Bupropion hydrochloride

Description

Bupropion hydrochloride, USP, 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. The compound is designated as (±)-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 substance appears as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and producing a local anesthetic sensation on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets, USP (XL), available for oral administration in dosages of 150 mg and 300 mg. These tablets are white to off-white and contain the labeled amount of bupropion hydrochloride along with inactive ingredients, which include hydroxyl propyl methyl cellulose, microcrystalline cellulose, povidone, citric acid monohydrate, colloidal silicon dioxide, magnesium stearate, methacrylic acid copolymer, talc, titanium dioxide, colloidal anhydrous silica, sodium bicarbonate, sodium lauryl sulfate, and triethyl citrate. The formulation meets the USP Dissolution Test 18.

Uses and Indications

Bupropion hydrochloride is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD) in individuals at risk for this condition.

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride.

Dosage and Administration

For the treatment of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily. After an initial period of 4 days, the dose may be increased to 300 mg once daily if clinically indicated.

In the case of Seasonal Affective Disorder, treatment should be initiated 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. It is advised to continue treatment throughout the winter season.

For patients with hepatic impairment, those with moderate to severe hepatic impairment should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of dosing.

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

Contraindications

Use of bupropion 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 should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion. Additionally, bupropion should not be started in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the components of bupropion hydrochloride extended-release tablets (XL).

Warnings and Precautions

Serious neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and aggressive behaviors. Healthcare professionals should closely observe patients for the emergence of these symptoms and advise them to discontinue bupropion hydrochloride extended-release tablets and seek immediate medical attention if they experience any of these adverse effects.

The risk of seizures associated with bupropion is dose-dependent. To minimize this risk, it is recommended that the daily dose not exceed 450 mg, with a gradual increase in dosage as clinically appropriate. Should a seizure occur, bupropion should be discontinued immediately.

Bupropion 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.

In addition, patients should be informed about the risk of angle-closure glaucoma, particularly those with untreated anatomically narrow angles, as the use of antidepressants may precipitate this condition.

There is a notable warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including bupropion. Healthcare providers should monitor these patients for any worsening of symptoms or the emergence of suicidal ideation.

General precautions include vigilant monitoring for any worsening or emergence of suicidal thoughts and behaviors throughout the treatment period.

Healthcare professionals should instruct patients to seek emergency medical help if they experience psychosis or other neuropsychiatric reactions. Additionally, patients should be advised to discontinue the use of bupropion hydrochloride extended-release tablets and contact their healthcare provider if they experience any neuropsychiatric adverse events.

Side Effects

Patients may experience a range of adverse reactions while using this medication. 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. A significant warning is the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors. Additionally, neuropsychiatric adverse events may occur during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

There is a dose-related risk of seizures associated with this medication. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. If a seizure occurs, discontinuation of the medication is advised. Furthermore, bupropion has been associated with increased blood pressure; therefore, blood pressure should be monitored before initiating treatment and periodically throughout the treatment course.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. In the event of psychosis or other neuropsychiatric reactions, patients are instructed to contact a healthcare professional immediately.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Additional considerations include the presence of a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

It is crucial to avoid the use of monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders in conjunction with bupropion or within 14 days of stopping treatment with bupropion. Similarly, bupropion should not be initiated in patients currently being treated with linezolid or intravenous methylene blue. Lastly, known hypersensitivity to bupropion or any of its components should be taken into account when prescribing this medication.

Drug Interactions

Coadministration of bupropion with CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in bupropion dosage to maintain clinical exposure. However, any dosage adjustment should not exceed the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to increased plasma concentrations of various drugs metabolized by this enzyme. This includes certain 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). When these medications are used concurrently with bupropion, a dose reduction of the affected drugs should be considered.

Caution is advised when prescribing bupropion alongside drugs that lower the seizure threshold, as this combination may increase the risk of seizures.

The concomitant use of bupropion with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring of patients.

Additionally, the use of bupropion in conjunction with monoamine oxidase inhibitors (MAOIs) poses an increased risk of hypertensive reactions, warranting close observation and potential avoidance of this combination.

It is important to note that bupropion can interfere with laboratory tests, specifically causing false-positive results for amphetamines in urine drug screenings.

