Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets USP (XL) are chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. The chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO·HCl. The powder form of bupropion hydrochloride is white, crystalline, and exhibits high solubility in water. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. The extended-release tablets are formulated for oral administration, each containing 300 mg of bupropion hydrochloride, USP, and include the following inactive ingredients: colloidal anhydrous silica, colloidal silicon dioxide, copovidone, hydroxypropyl cellulose, magnesium stearate, methacrylic acid copolymer type C, polyethylene glycol, polyvinyl alcohol, povidone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, and triethyl citrate.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, this medication is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL).

Dosage and Administration

The dosage of the medication should be increased gradually to minimize the risk of seizures. Healthcare professionals are advised to periodically reassess the patient's dose and the necessity for maintenance treatment.

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

In the case of Seasonal Affective Disorder, treatment should be initiated in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a usual target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily, and it is recommended to continue treatment throughout the winter season.

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

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

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in the following situations:

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

The use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased risk of seizures.

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs may increase the risk of seizures; therefore, bupropion hydrochloride extended-release tablets (XL) should not be used in these patients.

The concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders with bupropion hydrochloride extended-release tablets (XL) is contraindicated, as is the use of bupropion hydrochloride extended-release tablets (XL) within 14 days of stopping an MAOI. Additionally, bupropion hydrochloride extended-release tablets (XL) should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the other components of bupropion hydrochloride extended-release tablets (XL) constitutes a contraindication to its use.

Warnings and Precautions

Increased risk of suicidal thinking and behavior has been observed in children, adolescents, and young adults taking antidepressants. Healthcare professionals should closely monitor these populations for any worsening or emergence of suicidal thoughts and behaviors (5.1).

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated serious or clinically significant neuropsychiatric adverse events associated with bupropion hydrochloride extended-release tablets (XL) during smoking cessation. These events may include 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. Patients attempting to quit smoking should be observed for these symptoms, and they must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider if they experience any of these adverse events.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose as clinically appropriate. If a seizure occurs, bupropion hydrochloride extended-release tablets (XL) should be discontinued immediately.

Hypertension Bupropion hydrochloride extended-release tablets (XL) may increase blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

General Precautions Healthcare professionals should ensure that blood pressure is monitored before and during treatment. Additionally, screening for bipolar disorder and monitoring for symptoms of mania or hypomania is recommended.

Emergency Instructions Patients must be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical assistance if they experience any neuropsychiatric adverse events.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (XL) may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of patients and at least twice the rate of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

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 the emergence or worsening of these thoughts and behaviors during treatment.

Postmarketing reports have identified serious neuropsychiatric adverse events during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking while on bupropion should be observed for these symptoms and instructed to discontinue the medication and contact a healthcare provider if they occur.

The risk of seizures is dose-related, with recommendations to limit the daily dose to 450 mg and to gradually increase the dose. If a seizure occurs, the medication should be discontinued. Additionally, bupropion can elevate 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. Neuropsychiatric reactions, including psychosis, may occur, and patients should be advised to contact a healthcare professional if such reactions arise.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of 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 overdose, which have been reported at doses of 30 grams or more, seizures occurred in approximately one-third of cases. Other serious reactions included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with bupropion overdose have been reported, often following multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

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

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, an increase in bupropion dosage may be necessary to maintain clinical exposure. However, any dosage adjustment should not exceed the maximum recommended dose.

CYP2D6 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including:

• Antidepressants: venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline.

• Antipsychotics: haloperidol, risperidone, and thioridazine.

• Beta-blockers: metoprolol.

• Type 1C antiarrhythmics: propafenone and flecainide.

When bupropion is used in conjunction with these agents, a dose reduction of the affected medications should be considered to mitigate the risk of adverse effects.

Seizure Threshold Caution is advised when prescribing bupropion XL with other medications that may lower the seizure threshold, as this combination can increase the risk of seizures.

CNS Toxicity Concomitant use of bupropion XL with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

MAO Inhibitors (MAOIs) The use of bupropion XL in combination with MAOIs can elevate the risk of hypertensive reactions. Close monitoring of blood pressure is advised in patients receiving this combination.

Urine Drug Testing It is important to note that bupropion XL may cause false-positive results in urine tests for amphetamines. This should be taken into account when interpreting drug screening results.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established 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 for treatment.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 and older participated in clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects in these studies. However, while clinical experience has not identified significant differences in responses between these age groups, it is important to note that greater sensitivity to the drug 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, careful consideration of renal function is advised when selecting a dose for geriatric patients, and it may be beneficial to monitor renal function throughout treatment.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. In a prospective, longitudinal study, women with a history of major depressive disorder who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, 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, with decreased fetal weights noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures did not show an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall has been observed. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which is similar to the background rate of approximately 1%.

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

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, 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 extended-release tablets (XL) 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 available 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 have been documented, with instances involving doses of 30 grams or more. In approximately one third of these cases, seizures have been reported.

Clinical Manifestations Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and changes in electrocardiogram (ECG) readings. Additional symptoms that may present include sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, hypotension, stupor, coma, and respiratory failure. It is important to note that fatalities have been linked to bupropion overdose, particularly in scenarios involving high doses and poly-drug use.

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

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases should focus on supportive care and close medical supervision to monitor and address the symptoms as they arise.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with 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, which is approximately 2 to 7 times the MRHD on a mg/m² basis. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, the mouse study did not demonstrate similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion exhibited 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 negative results in another assay. Additionally, an increase in chromosomal aberrations was noted 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.

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 individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

Patients experiencing a seizure while taking bupropion hydrochloride extended-release tablets (XL) are advised to discontinue use immediately and contact their healthcare provider. It is contraindicated to resume bupropion hydrochloride extended-release tablets (XL) after a seizure.

Instances of severe hypertension have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL).

Additionally, some patients may experience episodes of mania while on bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported among patients taking bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been documented, with signs including rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

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 closely on a day-to-day 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. Such symptoms may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Patients should be informed that some individuals have reported mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal thoughts and actions when attempting to quit smoking while using bupropion. If patients experience any of these symptoms, they should discontinue bupropion hydrochloride extended-release tablets (XL) 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 (XL) 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.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can elevate 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. Therefore, bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with ZYBAN® or any other medications containing bupropion hydrochloride.

Patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), 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, hazardous 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 (XL) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride extended-release tablets (XL).

Patients should be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole to ensure the release rate is not altered. 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. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed with or without food.

Storage and Handling

The product is supplied in tight, light-resistant containers as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Patients prescribed bupropion hydrochloride extended-release tablets (XL) should be advised to discontinue use and contact a healthcare provider immediately if they experience agitation, depressed mood, or any atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers are encouraged to closely monitor patients for signs of agitation, irritability, and other behavioral changes, as well as the emergence of suicidality, and to report any concerning symptoms to healthcare providers promptly. Prescriptions should be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use, particularly in patients using it for smoking cessation. Reported events include mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal thoughts or actions. While many cases resolved after discontinuation of the medication, some patients continued to experience symptoms, highlighting the need for ongoing monitoring and supportive care until symptoms fully resolve.

FDA Insert (PDF)

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

View full prescribing information (PDF)