Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its chemical structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1 propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.21, with a molecular formula of C13H18ClNO•HCl.

The drug is presented as a white powder that is soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. Bupropion hydrochloride extended-release tablets USP (XL) are formulated for oral administration, available in dosages of 150 mg and 300 mg. These tablets are off-white to pale yellow in color and contain the labeled amount of bupropion hydrochloride along with inactive ingredients, including ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, glyceryl behenate, hydrophobic colloidal silica, hydroxypropyl cellulose, iron oxide black, L-cysteine hydrochloride monohydrate, methacrylic acid copolymer dispersion, polyvinyl alcohol, povidone, propylene glycol, shellac, and triethyl citrate. The tablets are printed with edible black ink.

The extended-release tablet's insoluble shell may remain intact during gastrointestinal transit and is excreted in feces. The drug product meets the USP Dissolution Test 20.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for 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 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, the dose may be increased to 300 mg once daily, and 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 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 use.

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.

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

Warnings and Precautions

Increased risk of suicidal thinking and behavior has been observed in children, adolescents, and young adults taking antidepressants, including bupropion hydrochloride extended-release tablets (XL). Healthcare professionals should closely monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

General Precautions

Neuropsychiatric adverse events have been reported during smoking cessation attempts with bupropion hydrochloride extended-release tablets (XL). These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Patients should be observed for these symptoms, and if they occur, they must discontinue the medication and contact a healthcare provider immediately.

The risk of seizures is dose-related; therefore, it is essential 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.

Bupropion hydrochloride extended-release tablets (XL) may elevate blood pressure. It is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Patients should be screened for bipolar disorder prior to treatment, as bupropion can activate mania or hypomania. Continuous monitoring for these symptoms is recommended.

Instruct patients to report any occurrences of psychosis or other neuropsychiatric reactions to a healthcare professional promptly.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in these patients.

Laboratory Tests

Blood pressure should be monitored before the initiation of treatment and periodically during the course of therapy to ensure patient safety.

Emergency Medical Help Instructions

Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention if they experience any neuropsychiatric adverse events.

Stop Taking and Call Your Doctor Instructions

Patients should be advised to stop taking bupropion hydrochloride extended-release tablets (XL) and contact their healthcare provider if they experience any neuropsychiatric adverse events.

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 warrant particular attention. 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. Neuropsychiatric adverse events have been observed 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 increase blood pressure, so monitoring is essential before and during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should be instructed 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. 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, either during treatment or within 14 days of stopping treatment. It is also contraindicated in patients receiving linezolid or intravenous methylene blue.

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), mental status changes, clonus, myoclonus, and hyperreflexia. Severe outcomes such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been noted, particularly in the context of multiple drug overdoses. Fatalities 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 necessitate careful monitoring and potential dosage adjustments due to significant interactions.

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 required to maintain clinical efficacy. However, the dosage should not exceed the maximum recommended limit.

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

Drugs That Lower Seizure Threshold Caution is advised when prescribing bupropion XL in conjunction with other medications that may lower the seizure threshold. Close monitoring for seizure activity is recommended.

Dopaminergic Drugs The concurrent use of bupropion XL with dopaminergic agents such as levodopa and amantadine may increase the risk of central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is warranted.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion XL with MAOIs can elevate the risk of hypertensive reactions. It is essential to avoid this combination or to monitor blood pressure closely if coadministration is necessary.

Drug-Laboratory Test Interactions Bupropion XL may interfere with urine drug screening tests, potentially resulting in false-positive results for amphetamines. This should be taken into account when interpreting test results in patients receiving bupropion.

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 subjects. However, while clinical experience has not identified significant differences in responses, it is important to note that greater sensitivity 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, careful consideration of renal function is essential when selecting doses for geriatric patients. Monitoring of renal function may be beneficial to ensure safe and effective use of bupropion in this demographic.

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 indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks 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, with decreased fetal weights noted at doses twice the MRHD and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less in these studies.

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. However, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, 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

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.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for bupropion hydrochloride extended-release tablets (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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

In cases of bupropion overdosage, reports indicate that ingestion of 30 grams or more can occur. The clinical manifestations of such overdoses can be severe and varied. Approximately one third of patients experiencing an overdose have reported seizures, which are a significant concern in the management of these cases.

Symptoms of Overdosage

Serious reactions associated with bupropion overdoses include:

• Hallucinations

• Loss of consciousness

• Sinus tachycardia

• ECG changes, such as conduction disturbances or arrhythmias

• Altered mental status

• Clonus

• Myoclonus

• Hyperreflexia

In instances where bupropion is involved in multiple drug overdoses, additional symptoms may present, including fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. While many patients recover without lasting effects, there have been reports of fatalities linked to bupropion overdoses, particularly in those who ingested large quantities. These cases often involved multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Management of Overdosage

There are no known antidotes for bupropion; therefore, management focuses on supportive care. This includes close medical supervision and monitoring of the patient. It is crucial to consider the possibility of a multiple drug overdose, as this can complicate the clinical picture and management strategies.

For immediate guidance and advice, healthcare professionals are encouraged to consult a Certified Poison Control Center by calling 1-800-222-1222 or visiting www.poison.org.

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 liver neoplasms remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was noted in 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, 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 therapy. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the important information regarding their treatment with bupropion hydrochloride extended-release tablets (XL). Healthcare providers should inform patients, their families, and caregivers about the benefits and risks associated with this medication and counsel them on its appropriate use.

It is essential for patients, their families, and caregivers to read the Medication Guide thoroughly and to seek assistance in understanding its contents. Patients should be encouraged to discuss the Medication Guide and ask any questions they may have.

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 changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial stages of treatment or when the dosage is adjusted. Families and caregivers should monitor for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient's prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts when attempting to quit smoking while taking bupropion. If such symptoms arise, patients should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

Patients must be educated about the signs of hypersensitivity and instructed to discontinue the medication if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should stop taking bupropion hydrochloride extended-release tablets (XL) and not restart the medication.

Healthcare providers should advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should minimize or avoid alcohol consumption. Patients should also 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 important to note that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be cautioned that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks that require judgment, motor skills, or cognitive function. Until they are confident that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Finally, patients should be encouraged to inform their healthcare provider of any prescription or over-the-counter medications they are currently taking or plan to take, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs, affecting their metabolism.

Storage and Handling

The product is supplied in Unit Dose Packaging and is intended for institutional use only. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy 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, any signs of allergic reactions, such as skin rash, pruritus, or respiratory distress, warrant immediate 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, necessitating medical intervention. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, have been associated with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)