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. When considering the use of bupropion in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need. For further information, refer to the Boxed Warning and Warnings and Precautions (5.1).

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 clinical trials 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 in these studies. However, while clinical experience has not identified significant differences in responses between these age groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those 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 the 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. In contrast, 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.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown. 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. However, 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 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. Overall, healthcare providers should weigh the potential risks and benefits of bupropion use during pregnancy, considering both maternal mental health and fetal outcomes.

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 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 (glomerular filtration rate: <90 mL/min) may require a reduced dose and/or dosing frequency of bupropion. Due to the renal clearance of bupropion and its metabolites, there is a potential for accumulation in this population, which may lead to increased exposure. Therefore, it is essential to monitor these patients closely for adverse reactions that could suggest elevated levels of bupropion or its metabolites.

Hepatic Impairment

In patients with moderate to severe hepatic impairment, as defined by a Child-Pugh score of 7 to 15, the maximum recommended dose of bupropion is 150 mg every other day. For patients with mild hepatic impairment, indicated by a Child-Pugh score of 5 to 6, it is advisable to consider a reduction in the dose and/or frequency of dosing.

Monitoring of liver function is recommended in patients with hepatic impairment to ensure safety and efficacy of treatment. Adjustments to the dosing regimen should be made based on the patient's clinical response and any changes in liver function status.

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. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, alterations in mental status, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Additional symptoms may encompass clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

While the majority of patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, especially in cases where large doses were ingested. Reports indicate that patients who succumbed to overdose experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for current guidance and recommendations. Healthcare professionals can find contact information for certified poison control centers in the Physicians’ Desk Reference (PDR) or by calling 1-800-222-1222 or visiting www.poison.org.

There are no known antidotes for bupropion. Management of an overdose should focus on providing supportive care, which includes close medical supervision and monitoring. It is also essential to consider the potential for a multiple drug overdose when assessing the patient’s condition.

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 of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. 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, 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.

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, particularly in the context of smoking cessation attempts while on bupropion. 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. Healthcare providers should inform patients, their families, and caregivers about the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL) and counsel them on its appropriate use. It is essential to instruct patients and their support systems to read the Medication Guide, which includes critical information about antidepressant medicines, depression, suicidal thoughts or actions, and the use of quit-smoking medications.

Patients should be encouraged to discuss the contents of the Medication Guide and to ask any questions they may have. Healthcare providers should advise patients to be vigilant for the emergence of 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 doses are adjusted. Families and caregivers should monitor patients closely for these symptoms, as changes can occur abruptly, and any severe or sudden changes should be reported to the prescriber.

Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal thoughts when attempting to quit smoking while on bupropion. If such symptoms arise, patients should discontinue the medication and contact a healthcare professional immediately. Additionally, patients should be educated about the signs of hypersensitivity and instructed to stop taking bupropion if they experience a severe allergic reaction.

It is crucial to inform patients that they should discontinue bupropion if they experience a seizure during treatment. They should also be advised that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and therefore, minimizing or avoiding alcohol is recommended.

Patients should be made aware that bupropion can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. They may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure if necessary. Furthermore, patients should be informed 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 bupropion-containing medications.

Healthcare providers should counsel patients that bupropion may impair their ability to perform tasks requiring judgment, motor, and cognitive skills. Until they are certain that the medication does not adversely affect their performance, patients 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).

Storage and Handling

Bupropion HCl extended-release tablets are supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It is essential to store the tablets at room temperature, maintaining a temperature range between 20° to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are crucial to ensure the integrity and efficacy of the medication.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets should be closely monitored for the emergence of agitation, irritability, and unusual behavioral changes, as well as symptoms of suicidality. Families and caregivers are advised to conduct daily observations and report any concerning symptoms to healthcare providers immediately. Patients should discontinue the medication and seek medical advice if they experience agitation, changes in mood or behavior, or develop suicidal thoughts or actions. Additionally, any signs of an allergic or anaphylactoid reaction, such as skin rash, pruritus, or difficulty breathing, warrant immediate cessation of the drug and consultation with a healthcare provider.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson Syndrome, and anaphylactic shock have been documented in association with bupropion use.

FDA Insert (PDF)

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

View full prescribing information (PDF)