Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets USP (XL) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. The chemical structure 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 active ingredient is presented as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration, each containing 300 mg of bupropion hydrochloride in an off-white tablet form. Inactive ingredients include copovidone, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, methacrylic acid copolymer type C, triethyl citrate, colloidal anhydrous silica, sodium bicarbonate, sodium lauryl sulfate, and povidone.

The extended-release tablet features an insoluble shell that may remain intact during gastrointestinal transit and is excreted in feces. This drug product meets the standards of USP Drug Dissolution Test #11.

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) in individuals at risk for this condition.

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

Dosage and Administration

The dosage and administration of the medication should be approached with caution, particularly with regard to the gradual increase of the dose 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 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 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 potential increase to 300 mg once daily after one week. 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 administration.

In patients with renal impairment, a reduction in the 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 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 is contraindicated, as it may elevate the risk of seizures.

Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders, or within 14 days of discontinuing either treatment. Additionally, it is contraindicated to initiate bupropion hydrochloride extended-release tablets (XL) 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) is also a contraindication for use.

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors There is a documented increased risk of suicidal thinking and behavior in children, adolescents, and young adults who are prescribed antidepressants. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports indicate that patients attempting to quit smoking while using bupropion hydrochloride XL may experience serious neuropsychiatric adverse events. These can 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. It is imperative to observe patients for these symptoms and instruct them to discontinue bupropion hydrochloride XL and seek immediate medical advice if such adverse events occur.

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

Hypertension 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.

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

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. Caution is advised in these patients.

Monitoring and Laboratory Tests Blood pressure should be monitored before starting treatment and periodically during the treatment course to ensure patient safety.

In the event of neuropsychiatric adverse events, patients must be instructed to discontinue bupropion hydrochloride XL and contact their healthcare provider immediately. Additionally, if a seizure occurs, the medication should be stopped without delay.

Side Effects

Patients may experience a range of adverse reactions while using the medication. The most 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.

A significant warning associated with this medication is the increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

During smoking cessation, serious or clinically significant neuropsychiatric adverse events have been observed. These include changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

There is a dose-related risk of seizures associated with this medication. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. If a seizure occurs, discontinuation of the medication is advised.

Patients should also be aware that the use of bupropion hydrochloride extended-release tablets (XL) can lead to increased blood pressure. Blood pressure should be monitored before initiating treatment and periodically throughout the treatment course.

Additionally, there is a risk of activation of mania or hypomania in patients with bipolar disorder; therefore, screening for this condition is essential, and patients should be monitored for these symptoms.

Psychosis and other neuropsychiatric reactions may occur, and patients are 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.

In cases of overdose, serious reactions have been reported, including seizures in approximately one third of all overdose cases. Other serious adverse 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, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

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, and phenytoin, an increase in bupropion dosage may be necessary to achieve desired clinical exposure. However, any dosage adjustments should not exceed the maximum recommended dose.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of drugs metabolized by this enzyme. This includes various antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). A dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects.

Drugs That Lower Seizure Threshold Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) in conjunction with other medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

Dopaminergic Drugs The concurrent use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion hydrochloride extended-release tablets (XL) with MAOIs poses an increased risk of hypertensive reactions. Caution is warranted, and close monitoring is advised if these agents must be used together.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

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 years 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 patients in these studies. However, while clinical experience has not identified significant differences in responses between these groups, it is important to note that some older individuals may exhibit greater sensitivity to the medication.

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 a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

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 involving pregnant women exposed to bupropion during 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 animal studies, when bupropion was administered to pregnant rats during organogenesis, no evidence of fetal malformations was observed at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were noted at doses approximately equal to the MRHD and greater, with decreased fetal weights observed at doses twice the MRHD and higher.

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. A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those 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.

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 overall increased risk for malformations. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding bupropion exposure during the first trimester and the risk of left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions regarding possible associations. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during organogenesis at doses of up to 450 mg and 150 mg/kg/day, respectively. While no fetal malformations were observed in rats, pregnant rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose and greater, with decreased fetal weights at doses of 50 mg/kg/day and higher. No maternal toxicity was evident at doses of 50 mg/kg/day or less. Additionally, a pre- and postnatal development study indicated that bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no adverse effects 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 were reported. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, alterations in mental status, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Additional symptoms may encompass clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

While the majority of patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, particularly in individuals who ingested large quantities of the drug. Reports indicate that these cases often involved multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for current guidance and recommendations. Healthcare professionals can reach the Poison Control Center at 1-800-222-1222 or visit www.poison.org for further assistance.

There are no known antidotes for bupropion; therefore, management of an overdose should focus on supportive care. This includes close medical supervision and monitoring of the patient. It is also essential to consider the possibility of a multiple drug overdose when assessing the situation.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice, administering bupropion hydrochloride 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 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

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. Suicidal ideation and suicide attempts have also 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. 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 on bupropion hydrochloride extended-release tablets (XL) are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride extended-release tablets (XL) is contraindicated in individuals with a history of seizures.

Instances of severe hypertension have been reported in some patients taking bupropion hydrochloride extended-release tablets (XL), with an increased risk noted in those concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Periods of mania, characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech, have been observed in some individuals during treatment with bupropion hydrochloride extended-release tablets (XL).

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. Healthcare providers should instruct patients, their families, and caregivers to remain 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 be encouraged to monitor patients closely for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional. It is important to note that these symptoms may be associated with an increased risk of suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Patients should be informed that some individuals have reported experiencing mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal thoughts and actions when attempting to quit smoking while taking bupropion. Patients should 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 bupropion-containing products.

Healthcare providers should advise patients that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until patients are confident that bupropion hydrochloride extended-release tablets (XL) do not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

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

Patients must 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 and their caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (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 receiving antidepressants for major depressive disorder or other indications should be vigilant in monitoring for signs of agitation, irritability, and other behavioral changes, as well as the emergence of suicidality, and report any concerning symptoms to healthcare providers. Daily observation is recommended.

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, presenting with symptoms such 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 association with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)