Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.21 g/mol, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride appears as a white to off-white crystalline powder and is highly soluble in water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride is supplied for oral administration as 75-mg (orange) and 100-mg (purple) film-coated tablets. Each 75-mg tablet contains colloidal silicon dioxide, crospovidone, FD&C Yellow #6 Aluminum Lake, fumaric acid granular, hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol, and titanium dioxide. Each 100-mg tablet contains colloidal silicon dioxide, crospovidone, D&C Red #7 Calcium Lake, fumaric acid granular, hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol, and titanium dioxide.

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, administered in the same manner.

The maximum allowable dose is 450 mg per day, which can be given as 150 mg three times daily. It is essential for healthcare professionals to periodically reassess the patient's dose and the necessity for maintenance treatment.

For patients with moderate to severe hepatic impairment, the recommended dose is 75 mg once daily. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, for patients with renal impairment, a reduction in dose and/or frequency may also be warranted.

Contraindications

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

Patients with a seizure disorder are at increased risk of seizures when using this medication.

Current or prior diagnoses of bulimia or anorexia nervosa are contraindicated due to the potential for exacerbating these conditions.

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs can increase the risk of seizures; therefore, use is contraindicated in these circumstances.

The concomitant use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders with bupropion hydrochloride tablets is contraindicated. This includes use within 14 days of stopping either treatment. Additionally, bupropion hydrochloride tablets should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride tablets is also a contraindication for use.

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. It is imperative that healthcare providers observe patients for these symptoms and instruct them to discontinue bupropion and seek immediate medical attention if such adverse events occur.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the maximum daily dose to 450 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride tablets have the potential to elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

Patients with a history of bipolar disorder should be screened prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is advised.

Additionally, 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.

There is a risk of angle-closure glaucoma 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 or emergence of suicidal thoughts and behaviors.

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

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride tablets. The most common adverse reactions reported 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.

A significant warning associated with bupropion is the increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation during treatment.

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.

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 450 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.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is essential.

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

Other important considerations include the contraindications for patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who have abruptly discontinued 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 overdosage, 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 (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

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate a dose increase of the affected medication when coadministered. This adjustment should be guided by clinical response, ensuring that the dosage does not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). A dose reduction of these medications should be considered to mitigate potential adverse effects.

Additionally, bupropion may lower plasma levels of digoxin; therefore, monitoring of digoxin concentrations is advised to ensure therapeutic efficacy.

Caution is warranted when prescribing bupropion hydrochloride tablets to patients who are concurrently taking medications that lower the seizure threshold, as this may increase the risk of seizures.

The concomitant use of bupropion hydrochloride tablets with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring of patients.

There is an increased risk of hypertensive reactions when bupropion hydrochloride tablets are used alongside monoamine oxidase inhibitors (MAOIs). Close monitoring of blood pressure is recommended in such cases.

Lastly, it is important to note that bupropion hydrochloride tablets can cause false-positive results in urine drug screenings for amphetamines, which may lead to misinterpretation of drug use.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for additional information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

Geriatric Use

Clinical trials involving bupropion sustained-release tablets included approximately 6,000 subjects, of which 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred subjects aged 65 years and older participated in trials 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 between these groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Elderly patients are at an increased risk of adverse reactions, particularly those with impaired renal function. Given that this population is more likely to experience decreased renal function, careful consideration should be given to this factor when selecting dosages. Monitoring of renal function may be beneficial in this demographic 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. 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, which should be considered when evaluating treatment options.

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. 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. Additionally, decreased fetal weights were noted at doses twice the MRHD and greater in rabbits.

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. 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 important 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 and a retrospective cohort study did not show an increased risk for malformations overall. However, the Registry 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 cardiovascular malformations in pregnancies exposed to bupropion in the first trimester being 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) are inconsistent, with the National Birth Defects Prevention Study (NBDPS) indicating an increased risk, while other studies did not find an association. Similarly, findings on the risk for ventricular septal defect (VSD) are inconsistent; the Slone Epidemiology Study found an increased risk following first trimester maternal bupropion exposure, but other studies did not support this association.

