Bupropion hydrochloride

Description

Bupropion hydrochloride, USP is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.20 g/mol, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride appears as a white powder and is soluble in water, 0.1 N Hydrochloric acid, and in alcohol.

Bupropion hydrochloride extended-release tablets USP (SR) are supplied for oral administration in strengths of 100 mg (red), 150 mg (green), and 200 mg (yellow). These are film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride USP along with inactive ingredients, which include colloidal silicon dioxide, diluted hydrochloric acid, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium stearyl fumarate, titanium dioxide, and edible black ink. The 100 mg tablet contains FD&C Red #40, the 150 mg tablet contains FD&C Blue #1 and D&C Yellow #10 Lake, and the 200 mg tablet contains D&C Yellow #10 Lake.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) 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 should not be used within 14 days of discontinuing an MAOI, nor should it be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

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, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare professionals closely monitor patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and seek immediate medical attention if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-dependent. To mitigate this risk, it is recommended to gradually increase the dosage and limit the maximum daily dose to 400 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) 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.

There is a risk of psychosis and other neuropsychiatric reactions in patients taking bupropion. Patients should be advised to contact their healthcare provider if they experience any such reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion. Caution is warranted 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 populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion, healthcare professionals should conduct regular blood pressure assessments before and during treatment. Patients must be instructed to discontinue bupropion and contact their healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs.

Side Effects

Patients may experience a range of adverse reactions while taking bupropion hydrochloride extended-release tablets (SR). The most common adverse reactions reported include headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitations, myalgia, sweating, rash, and anorexia.

Serious adverse reactions warrant particular attention. A WARNING regarding suicidal thoughts and behaviors is indicated, as there is an increased risk of suicidal thinking and behavior 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 also been observed, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients should be instructed 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 hydrochloride extended-release tablets (SR) can increase blood pressure, necessitating monitoring of blood pressure 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. Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants, necessitating caution in such individuals.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnosis 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 extended-release tablets (SR) is contraindicated, as is the use of bupropion hydrochloride extended-release tablets (SR) within 14 days of stopping an MAOI intended to treat psychiatric disorders.

In cases of overdosage, 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), arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with overdoses of bupropion alone have been documented, 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 an increase in the dosage of bupropion based on clinical response, without exceeding the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain 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 reduce plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (SR) alongside medications that lower the seizure threshold, as this combination may increase the risk of seizures.

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

There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are administered in conjunction with monoamine oxidase inhibitors (MAOIs). Close monitoring of blood pressure is advised in these cases.

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) can lead to false-positive results in urine drug screenings for amphetamines, which may require further confirmatory testing.

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, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

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 clinical trials utilizing 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 between these groups, it is important to note that greater sensitivity 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 doses for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from a pregnancy exposure registry indicates that there is ongoing monitoring of pregnancy outcomes in women exposed to antidepressants, including bupropion, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting the registry's website.

Epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not demonstrated an overall increased risk of congenital malformations. However, untreated depression during pregnancy poses significant risks to the mother and potentially to the fetus. Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there were no fetal malformations observed at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, in pregnant rabbits, non-dose-related increases in fetal malformations and skeletal variations were noted at doses approximately equal to the MRHD and higher, with decreased fetal weights observed at doses twice the MRHD and above.

The estimated background risk for major birth defects and miscarriage in the general population is not well defined for the indicated population. However, it is acknowledged that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes, with the estimated background risk of major birth defects ranging from 2% to 4% and miscarriage from 15% to 20% in clinically recognized pregnancies.

Clinical considerations suggest that women with a history of major depressive disorder who discontinue antidepressants during pregnancy are at a higher risk of experiencing a relapse compared to those who continue treatment. Therefore, it is crucial to weigh the risks of untreated depression against the potential effects on the fetus when considering changes to antidepressant therapy during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study involving 1,213 first trimester exposures, did not indicate an overall increased risk for malformations. While the registry was not specifically designed to evaluate particular defects, it suggested a possible increase in cardiac malformations. The observed rate of cardiovascular malformations in pregnancies with first trimester bupropion exposure was 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent findings have been reported regarding the association between bupropion exposure during the first trimester and risks for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). While some studies indicated an increased risk for VSD, others did not find significant associations for LVOTO or other cardiovascular malformations.

