudden, or not part of the patient’s initial presentation, they should be reported to the prescriber or healthcare professional immediately. It is crucial to understand that these 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 may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, and panic, along with suicidal ideation and suicide attempts when attempting to quit smoking while taking bupropion. Patients must be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride extended-release (SR) tablets 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.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can elevate the risk of seizures. Therefore, minimizing or avoiding alcohol consumption is recommended. During the initial titration phase, as the dose increases above 150 mg/day, patients should take bupropion hydrochloride extended-release (SR) tablets in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures.

It is important to inform patients 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. 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 also be made aware that bupropion hydrochloride extended-release (SR) tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride extended-release (SR) tablets should not be used in conjunction with ZYBAN or any other medications containing bupropion.

Furthermore, patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release (SR) tablets, may impair their ability to perform tasks that require 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, hazardous machinery.

Finally, patients should be counseled to notify their healthcare provider if they are currently taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release (SR) tablets and other drugs may interact and affect each other's 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 their caregivers should be advised to discontinue bupropion hydrochloride and seek immediate medical attention if they experience agitation, depressed mood, or any 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.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes (depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been reported during clinical trials, presenting as pruritus, urticaria, angioedema, and dyspnea requiring medical intervention. Rare spontaneous reports have also linked bupropion to erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bupropion Hydrochloride as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)