Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (XL) is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.2 g/mol, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets (XL) are supplied for oral administration as 150 mg, white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with the inactive ingredients: colloidal silicon dioxide, ethylcellulose, hydroxypropyl cellulose, methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, stearic acid, talc, titanium dioxide, and triethyl citrate. The tablets are printed with edible black ink, which consists of hypromellose 2910, iron oxide black, and propylene glycol.

Uses and Indications

This drug 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 drug.

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After a period of four days, the dose may be increased to a usual target dose of 300 mg once daily.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The initial dose is also 150 mg once daily, with a potential increase to 300 mg once daily after one week. Treatment should be continued 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 associated with bupropion.

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

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

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

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

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Increased Risk of Suicidal Thoughts and Behaviors There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated serious neuropsychiatric adverse events associated with smoking cessation attempts using bupropion hydrochloride extended-release tablets (XL). These events may include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients should be observed for these symptoms, and if they occur, bupropion hydrochloride extended-release tablets (XL) should be discontinued immediately, and the patient should contact a healthcare provider.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, bupropion hydrochloride extended-release tablets (XL) should be discontinued.

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

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment, and ongoing monitoring for symptoms of mania or hypomania is advised.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

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

In the event of neuropsychiatric adverse events, patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention from a healthcare provider.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride extended-release tablets (XL). These reactions can be categorized into common adverse reactions, serious warnings, and other important considerations.

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. These reactions were observed in clinical trials and may vary in frequency among patients.

A significant warning associated with bupropion is the increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation during treatment.

Neuropsychiatric adverse events have been noted during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should seek immediate medical attention.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, 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.

Bupropion can also lead to increased blood pressure; therefore, it is essential to monitor blood pressure before and periodically during treatment. Additionally, patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania.

Psychosis and other neuropsychiatric reactions may occur, and patients are advised to contact a healthcare professional if such reactions arise. Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, necessitating caution in these individuals.

Other important considerations include the contraindications for patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who have abruptly discontinued 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. Additionally, known hypersensitivity to bupropion or any of its components is a contraindication for use.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion. However, it is important to ensure that the dosage does not exceed the maximum recommended limit.

Bupropion acts as an inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). In such cases, a dose reduction of these concomitant medications should be considered.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (XL) alongside drugs that may lower the seizure threshold. Additionally, the concurrent use of bupropion XL with dopaminergic agents, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity.

There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are administered in conjunction with monoamine oxidase inhibitors (MAOIs).

Furthermore, it should be noted that bupropion hydrochloride extended-release tablets (XL) can produce false-positive results in urine tests for amphetamines.

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 of bupropion hydrochloride extended-release tablets (XL) in the pediatric population have not been established. When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks against the clinical need for treatment.

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 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, it is important to note that while clinical experience has not identified significant differences in responses between these age groups, the possibility of greater sensitivity in some older individuals cannot be excluded.

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, there is an increased risk of adverse reactions in this population. Therefore, careful consideration of renal function is essential when selecting a dose 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 https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/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, which should be considered when evaluating treatment options. 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 their medication.

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.

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. The international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures did not show an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 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. Given these considerations, healthcare providers should weigh the risks of untreated depression against the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

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, to bupropion and its active metabolites 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

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 adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly concerning in the context of multiple drug overdoses, where the risk of severe complications is heightened.

Potential Outcomes

Fatalities linked to bupropion overdose have been observed, often occurring after multiple uncontrolled seizures. Other critical conditions that may arise include bradycardia, cardiac failure, and cardiac arrest.

Management Recommendations

Currently, there are no known antidotes for bupropion overdose. Therefore, the primary approach involves supportive care and close medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for specific guidance in managing an overdose situation. For assistance, they can contact 1-800-222-1222 or visit www.poison.org.

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, 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 2 to 3 times increase in the control mutation rate, while yielding 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

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs in patients taking bupropion hydrochloride extended-release tablets (XL).

Some patients have reported changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, suicidal ideation and suicide attempts have been noted, particularly in individuals attempting to quit smoking while on this medication.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, and suicidal thoughts or actions, have also been documented in some individuals using bupropion for smoking cessation. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, and confusion, have been observed in certain patients.

The risk of seizures associated with bupropion hydrochloride extended-release tablets (XL) has been reported, particularly in individuals with specific medical conditions or those taking certain medications. The likelihood of seizures appears to increase with higher doses of the medication.

Instances of severe hypertension have been reported in some patients taking bupropion hydrochloride extended-release tablets (XL). Additionally, episodes of mania, characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech, have been noted.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have also been reported, with symptoms including rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, and difficulty breathing.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important to instruct patients, their families, and/or caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms may occur, particularly during the initial stages of antidepressant 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, as these can be significant. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts or actions, particularly when attempting to quit smoking while taking bupropion. Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (XL) and not to restart if they experience a seizure during treatment.

Healthcare providers should counsel patients regarding the risks associated with excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase the risk of seizures. Patients should be advised to 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 an episode of angle-closure glaucoma in susceptible individuals. It is important to educate patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) found in ZYBAN®, which is used for smoking cessation, and that these should not be used in combination with ZYBAN® or any other medications containing bupropion hydrochloride.

Patients should be made aware 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. Until they are certain that bupropion hydrochloride extended-release tablets (XL) do not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

Counseling should include advising patients 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) and other drugs may interact with each other. Patients should also be instructed to inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with bupropion hydrochloride extended-release tablets (XL).

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole to ensure the release rate is not altered. 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. Furthermore, bupropion hydrochloride extended-release tablets (XL) should not be crushed, divided, or chewed and should be administered in the morning, 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 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients and their caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention if they experience agitation, depressed mood, or any atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients receiving antidepressants for major depressive disorder or other indications should be vigilant in monitoring for signs of agitation, irritability, and other behavioral changes, as well as the emergence of suicidality, and report any concerning symptoms to healthcare providers. It is recommended that prescriptions for bupropion XL be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been reported, characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been associated with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)