Bupropion Hydrochloride (xl)

Description

Bupropion hydrochloride extended-release tablets (XL) are chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. The structure of bupropion closely resembles that of diethylpropion and is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO·HCl.

The bupropion hydrochloride powder is white, crystalline, and highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (XL) are available for oral administration in strengths of 150 mg and 300 mg, appearing as white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including povidone, tartaric acid, glyceryl distearate, magnesium stearate, hydroxypropyl cellulose, ethylcellulose, methacrylic acid copolymer dispersion, and colloidal silicon dioxide. The tablets are printed with black ink, which consists of shellac glaze (modified) in SD-45, isopropyl alcohol, black iron oxide non-irradiated, n-butyl alcohol, propylene glycol, and ammonium hydroxide.

Uses and Indications

This drug is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After a period of 4 days, the dose may be increased to a usual target of 300 mg once daily.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The initial dose is also 150 mg once daily, with a potential increase to 300 mg once daily after one week. Treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in dose and/or frequency of administration.

In patients with renal impairment, a reduction in dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) 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 adverse effects.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may precipitate seizures.

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

Additionally, bupropion hydrochloride (XL) is contraindicated in individuals with known hypersensitivity to bupropion or any of its components.

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including but not limited to 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 attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Should any of these adverse events occur, patients must be instructed to discontinue the medication immediately and contact their healthcare provider.

The risk of seizures associated with bupropion hydrochloride XL is dose-related. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be made gradually. In the event of a seizure, the medication should be discontinued.

Bupropion hydrochloride XL has 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 such reactions occur.

There is a specific concern regarding angle-closure glaucoma, which has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

A critical warning must be emphasized regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the worsening or emergence of suicidal thoughts and behaviors is essential.

To ensure patient safety, it is crucial to instruct patients to discontinue bupropion hydrochloride XL and seek immediate medical assistance if they experience any neuropsychiatric adverse events or psychotic symptoms. Regular blood pressure monitoring is also recommended before and during treatment to mitigate potential complications.

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 reported include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash. These reactions are generally mild to moderate in severity.

Serious adverse reactions warrant careful monitoring. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for the emergence or worsening of these 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, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should be instructed to contact a healthcare professional immediately.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride (XL) 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 or those with a current or prior diagnosis of bulimia or anorexia nervosa. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs may also increase seizure risk. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion hydrochloride (XL) is contraindicated, as is the use of bupropion hydrochloride (XL) within 14 days of stopping an MAOI intended for psychiatric disorders.

In cases of overdose, 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 or arrhythmias), clonus, myoclonus, and hyperreflexia. Severe outcomes such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been documented, particularly in the context of multiple drug overdoses. Fatalities associated with bupropion overdose have been reported, often following multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Patients should be informed of these potential adverse reactions and the importance of reporting any concerning symptoms to their healthcare provider.

Drug Interactions

Coadministration of bupropion hydrochloride (XL) with certain drug classes may lead to significant interactions that require careful consideration.

CYP Enzyme Interactions Bupropion is both a substrate and an inhibitor of cytochrome P450 enzymes. Specifically, it is a potent inhibitor of CYP2D6, which may lead to increased plasma concentrations of drugs metabolized by this enzyme, including various antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics. A dose reduction of these medications should be considered to mitigate the risk of adverse effects.

Conversely, inducers of CYP2B6 may necessitate an increase in the bupropion dose if coadministered; however, the total dosage should not exceed the maximum recommended limit.

Seizure Threshold Considerations Caution is advised when prescribing bupropion hydrochloride (XL) alongside medications that lower the seizure threshold. The combination may increase the risk of seizures, necessitating careful monitoring and potential dosage adjustments.

CNS Toxicity Risks The concomitant use of bupropion hydrochloride (XL) with dopaminergic agents, such as levodopa and amantadine, may lead to central nervous system (CNS) toxicity. Clinicians should monitor patients closely for signs of CNS effects and consider alternative therapies if necessary.

Hypertensive Reactions There is an increased risk of hypertensive reactions when bupropion hydrochloride (XL) is used in conjunction with monoamine oxidase inhibitors (MAOIs). It is advisable to avoid this combination or to monitor blood pressure closely if coadministration is unavoidable.

