Bupropion hydrochloride

Description

Bupropion hydrochloride, USP is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.2 g/mol, and the molecular formula is C13H18ClNO·HCl. Bupropion hydrochloride, USP powder is white and soluble in water, in 0.1 N hydrochloric acid, and in alcohol. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (XL) are supplied for oral administration as 150 mg white to pale yellow, round, film-coated extended-release tablets. Each extended-release tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including ethylcellulose, glyceryl behenate, hydroxypropyl cellulose, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, polyethylene glycol, povidone, silicon dioxide, stearic acid, and triethyl citrate. The tablets are printed with opacode S-1-17823 (black), which contains ferrosoferric oxide, propylene glycol, and shellac glaze.

Uses and Indications

Bupropion hydrochloride extended-release tablets, USP (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, USP (XL).

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 (XL) is contraindicated in the following situations:

Patients with a seizure disorder, as bupropion may increase the risk of seizures.

Individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for exacerbating these conditions.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may heighten the risk of 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 stopping an MAOI, nor should it be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the components of bupropion hydrochloride (XL) is also a contraindication.

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious incidents, including mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and aggressive behaviors. Notably, there have been reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion hydrochloride (XL) for these symptoms and instruct them to discontinue the medication and seek immediate medical advice if such adverse events occur.

The risk of seizures associated with bupropion hydrochloride (XL) is dose-dependent. To mitigate this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be made gradually. Should a seizure occur, the medication must be discontinued immediately.

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 hydrochloride (XL) may activate mania or hypomania. Continuous monitoring for these symptoms is advised.

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.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion hydrochloride (XL).

There is a specific warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the emergence or worsening of suicidal thoughts and behaviors is crucial in these populations.

To ensure patient safety, it is essential to monitor blood pressure before starting treatment and periodically during treatment. Patients should be advised to discontinue bupropion hydrochloride (XL) 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 using this medication, which can be categorized by seriousness and frequency.

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

Serious warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor patients for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported 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 should be closely monitored for these symptoms.

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 increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised.

Hypertension is another concern, as bupropion hydrochloride (XL) can elevate blood pressure. Blood pressure should be monitored before initiating treatment and periodically throughout the treatment course.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Additionally, patients are advised to contact a healthcare professional if they experience any psychotic symptoms or other neuropsychiatric reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, necessitating caution in this population.

In cases of overdose, serious reactions have been observed, including seizures in approximately one third of cases. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, changes in mental status, 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 association with bupropion overdose, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of bupropion hydrochloride (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 a known inhibitor of CYP2D6 and may elevate the plasma concentrations of various medications metabolized by this enzyme. This includes 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 when used with bupropion.

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

CNS Toxicity The concurrent use of bupropion hydrochloride (XL) with dopaminergic agents such as levodopa and amantadine may lead to central nervous system toxicity. Monitoring for adverse effects is recommended.

MAO Inhibitors The combination of bupropion hydrochloride (XL) with monoamine oxidase inhibitors (MAOIs) can heighten the risk of hypertensive reactions. Close monitoring is warranted in such cases.

Urine Drug Testing It is important to note that bupropion hydrochloride (XL) may cause false-positive results for amphetamines in urine drug tests, which should be taken into account during clinical assessments.

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 (XL). When considering its use in children or adolescents, healthcare professionals should carefully balance the potential risks against 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 trials with the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses between these groups, it is important to note that greater sensitivity 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, 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 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. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued treatment. Therefore, healthcare providers should consider the risks to the mother 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. Decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; however, all pregnancies have a background rate of birth defects, loss, or other adverse outcomes. 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, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. 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 of left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow for definitive conclusions. The United Healthcare database lacked sufficient power to evaluate this association; however, the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, while the Slone Epidemiology case-control study did not find an increased risk for LVOTO. Similarly, findings regarding the risk for ventricular septal defect (VSD) are inconsistent, with the Slone Epidemiology Study indicating an increased risk for VSD following first trimester maternal bupropion exposure but not for any other cardiovascular malformations studied.

In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats. In rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside the lactating mother's clinical need for bupropion hydrochloride (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

There is no information available regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as specific guidelines or recommendations are not provided in the current data.

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, highlighting the potential neurological risks associated with excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly concerning in scenarios involving multiple drug overdoses, where the risk of severe complications is heightened.

Fatalities linked to bupropion overdose have been observed, often occurring after multiple uncontrolled seizures, bradycardia, and subsequent cardiac arrest. This underscores the critical nature of prompt and effective management in overdose situations.

Currently, there are no known antidotes for bupropion. Therefore, the primary approach to managing an overdose involves providing supportive care and ensuring close medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for expert guidance in the event of a bupropion overdose, ensuring that appropriate interventions are implemented swiftly and effectively.

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; lower doses were not evaluated. The potential for these lesions to serve as precursors to neoplasms of the liver 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 species.

Bupropion demonstrated a positive response in two out of five 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 Ames assay. Additionally, an increase in chromosomal aberrations was observed in one of three 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 in some individuals using bupropion for smoking cessation. These symptoms were more frequently observed in patients with a prior history of mental health disorders compared to those without such a history.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been reported. Patients are advised to discontinue use and contact their healthcare provider immediately if they experience symptoms such as 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, as these may indicate a serious allergic reaction.

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

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

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been observed in certain patients. Furthermore, visual disturbances such as eye pain, changes in vision, and swelling or redness in or around the eye have been reported, with some individuals being at risk for these complications.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they understand the medication's use and potential risks. It is important to instruct patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly concerning during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to monitor patients daily 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 significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and suicidal thoughts, particularly when attempting to quit smoking while on bupropion.

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

Healthcare providers should counsel patients on the risks associated with excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase the risk of seizures. Patients should be advised to minimize or avoid alcohol consumption. Additionally, patients should be informed that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

It is essential to educate patients that bupropion hydrochloride extended-release tablets (XL) 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 products containing bupropion hydrochloride. Patients should also be made aware 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.

Patients should notify 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. Furthermore, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole to maintain the intended release rate. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next dose at the regular scheduled time due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and can be consumed with or without food.

Storage and Handling

The product is supplied in bottles containing 30, 90, or 500 units, each equipped with a child-resistant closure. It should be stored at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride (XL) for major depressive disorder or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion hydrochloride (XL) and seek medical attention if they observe any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, any allergic or anaphylactoid reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath, warrant immediate cessation of the medication and consultation with a healthcare provider.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, characterized by symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been documented, along with reports of delayed hypersensitivity reactions presenting as arthralgia, myalgia, and fever with rash.

FDA Insert (PDF)

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

View full prescribing information (PDF)