Bupropion hydrochloride

Description

Bupropion hydrochloride tablets, USP are chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. The chemical designation is (±)-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 powder form of bupropion hydrochloride, USP is a white or almost white crystalline powder that is freely soluble in water, soluble in alcohol and 0.1N HCl, has a bitter taste, and produces a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride tablets, USP are supplied for oral administration as 75-mg and 100-mg film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid 50, titanium dioxide, and triacetin. The 75 mg tablets also contain red iron oxide and yellow iron oxide, while the 100 mg tablets include FD&C Blue #2/Indigo Carmine Aluminum Lake and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake.

Uses and Indications

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

Contraindications

Use of bupropion hydrochloride tablets is contraindicated in the following situations:

• Patients with a seizure disorder, due to the increased risk of seizures.

• Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of seizures.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

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

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

These contraindications are established to mitigate the risk of serious adverse effects associated with the use of bupropion hydrochloride tablets.

Warnings and Precautions

Patients undergoing treatment with bupropion should be closely monitored for a range of potential neuropsychiatric adverse events associated with smoking cessation. 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, and panic. Additionally, there have been reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers 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 is dose-related; therefore, it is essential to minimize this risk by gradually increasing the dosage and limiting the maximum daily dose to 450 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride has the potential to elevate blood pressure. Healthcare professionals should monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy to ensure patient safety.

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 recommended during treatment.

There is a risk of psychosis and other neuropsychiatric reactions; patients should be advised to contact a healthcare professional if they experience such reactions.

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

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

To ensure safe use of bupropion, healthcare providers should conduct regular blood pressure assessments before and during treatment. Patients should be instructed to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms.

Side Effects

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

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 frequently reported among participants in clinical trials.

Serious adverse reactions warrant careful monitoring. A significant warning is the increased risk of suicidal thoughts and behaviors 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, 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 450 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride may 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, highlighting the importance of screening and 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. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion hydrochloride is contraindicated, as is the use of bupropion hydrochloride within 14 days of stopping an MAOI intended for psychiatric disorders.

In cases of overdosage, seizures were reported in approximately one-third of all cases. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances and arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of bupropion hydrochloride with certain drug classes may lead to significant interactions that require careful management.

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 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to elevated concentrations of various medications, including 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 both medications.

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

CNS Toxicity The concomitant use of bupropion with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system toxicity. Monitoring for adverse effects is recommended.

MAO Inhibitors (MAOIs) The use of bupropion with MAOIs can heighten the risk of hypertensive reactions. Close monitoring of blood pressure is advised in such cases.

Urine Drug Testing Bupropion hydrochloride may cause false-positive results for amphetamines in urine drug tests. This should be taken into consideration 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 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 1-844-405-6185 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 10 times the maximum recommended human dose (MRHD) of 450 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. Notably, 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%.

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 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 3 times the MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

In summary, while data suggest that bupropion does not significantly increase the risk of congenital malformations overall, careful consideration of the risks associated with untreated maternal depression is essential when making treatment decisions during pregnancy.

Lactation

Bupropion is excreted in breast milk. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the maximum recommended human dose on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

The effects of bupropion on breastfed infants have not been established. Therefore, healthcare professionals should weigh the potential benefits of bupropion therapy against the risks to the nursing infant when considering its use in lactating mothers.

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 of these patients.

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 have been reported, highlighting the potential neurological risks associated with excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and significant electrocardiogram (ECG) changes, such as conduction disturbances. These symptoms necessitate immediate medical attention, as they can indicate severe toxicity.

Fatalities linked to bupropion overdose have been observed, particularly in patients who have ingested large quantities. Such cases often involve multiple uncontrolled seizures and can lead to cardiac failure, underscoring the critical nature of overdose management.

Currently, there are no known antidotes for bupropion. Therefore, the cornerstone of management in overdose situations is supportive care, which should be administered alongside close medical supervision. Healthcare professionals are advised to monitor the patient closely for any evolving symptoms and complications.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center at 1-800-222-1222 for assistance in managing the overdose effectively.

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 (approximately 6 times the maximum recommended human dose MRHD on a mg/m² basis) to female rats prior to mating, and either through Day 13 of gestation or through lactation, as well as to male rats for 60 days prior to and during mating, did not result in any effects on male or female fertility. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) or higher caused transient ataxia or behavioral changes in adult female rats. Additionally, 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 6 and 2 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 2 to 6 times the MRHD on a mg/m² basis), while lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. In contrast, 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, yielding a mutation rate that was 2 to 3 times higher than the control in 2 of 5 strains tested. Furthermore, an increase in chromosomal aberrations was observed in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts occurring in the context of smoking cessation efforts while on bupropion therapy. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. Instruct patients, their families, and/or caregivers to be vigilant for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening of depression and suicidal ideation, particularly during the initial stages of antidepressant treatment and when the dosage is adjusted.

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

Inform patients that some individuals may experience mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal thoughts when attempting to quit smoking while taking bupropion. Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these symptoms.

Educate patients about the signs of hypersensitivity and advise them to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Instruct patients to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Patients should be made aware that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should be advised to minimize or avoid alcohol consumption. Additionally, inform patients that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

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

Advise patients that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are confident that bupropion hydrochloride tablets do not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

Counsel patients to inform their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride and other drugs may interact with each other’s metabolism. Patients should also notify their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride tablets.

Instruct patients to store bupropion hydrochloride tablets at room temperature, between 20° to 25°C (68° to 77°F), and to keep the tablets dry and protected from light. Patients should take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, ensuring that doses are separated by at least 6 hours to minimize the risk of seizure. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular time due to the dose-related risk of seizure.

Instruct patients that bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. These tablets can be taken with or without food.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as outlined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light and moisture to maintain its integrity.

Additional Clinical Information

The maximum recommended dose of bupropion hydrochloride is 450 mg per day, administered as 150 mg three times daily, with a gradual titration rate to minimize the risk of seizure. Clinicians should counsel patients and caregivers to discontinue bupropion and seek immediate medical attention if they observe any unusual agitation, mood changes, or suicidal thoughts. Additionally, patients should be instructed to report any neuropsychiatric symptoms such as delusions, hallucinations, or confusion, as well as any signs of allergic reactions, including skin rash or difficulty breathing.

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

FDA Insert (PDF)

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

View full prescribing information (PDF)