Urine Drug Testing Bupropion hydrochloride (XL) may cause false-positive results in urine tests for amphetamines. Clinicians should inform patients and consider alternative testing methods if necessary.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride (xl) (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 for bupropion hydrochloride extended-release tablets (XL). When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need, as outlined in the Boxed Warning and Warnings and Precautions (5.1).

Geriatric Use

Clinical trials involving approximately 6,000 patients treated with bupropion hydrochloride sustained-release tablets included 275 patients aged 65 years and older, with 47 patients aged 75 years and older. Overall, no significant differences in safety or effectiveness were observed between elderly patients and their younger counterparts. However, it is important to note that while clinical experience has not identified distinct differences in responses between these groups, a greater sensitivity to the drug in some older individuals cannot be excluded.

Elderly patients are more likely to present with decreased renal function, which may increase the risk of adverse reactions. Therefore, careful consideration of renal function is essential when selecting dosages for this population. It may be beneficial to monitor renal function in elderly patients to ensure appropriate dosing and minimize potential risks associated with impaired renal clearance.

Pregnancy

There is no specific information available regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or special precautions that should be taken. Healthcare professionals are advised to consider the lack of data when prescribing this medication to pregnant patients and to weigh the potential risks and benefits. Women of childbearing potential should be counseled accordingly, and alternative treatment options may need to be considered in the context of pregnancy.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, was found to be 2% of the maternal weight-adjusted dose.

Currently, 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 (XL) and any potential adverse effects on the breastfed child from bupropion hydrochloride (XL) or from the underlying maternal condition.

Renal Impairment

There is no information available regarding renal impairment, including dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of specific guidance when treating patients with renal impairment.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the individual patient's liver status when prescribing this medication.

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.

Symptoms of Overdosage

Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as conduction disturbances or arrhythmias. Additional symptoms can manifest as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in cases involving multiple drug overdoses.

Management of Overdosage

There are no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are essential. In severe cases, fatalities have been reported, often linked to large doses and multiple uncontrolled seizures, which may lead to bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a suspected overdose, it is crucial to consult a Certified Poison Control Center for guidance. Healthcare professionals can reach the Poison Control Center by calling 1-800-222-1222 or by visiting www.poison.org for further assistance.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of 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 of bupropion hydrochloride, 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, 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.

In terms of mutagenicity, bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded a negative result in another assay. Additionally, an increase in chromosomal aberrations was reported in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility. No information is available regarding teratogenic effects or animal pharmacology and toxicology.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Some patients have experienced changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been reported, particularly 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, and suicidal thoughts or actions, have been documented. These symptoms have been observed in some patients upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

The risk of seizures is noted to increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some individuals may experience significant increases in blood pressure while on this medication.

Periods of mania have been reported in some patients taking bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as markedly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, and confusion, have also been observed in some patients. Furthermore, severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been reported.

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, as these may occur suddenly. Any severe, abrupt, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts or actions, particularly when attempting to quit smoking while on bupropion. Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (XL) and not to restart if they experience a seizure during treatment.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) found in ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride.

Counseling should include a discussion about the potential for bupropion hydrochloride extended-release tablets (XL) to impair the ability to perform tasks requiring judgment or motor and cognitive skills. Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL).

Patients must inform their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride extended-release tablets (XL). It is crucial to instruct patients to swallow the tablets whole to ensure the release rate is not altered and to avoid crushing, dividing, or chewing them.

In the event that a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next tablet at the regular scheduled time, due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may 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 a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients and their caregivers should be advised to discontinue bupropion hydrochloride (XL) and seek immediate medical attention if they experience agitation, depressed mood, or any atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients treated with antidepressants for major depressive disorder or other indications must be vigilant for signs of agitation, irritability, and other behavioral changes, as well as the emergence of suicidality, and report these symptoms to healthcare providers without delay. Prescriptions for bupropion hydrochloride (XL) should be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, hallucinations, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been reported during clinical trials, presenting as pruritus, urticaria, angioedema, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been documented in postmarketing reports associated with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)