Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, 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 drug is presented as a white powder that is soluble in water, 0.1 N hydrochloric acid, and alcohol. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (XL) are formulated for oral administration, available in a strength of 300 mg. These tablets are white to pale yellow and contain 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 edible black ink, which consists of 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 this drug.

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual dose increase 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. The usual target dose is 300 mg once daily, with the option to increase the dose to 300 mg after 4 days if clinically indicated.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a typical 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 advised to continue treatment 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 recommended to evaluate the need for dose reduction and/or adjustment of dosing frequency based on the severity of the impairment.

Contraindications

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

Patients with a seizure disorder due to the increased risk of seizures.

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

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

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 discontinuing an MAOI, nor should it be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Patients undergoing smoking cessation with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant events, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe these patients for the emergence of such symptoms and instruct them to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical advice if any adverse events occur.

The risk of seizures associated with bupropion hydrochloride extended-release tablets (XL) 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 promptly.

Bupropion hydrochloride extended-release tablets (XL) have 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 to ensure patient safety.

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 during treatment.

In addition, patients should be informed about the possibility of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional immediately if such reactions occur.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion hydrochloride extended-release tablets (XL). Caution is advised in these patients.

It is important to note the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the worsening or emergence of suicidal thoughts and behaviors is crucial throughout the treatment process.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride extended-release tablets (XL). 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.

Serious adverse reactions 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 the emergence or worsening of these thoughts and behaviors. Additionally, neuropsychiatric adverse events may occur 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 with bupropion should be closely observed for these symptoms and instructed to discontinue the medication and contact a healthcare provider if they arise.

The risk of seizures is dose-related, and it is recommended to limit the daily dose to 450 mg and to gradually increase the dose to minimize this risk. If a seizure occurs, the medication should be discontinued. Bupropion can also increase 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. Instruct patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions. Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Additional 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 an MAOI. Known hypersensitivity to bupropion or its ingredients is also a contraindication.

In cases of overdose, seizures were reported in approximately one-third of all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, changes in mental status, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), clonus, myoclonus, and hyperreflexia. Severe reactions such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been noted, particularly in cases involving multiple drug overdoses. Deaths associated with bupropion overdose have been reported, often following large doses, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest occurring prior to death.

Drug Interactions

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

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers, a dose increase may be necessary to achieve therapeutic effects. However, the total dosage should not exceed the maximum recommended dose to avoid potential toxicity.

CYP2D6 Inhibitors Bupropion is a known inhibitor of CYP2D6, which can lead to elevated plasma concentrations of various medications metabolized by this enzyme, including certain antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics. It is advisable to consider a dose reduction of these concomitant medications to mitigate the risk of adverse effects.

Drugs Lowering Seizure Threshold Caution is warranted when prescribing bupropion in conjunction with medications that lower the seizure threshold. Close monitoring of the patient is recommended to prevent seizure-related complications.

Dopaminergic Drugs The concurrent use of bupropion with dopaminergic agents, such as levodopa and amantadine, may result in increased central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is advised.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion hydrochloride extended-release tablets with MAOIs can elevate the risk of hypertensive reactions. It is essential to monitor blood pressure closely in patients receiving this combination.

Urine Drug Screening Patients taking bupropion hydrochloride extended-release tablets may test positive for amphetamines on urine drug screenings. This potential for false-positive results should be communicated to the patient and considered in the interpretation of drug 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 approximately 6,000 patients treated with Wellbutrin SR included 275 patients aged 65 years and older, with 47 patients aged 75 years and older. The data indicate that there are no overall differences in safety or effectiveness between elderly patients and their younger counterparts. However, it is important to note that while clinical experience has not identified significant differences in responses between these age groups, a greater sensitivity to the medication in some older individuals cannot be excluded.

Elderly patients may be at an increased risk of adverse reactions, particularly those with impaired renal function. Given that geriatric patients are more likely to experience decreased renal function, careful consideration should be given to this factor when selecting dosages. It is advisable to monitor renal function in elderly patients to ensure appropriate dosing and to mitigate potential risks associated with renal impairment.

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. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis, with no evidence of fetal malformations in rats. However, in rabbits, non-dose-related increases in fetal malformations and skeletal variations were observed at the lowest dose tested and greater, with decreased fetal weights at doses of 50 mg/kg/day and greater, although no maternal toxicity was evident at doses of 50 mg/kg/day or less.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. 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. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester being 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

Bupropion is excreted in breast milk. In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the maximum recommended human dose on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

The effects of bupropion on breastfed infants have not been established. Therefore, healthcare professionals should weigh the potential benefits of bupropion therapy against the risks to the nursing infant when considering its use in lactating mothers.

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 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.

Symptoms of Overdosage

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

Management of Overdosage

There are no known antidotes for bupropion; therefore, supportive care and close medical supervision are essential in managing an overdose. It is critical to monitor the patient for any severe symptoms and to provide appropriate interventions as necessary.

In cases of suspected overdose, it is advisable 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.

Prognosis

Fatalities associated with bupropion overdose have been reported, often linked to large doses and multiple uncontrolled seizures, which may lead to bradycardia, cardiac failure, and cardiac arrest prior to death. Prompt recognition and management of overdose symptoms are vital to improving patient outcomes.

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, 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 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 reported in 1 of 3 in vivo rat bone marrow cytogenetic studies. A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

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 observed. These symptoms may occur upon initiation of bupropion therapy, 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 such cases.

Instances of severe hypertension have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL), with an increased risk noted in those concurrently using nicotine replacement therapy.

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

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been reported. Patients experiencing these symptoms are advised to contact their healthcare provider.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been observed. Patients should discontinue the medication and seek immediate medical attention if they experience symptoms such as 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

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to 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 behavioral changes, as well as worsening depression and suicidal ideation. These symptoms may occur particularly early in the treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, which should be reported to the prescriber or healthcare professional, especially if they are severe or were not part of the patient's initial symptoms. Patients should be informed that some individuals have experienced significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and suicidal thoughts when attempting to quit smoking while taking 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 discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be informed that if they experience a seizure while on treatment, they should discontinue and not restart the medication. It is crucial to advise patients 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.

Patients should also be made aware that bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. It is important to inform patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as Zyban®, which is used for smoking cessation, and should not be used in combination with Zyban® or any other medications containing bupropion hydrochloride.

Healthcare providers should counsel 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. Patients should be advised to 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.

Patients should also be instructed to inform their healthcare provider if they become pregnant or plan to become pregnant during treatment. It is essential to instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to ensure the proper release rate. 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 administered in the morning and may be taken with or without food.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature.

It is essential to keep the product out of reach of children to ensure safety and prevent accidental ingestion. Proper handling and storage conditions must be maintained to preserve the integrity of the product.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants, including bupropion hydrochloride extended-release tablets (XL), should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion XL and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop. Additionally, patients should stop taking the medication and consult a healthcare provider if they experience any allergic or anaphylactoid reactions, such as skin rash, pruritus, or difficulty breathing.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. These events include mood changes, psychosis, and suicidal ideation, among others. Anaphylactoid and anaphylactic reactions have also been reported, necessitating medical intervention, with rare cases of severe skin reactions and anaphylactic shock noted in spontaneous reports.

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)