Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinguished by its chemical structure, which is unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitors, or other known antidepressant agents. Its chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO•HCl.

The compound appears as a white, crystalline powder that is highly soluble in water and possesses a bitter taste, which can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets (XL) for oral administration, available in dosages of 150 mg and 300 mg. Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including colloidal silicon dioxide, copovidone, ethyl cellulose, hydroxypropyl cellulose, glyceryl behenate, methacrylic acid copolymer, and silicon dioxide. The tablets are marked with edible black ink.

Notably, the insoluble shell of the extended-release tablet may remain intact throughout gastrointestinal transit and is subsequently excreted in the feces. The USP dissolution test for this formulation is currently pending.

Uses and Indications

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

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

Dosage and Administration

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. 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 usual target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily, and it is recommended to continue treatment throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in the dose and/or frequency of 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 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 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, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (XL). Additionally, bupropion hydrochloride extended-release tablets (XL) should not be started in patients receiving linezolid or intravenous methylene blue.

• Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (XL).

Warnings and Precautions

Postmarketing surveillance has identified serious neuropsychiatric adverse events associated with the use of bupropion hydrochloride extended-release tablets (XL) during smoking cessation. These events may include significant mood alterations such as depression and mania, as well as psychotic symptoms including hallucinations, paranoia, delusions, and aggressive behaviors. Healthcare professionals are advised to closely monitor patients for the emergence of these symptoms. Should any neuropsychiatric adverse events occur, patients should be instructed to discontinue the medication and seek immediate consultation with a healthcare provider.

The risk of seizures is dose-dependent when using bupropion hydrochloride extended-release tablets (XL). To mitigate this risk, it is recommended that the daily dosage not exceed 450 mg, and that the dose be increased gradually. In the event of a seizure, the medication should be discontinued promptly.

Bupropion hydrochloride extended-release tablets (XL) have been associated with an increase in blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and to conduct periodic assessments 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 recommended during treatment.

In addition, patients should be informed about the potential for psychosis and other neuropsychiatric reactions. They should be encouraged to report any such reactions to their healthcare professional without delay.

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).

It is critical to note the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Healthcare providers should monitor these populations closely for any worsening of symptoms or the emergence of suicidal ideation or behavior.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (XL) may experience a range of adverse reactions. 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 warranting caution include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for the emergence or worsening of these thoughts and behaviors during treatment. Neuropsychiatric events may also 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.

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, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been observed, particularly in patients with a history of bipolar disorder, and these patients should be screened and monitored accordingly. Patients are also 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. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI.

In cases of overdose, seizures were reported in approximately one third of all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Fatalities have been documented in patients who ingested large doses of bupropion, with reports of multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest preceding death.

Drug Interactions

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

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

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 when used with bupropion.

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 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 monitoring for hypertensive symptoms is advised.

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.

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 using the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients. However, while clinical experience has not identified significant differences in responses, it is important to note that greater sensitivity in some older individuals cannot be ruled out.

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 doses for geriatric patients. Monitoring of renal function may also be beneficial to ensure safe and effective use of the medication in this demographic.

Pregnancy

Pregnancy Category C. Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester indicate no overall increased risk of congenital malformations. It is important to note that all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. Reproductive developmental studies in rats and rabbits did not demonstrate clear evidence of teratogenic activity; however, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations observed at doses approximately equal to the maximum recommended human dose (MRHD) and higher. Additionally, decreased fetal weights were noted at doses twice the MRHD and greater.

Bupropion hydrochloride extended-release tablets (XL) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical considerations must include the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Human data from an international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures, did not show an increased risk for malformations overall. Specifically, no increased risk for cardiovascular malformations has been observed following bupropion exposure during the first trimester. 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%.

However, findings regarding the association between bupropion exposure during the first trimester and left ventricular outflow tract obstruction (LVOTO) are inconsistent, with the United Healthcare database lacking sufficient power to evaluate this association. The National Birth Defects Prevention Study (NBDPS) identified an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7), while the Slone Epidemiology case-control study did not find an increased risk. Similarly, findings regarding ventricular septal defect (VSD) are inconsistent; the Slone Epidemiology Study reported an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0), whereas the NBDPS and United Healthcare database studies did not find an association. The limitations of these studies include small numbers of exposed cases and the potential for chance findings due to multiple comparisons.

Animal studies involving bupropion administered orally to rats and rabbits during organogenesis did not reveal clear teratogenic effects. However, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at doses starting from 25 mg/kg/day (approximately equal to the MRHD on a mg/m² basis) and higher, with decreased fetal weights observed at doses of 50 mg/kg and above. In rats, administration of bupropion at doses up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

Lactation

Bupropion and its metabolites are present 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.

Caution is advised when administering bupropion hydrochloride extended-release tablets (XL) to lactating mothers.

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 and consider individual patient factors when prescribing to patients with reduced kidney function, as the absence of specific guidance necessitates careful clinical judgment.

Hepatic Impairment

There is no available information regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the lack of data when prescribing this medication to patients with liver problems.

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 as a significant adverse effect. Other serious reactions associated with bupropion overdoses include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances or arrhythmias.

In cases where bupropion was part of a multiple drug overdose, additional severe symptoms have been observed. These include fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. While most patients have recovered without lasting effects, there have been reports of fatalities linked to overdoses of bupropion alone, particularly in individuals who ingested large quantities of the drug. In these severe cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

Healthcare professionals are advised to monitor patients closely for these symptoms in the event of a suspected overdose. Immediate medical intervention is crucial, and supportive care should be initiated as necessary.

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 of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. The implications of these lesions as potential precursors to liver neoplasms remain 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 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, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts in individuals attempting to quit smoking while on bupropion. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL). It is essential to counsel patients, their families, and caregivers on the appropriate use of this medication.

Providers should ensure that patients are aware of the available Medication Guide, which includes critical information about antidepressant medicines, depression, serious mental illnesses, suicidal thoughts or actions, quitting smoking, and other important considerations related to bupropion hydrochloride extended-release tablets (XL). Patients, along with their families and caregivers, should be instructed to read the Medication Guide thoroughly and be assisted in understanding its contents. They should also be encouraged to discuss any questions or concerns regarding the Medication Guide with their healthcare provider.

Healthcare providers should advise patients 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 are particularly important to monitor during the initial stages of treatment and when dosage adjustments occur. Families and caregivers should be encouraged to observe patients daily for any abrupt changes in behavior and to report any severe or unexpected symptoms to the prescriber.

Patients should be informed that certain mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, aggression, and suicidal thoughts, may occur, especially when attempting to quit smoking while on bupropion. If patients experience any of these symptoms, they should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

Healthcare providers should educate patients about the signs of hypersensitivity and instruct them to discontinue the medication if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking bupropion hydrochloride extended-release tablets (XL) if they experience a seizure during treatment. It is important to inform 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) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. Furthermore, it should be emphasized 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 bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment, motor, and cognitive skills. Until patients are confident that the medication does not adversely affect their performance, they should refrain from driving or operating complex machinery. Lastly, patients should be encouraged to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL) and other drugs.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 Epic Pharma, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)