Animal studies have shown that bupropion, administered during organogenesis in pregnant rats and rabbits, did not result in fetal malformations at certain doses. However, increases in fetal malformations and skeletal variations were observed in rabbits at doses equal to or greater than the MRHD. Additionally, decreased fetal weights were noted at higher doses, although no maternal toxicity was evident at lower doses. In a pre- and postnatal development study, bupropion did not adversely affect pup growth or development when administered to pregnant rats at doses up to approximately four times the MRHD.

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 tablets (SR) 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. 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

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. Healthcare professionals should be aware that serious reactions can occur following a bupropion overdose, including hallucinations, loss of consciousness, alterations in mental status, and various cardiac complications.

Fatalities associated with bupropion overdose have been noted, particularly in individuals who have ingested large quantities of the medication. Therefore, it is crucial to approach suspected overdose cases with caution and thoroughness.

In the event of an overdose, immediate supportive care is essential. This includes close medical supervision and continuous monitoring of cardiac rhythm and vital signs. There are no known antidotes for bupropion; thus, healthcare providers should ensure adequate airway management, oxygenation, and ventilation for affected patients.

For further guidance in managing bupropion overdose, it is recommended to consult a Certified Poison Control Center. Healthcare professionals can reach the center by calling 1-800-222-1222 or visiting www.poison.org for additional resources and support.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered at doses up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, which is approximately 2 to 7 times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate 2 to 3 times higher than the control in 2 of 5 strains tested. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Regarding reproductive toxicity, no adverse effects on male and female fertility were observed when rats received oral doses of bupropion up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and during gestation or lactation. Males were treated for 60 days prior to and through mating without any noted fertility issues. However, doses of 200 mg/kg/day (approximately 5 times the MRHD on a mg/m² basis) or higher resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects on the fertility, reproduction, or growth and development of male or female offspring.

Postmarketing Experience

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

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented in some individuals using bupropion for smoking cessation. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported among patients taking bupropion hydrochloride extended-release tablets (SR).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have been observed, with signs including 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.

The risk of seizures may increase with higher doses of bupropion hydrochloride extended-release tablets (SR). Some patients have experienced high blood pressure, which can be severe, particularly when combined with nicotine replacement therapy during smoking cessation efforts.

Episodes of mania, characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech, have been reported in some individuals taking bupropion hydrochloride extended-release tablets (SR).

Visual disturbances, including eye pain, changes in vision, and swelling or redness in or around the eye, have also been documented.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the medication's use and potential risks. 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 behavioral changes, as well as worsening depression and suicidal ideation. These symptoms are particularly concerning during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to monitor patients closely for any abrupt changes in behavior, as these can occur suddenly. Any severe or unexpected symptoms should be reported to the patient's prescriber or healthcare professional promptly. Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and suicidal thoughts, particularly when attempting to quit smoking while on bupropion.

Patients must be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these concerning symptoms. Additionally, they should be educated about the signs of hypersensitivity and advised to stop taking bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. In the event of a seizure while on treatment, patients should discontinue the medication and not restart it.

Healthcare providers should inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should be advised to minimize or avoid alcohol consumption. During the initial titration phase, particularly at doses above 150 mg/day, patients should take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures.

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. It is also important to inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in combination with ZYBAN or any other bupropion-containing medications.

Patients should be counseled that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks that require judgment or motor and cognitive skills. They should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect drug metabolism.

Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride extended-release tablets (SR). Proper storage of the medication is essential; patients should keep the tablets at room temperature, between 68° and 77°F (20° to 25°C), and ensure they remain dry and protected from light.

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole, without chewing, dividing, or crushing them, to maintain the intended release rate. If a dose is missed, patients should not take an extra tablet to compensate but should take the next dose at the regular time to minimize the risk of seizure. Patients should be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and that they can be taken with or without food.

Storage and Handling

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

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

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets (SR) for major depressive disorder (MDD) or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue the medication and seek medical attention if they observe any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, patients should contact a healthcare professional if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion, or if they develop any allergic reactions during treatment.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. These events include mood changes, psychosis, and suicidal ideation, among others. While some patients may experience symptoms of nicotine withdrawal, including depression, it is important to note that adverse events have also occurred in patients who continued to smoke while on bupropion. In many cases, symptoms resolved after discontinuation of the medication, but persistent symptoms have been reported, necessitating ongoing monitoring and supportive care until resolution.

FDA Insert (PDF)

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

View full prescribing information (PDF)