Bupropion hydrochloride

Description

Bupropion Hydrochloride USP is an antidepressant belonging to the aminoketone class, which is chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2, and its molecular formula is C13H18ClNO•HCl. The substance appears as a white, crystalline powder that is highly soluble in water, has a bitter taste, and induces a sensation of local anesthesia on the oral mucosa.

Bupropion Hydrochloride Extended-Release Tablets USP (XL) are formulated for oral administration and are available in strengths of 150 mg and 300 mg. These tablets are white to pale yellow in color and contain the labeled amount of bupropion hydrochloride along with the following inactive ingredients: cysteine hydrochloride, ethylcellulose, methacrylic acid copolymer dispersion, lecithin, magnesium stearate, polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, talc, triethyl citrate, and titanium dioxide.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) and the prevention of seasonal affective disorder (SAD).

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

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 four 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 of treatment. It is recommended to continue this regimen 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, consideration should be given to reducing the dose and/or frequency of administration.

In patients with renal impairment, it is advisable to consider a reduction in the dose and/or frequency of dosing based on individual patient assessment.

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 associated with bupropion.

Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of seizures.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

Patients with known hypersensitivity to bupropion or any other ingredients in bupropion hydrochloride extended-release tablets (XL) should not use this medication.

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, suicidal ideation, suicide attempts, and completed suicide. 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 also a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion hydrochloride XL.

A critical warning must be emphasized regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Close 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 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.

Serious adverse reactions have been reported, particularly concerning neuropsychiatric events. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, necessitating careful monitoring for the emergence or worsening of these symptoms. During smoking cessation, serious neuropsychiatric events may occur, 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.

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 can elevate blood pressure, warranting monitoring before and 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 are advised to contact a healthcare professional if such symptoms arise. Angle-closure glaucoma has been reported 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, current or prior diagnoses of bulimia or anorexia nervosa, and the potential for serious reactions following 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, seizures were reported in approximately one-third of patients. 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, 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, the dosage should not exceed the maximum recommended limit.

CYP2D6 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to elevated concentrations of various medications, including 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 medications should be considered when used concurrently with bupropion.

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

CNS Toxicity The concomitant use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic agents such as levodopa and amantadine may result in central nervous system (CNS) toxicity. Monitoring for adverse effects is recommended.

Hypertensive Reactions The use of bupropion hydrochloride extended-release tablets (XL) in combination with monoamine oxidase inhibitors (MAOIs) can lead to an increased risk of hypertensive reactions. Close monitoring of blood pressure is advised in such cases.

Urine Drug Testing It is important to note that bupropion hydrochloride extended-release tablets (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.

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 studies 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. However, while clinical experience has not identified significant differences in responses, 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, careful consideration of renal function is essential 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 indicate that exposure to bupropion during the first trimester has not been associated with an increased risk of congenital malformations overall. However, untreated depression poses risks to the mother that should be considered. In animal studies, bupropion administered to pregnant rats during organogenesis did not result in fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, when administered to pregnant rabbits, non-dose-related increases in 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 higher.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. A prospective longitudinal study involving 201 pregnant women with a history of major depressive disorder found that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, the risks associated with untreated depression and potential effects on the fetus should be carefully weighed when considering changes to antidepressant therapy 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 demonstrate an overall increased risk for malformations. However, the registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall was observed. The prospectively observed rate of cardiovascular malformations in pregnancies with first-trimester exposure to bupropion was 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and risks for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions. In studies involving 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 doses starting from 25 mg/kg/day, with decreased fetal weights at doses of 50 mg/kg/day and higher. Notably, 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 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, was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

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

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 quantities 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 pronounced in cases involving multiple drug overdoses, which can complicate the clinical picture and necessitate more intensive management.

Fatalities linked to bupropion overdose have also been recorded, often occurring after multiple uncontrolled seizures. Other critical cardiovascular events such as bradycardia, cardiac failure, and cardiac arrest may precede these tragic outcomes, underscoring the importance of prompt recognition and intervention.

Currently, there are no known antidotes for bupropion overdose. Therefore, the primary approach to management involves supportive care and close medical supervision. Healthcare professionals are advised to monitor the patient closely for any signs of deterioration.

In the event of a suspected overdose, it is crucial to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center by calling 1-800-222-1222 or by visiting www.poison.org for additional resources and information.

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, 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.

In terms of mutagenicity, bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, indicating 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. There is no information available regarding teratogenic effects or animal pharmacology and toxicology.

Postmarketing Experience

Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports include changes in mood, such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, instances of suicidal ideation, suicide attempts, and completed suicides have been documented.

Neuropsychiatric adverse events have occurred in both patients with and without pre-existing psychiatric conditions, with some individuals experiencing a worsening of their psychiatric illnesses. It is recommended that patients be observed for the occurrence of these neuropsychiatric adverse events. Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if symptoms such as agitation, depressed mood, or atypical changes in behavior or thinking arise, or if suicidal ideation or behavior develops.

In many postmarketing cases, resolution of symptoms following the discontinuation of bupropion has been reported. However, in some instances, symptoms persisted, indicating the need for ongoing monitoring and supportive care until resolution occurs.

Patient Counseling

Healthcare providers should inform patients that the use of antidepressants, including bupropion hydrochloride extended-release tablets (XL), is associated with an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults during short-term trials. It is important to note that these trials did not indicate an increased risk in patients aged 65 and older.

Patients of all ages who are initiated on antidepressant therapy require close monitoring for any worsening of their condition, as well as for the emergence of suicidal thoughts and behaviors. Healthcare providers should advise families and caregivers about the necessity of vigilant observation and open communication with the prescriber regarding the patient's mental health status.

Families and caregivers should be alerted to monitor patients being treated with antidepressants for major depressive disorder or other indications—both psychiatric and nonpsychiatric. They should be particularly watchful for signs of agitation, irritability, unusual changes in behavior, and any symptoms indicative of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation by families and caregivers is recommended.

When prescribing bupropion hydrochloride extended-release tablets (XL), healthcare providers should write prescriptions for the smallest quantity of tablets necessary for effective patient management. This practice is intended to minimize the risk of overdose.

Patients and their caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if they observe any signs of agitation, a depressed mood, or atypical changes in behavior or thinking. Additionally, if the patient develops suicidal ideation or engages in suicidal behavior, prompt communication with a healthcare provider is crucial.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product 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) as outlined by USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep the product out of reach of children to ensure safety.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)