Bupropion hydrochloride

Description

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

Bupropion hydrochloride extended-release tablets USP (SR) are available for oral administration in strengths of 100 mg, 150 mg, and 200 mg. These film-coated, sustained-release tablets contain 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, and titanium dioxide, and are printed with 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 escalated 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 based on individual patient assessment.

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

• Individuals with known hypersensitivity to bupropion or any other ingredients in bupropion hydrochloride extended-release tablets (SR).

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. Healthcare professionals are advised to observe these patients for the emergence of such symptoms and to instruct them 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-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the daily dose to a maximum of 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 also recommended.

In addition, 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 of their condition or the emergence of suicidal thoughts and behaviors.

To ensure patient safety, blood pressure should be monitored before starting treatment and periodically during treatment. Patients should be advised to discontinue bupropion and contact a 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) may 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 who were treated with antidepressants.

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) or within 14 days of stopping treatment with either is contraindicated.

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, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest reported prior to death in these patients.

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 (CNS) 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 cause false-positive results in urine drug tests for amphetamines, which may lead to unnecessary clinical interventions.

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, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Bupropion undergoes extensive hepatic metabolism to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to experience decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, careful consideration of renal function is advised when selecting a dose 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 identified an overall increased risk of congenital malformations. However, untreated depression during pregnancy poses risks to the mother and potentially to fetal outcomes. Animal studies have shown that administration of bupropion to pregnant rats during organogenesis did not result in fetal malformations 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 observed at doses approximately equal to the MRHD and higher, with decreased fetal weights noted at doses twice the MRHD and above.

The estimated background risk for major birth defects and miscarriage in the general population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of adverse outcomes, and the specific background risk for the indicated population remains unknown.

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

Human 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 demonstrate an overall increased risk for malformations. While the registry was not specifically designed to evaluate individual 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 regarding the association between bupropion exposure during the first trimester and specific cardiovascular defects, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), limit definitive conclusions. Some studies indicated an increased risk for VSD, while 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, although fetal malformations and skeletal variations were noted in rabbits at doses equal to or greater than the MRHD. Additionally, decreased fetal weights were observed at higher doses. No maternal toxicity was evident at doses of 50 mg/kg/day or less in these studies. 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 150 mg/kg/day.

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

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 can occur with significant consequences, particularly when doses of 30 grams or more are ingested. In such cases, seizures are reported to occur in approximately one-third of affected individuals.

Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and various cardiac complications. Notably, fatalities have been documented, especially in instances involving large doses, where multiple uncontrolled seizures and cardiac arrest have been observed.

Management of bupropion overdose requires immediate medical attention, as there are no known antidotes. Supportive care and close medical supervision are critical in these situations. Healthcare professionals are advised to ensure adequate airway management, oxygenation, and ventilation for the patient. The induction of emesis is not recommended due to the potential for further complications.

In the event of a bupropion overdose, it is essential to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control 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.

In terms of reproductive toxicity, no adverse effects on male or female fertility were observed when rats were administered oral doses of bupropion up to 300 mg/kg/day, which is approximately 7 times the MRHD on a mg/m² basis. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males received the treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately 5 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 on fertility, reproduction, or the 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 individuals have experienced high blood pressure, which can be severe, while taking bupropion hydrochloride extended-release tablets (SR). The likelihood of developing high blood pressure may be elevated in those also using nicotine replacement therapy for smoking cessation. Furthermore, 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.

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

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important for 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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should monitor patients on a daily basis 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, homicidal ideation, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion and contact a healthcare professional immediately.

Patients should be educated about the signs of hypersensitivity and instructed to stop taking bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue the medication and not restart it. It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

During the initial titration phase, particularly when doses exceed 150 mg/day, patients should be instructed to 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 also be made aware that taking bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be informed that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other bupropion-containing products. It is important to advise patients 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. Until they are certain that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Patients should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (SR) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients should be instructed to store bupropion hydrochloride extended-release tablets (SR) at room temperature, between 68°F and 77°F (20°C to 25°C), and to keep the tablets dry and protected from light. They should swallow the tablets whole to ensure the release rate is not altered and should not chew, divide, or crush them. If patients miss a dose, they 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. Patients should also be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and that the medication can be taken with or without food.

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° to 25°C (68° to 77°F). Temporary excursions are permissible within the range of 15° to 30°C (59° to 86°F).

It is essential to protect the product from light and moisture to maintain its integrity and efficacy. Proper handling and storage conditions are crucial for ensuring the quality of the product throughout its shelf life.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants for major depressive disorder (MDD) or other indications should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop.

Additionally, patients should contact a healthcare professional 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 or shortness of breath, patients must stop the medication and consult a healthcare provider. Postmarketing reports indicate that serious neuropsychiatric adverse events, including mood changes and suicidal ideation, have occurred in patients using bupropion for smoking cessation. While many cases resolved after discontinuation, some patients required ongoing monitoring and supportive care until symptoms subsided.

FDA Insert (PDF)

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

View full prescribing information (PDF)