In summary, while animal studies indicate no significant fetal malformations in rats, caution is warranted due to the observed fetal malformations in rabbits and the potential risks associated with untreated maternal depression. Healthcare professionals 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, 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.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for bupropion hydrochloride 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 data regarding dosage adjustments, special monitoring, or safety considerations. As such, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, given the absence of detailed guidance on its use in this population. Regular monitoring of renal function may be prudent in these cases, although specific recommendations are not provided.

Hepatic Impairment

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

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one-third of these cases, seizures have been reported, highlighting the potential neurological risks associated with excessive intake.

Symptoms of Overdosage

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and various cardiac complications. The severity of these symptoms can escalate, particularly in cases involving large doses, where multiple uncontrolled seizures and cardiac arrest have been observed. Tragically, fatalities linked to bupropion overdose have also been documented.

Management of Overdosage

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and vigilant medical supervision. Healthcare professionals are advised to monitor the patient closely for any signs of severe reactions and to provide appropriate interventions as necessary.

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

Nonclinical Toxicology

No teratogenic effects were observed in nonclinical studies. In terms of non-teratogenic effects, oral administration of bupropion at 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 continuing through Day 13 of gestation or lactation, as well as to male rats for 60 days prior to and during mating, did not affect male or female fertility. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) or higher resulted in 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 conducted in rats and mice involved 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. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was identified 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 noted in 1 of 3 in vivo rat bone marrow cytogenetic studies. No specific details were provided under the animal pharmacology and toxicology section.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as symptoms such as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, including changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been observed. These symptoms may occur upon initiation of bupropion therapy, after several weeks of treatment, or following discontinuation of the medication.

Severe allergic reactions to bupropion hydrochloride tablets have been reported. Patients are advised to discontinue use and contact their healthcare provider immediately if they experience symptoms such as rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing, as these may indicate a serious allergic reaction.

The incidence of seizures may increase with higher doses of bupropion hydrochloride tablets. Patients who experience a seizure while on this medication should stop taking it and consult their healthcare provider immediately. It is advised that individuals who have had a seizure should not resume bupropion hydrochloride tablets.

Additionally, some patients have developed high blood pressure, which can be severe, while taking bupropion hydrochloride tablets. The risk of elevated blood pressure may be heightened in those also using nicotine replacement therapy, such as nicotine patches, to assist in smoking cessation.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important to instruct patients, their families, and/or caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. 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. Any severe or sudden onset of these symptoms, especially if they were not part of the patient’s initial presentation, should be reported to the prescriber or healthcare professional promptly.

Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience significant changes in mood, including depression and mania, as well as symptoms of psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, or thoughts of suicide, particularly when attempting to quit smoking while on bupropion.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, patients must be informed to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Healthcare providers should counsel patients regarding the risks associated with excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase the risk of seizures. Patients should be advised to minimize or avoid alcohol consumption.

Patients should also be informed that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. It is important to 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 combination with ZYBAN or any other medications containing bupropion.

Healthcare providers should 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 patients are confident that bupropion does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Patients should be encouraged to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride tablets may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with bupropion hydrochloride tablets.

Instructions for storage should include keeping bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and ensuring they are kept dry and out of light. Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, with doses 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.

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

Storage and Handling

The product is supplied in a tight, light-resistant container to ensure its integrity. It should be stored at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), with permissible excursions between 15ºC and 30ºC (59ºF to 86ºF). It is essential to protect the product from moisture to maintain its quality and efficacy.

Additional Clinical Information

The maximum recommended dose of bupropion hydrochloride tablets is 450 mg per day, and clinicians should increase the dose gradually. Patients and caregivers must be advised to discontinue the medication and contact a healthcare provider immediately if they observe any signs of agitation, depressed mood, or atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers should monitor for the emergence of agitation, irritability, and other concerning symptoms, reporting any such changes to healthcare providers promptly.

Patients should also be instructed to seek medical attention if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion. In the event of an allergic or anaphylactoid reaction, characterized by symptoms like skin rash, hives, or shortness of breath, patients should discontinue use and consult a healthcare provider. Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts. Additionally, anaphylactoid reactions have been reported, with rare cases of severe skin reactions and anaphylactic shock associated with the medication.

FDA Insert (PDF)

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

View full prescribing information (PDF)