Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (XL) are chemically designated as 1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.20 g/mol, and its molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride USP appears as a white powder and is soluble in water, 0.1 N hydrochloric acid, and alcohol.

These extended-release tablets are available for oral administration in strengths of 150 mg and 300 mg. Each 150 mg tablet contains the following inactive ingredients: ethyl cellulose, glyceryl behenate, hydrochloric acid, hypromellose, methacrylic acid and ethyl acrylate copolymer, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, sodium stearyl fumarate, titanium dioxide, triethyl citrate, and FD&C blue # 2. Each 300 mg tablet includes the same inactive ingredients as the 150 mg tablet, with the addition of iron oxide red, iron oxide yellow, and talc. The tablets are printed with black ink composed of ammonium hydroxide, ferrosoferric oxide, propylene glycol, and shellac.

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) in individuals at risk.

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 Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After a period of 4 days, the dose may be increased to a usual target 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 starting 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 are at increased risk of seizures when using this medication.

Bupropion hydrochloride extended-release tablets (XL) should not be administered to individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased risk of seizures.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated, as it may elevate the risk of seizures.

Concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with MAOIs or within 14 days of discontinuing either treatment. Additionally, initiation of bupropion hydrochloride extended-release tablets (XL) is contraindicated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

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

Suicidal Thoughts and Behaviors There is a documented increased risk of suicidal thinking and behavior in children, adolescents, and young adults who are prescribed antidepressants. Healthcare professionals are advised to 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 efforts using bupropion hydrochloride extended-release tablets (XL). These events may include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking should be observed for these symptoms, and they must be instructed to discontinue the medication and seek immediate medical advice if any adverse events occur.

Seizure Risk The risk of seizures is dose-dependent. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be made gradually. Should a seizure occur, the medication must be discontinued immediately.

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

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is also recommended during treatment.

Psychosis and Other Neuropsychiatric Reactions Patients should be advised 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. Caution is advised in these patients.

General Precautions Regular monitoring of blood pressure is essential before starting treatment and at intervals during therapy. Additionally, screening for bipolar disorder and monitoring for mania or hypomania symptoms should be conducted.

Emergency Medical Help Instructions Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if they experience any neuropsychiatric adverse events.

Discontinuation Instructions Patients should also be advised to stop taking the medication and seek medical attention if they experience a seizure.

Side Effects

Patients may experience a range of adverse reactions while taking 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. A WARNING regarding suicidal thoughts and behaviors is indicated, as there is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been observed 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. Patients should be instructed to contact a healthcare professional if any of these reactions occur.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion can increase blood pressure, necessitating monitoring of blood pressure before and periodically during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Angle-closure glaucoma has also been noted in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnoses of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion is contraindicated, as is the use of bupropion within 14 days of stopping an MAOI intended for psychiatric disorders.

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, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths 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

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion. However, it is important 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). A dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (XL) alongside drugs that may lower the seizure threshold, as this combination could increase the risk of seizures.

The concurrent use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic medications, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Therefore, careful monitoring is advised.

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

It is also noteworthy that bupropion hydrochloride extended-release tablets (XL) can lead to false-positive results in urine drug screenings for amphetamines, which should be taken into account during testing.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

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

Geriatric Use

Clinical trials involving 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 utilizing 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 between these 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 elderly patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an overall increased risk of congenital malformations. However, there are inherent risks to the mother associated with untreated depression, which should be considered when evaluating treatment options during pregnancy.

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, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Additionally, decreased fetal weights were noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the general U.S. population is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background rate of birth defects, loss, or other adverse outcomes. 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 their medication.

The international bupropion Pregnancy Registry, which included 675 first-trimester exposures, along with a retrospective cohort study using the United Healthcare database (1,213 first-trimester exposures), did not demonstrate an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall was observed. 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%.

Inconsistent findings have been reported regarding the association between bupropion exposure during the first trimester and specific cardiac defects, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). While the Slone Epidemiology Study found an increased risk for VSD, the NBDPS and United Healthcare database studies did not find a significant association for either LVOTO or VSD. These studies were limited by small sample sizes and the potential for chance findings.

In summary, healthcare professionals should weigh the risks of untreated depression against the potential fetal impacts when considering the use of bupropion in pregnant patients. Careful monitoring and individualized treatment plans are recommended for women of childbearing potential who are considering or currently using bupropion during pregnancy.

Lactation

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

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

Renal Impairment

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 when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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 outlined 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 quantities of 30 grams or more. In approximately one third of these cases, seizures have been reported, highlighting the potential neurological risks associated with excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These effects are particularly pronounced in scenarios involving multiple drug overdoses, where the risk of severe complications is significantly heightened.

Fatalities linked to bupropion overdose have also been recorded, frequently occurring after multiple uncontrolled seizures. Other critical cardiovascular events such as bradycardia, cardiac failure, and cardiac arrest may precede these tragic outcomes.

Currently, there are no known antidotes for bupropion overdose. Therefore, the primary approach to management involves supportive care and vigilant medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for expert guidance in managing cases of bupropion overdose, ensuring that appropriate interventions are implemented promptly.

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, 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, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide during attempts to quit smoking while taking bupropion hydrochloride extended-release tablets (XL). New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been observed. These symptoms have manifested in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

The incidence of these symptoms appears to be higher in individuals with a prior history of mental health disorders compared to those without such a history. Patients are advised to discontinue bupropion hydrochloride extended-release tablets (XL) and promptly contact their healthcare provider if they, their family, or caregivers notice any of these symptoms.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have also been reported. Symptoms indicative of a serious allergic reaction include rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing. Patients experiencing these symptoms should stop taking the medication and seek immediate medical attention.

The risk of seizures is known to increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some patients may develop severe hypertension while on this medication, with an increased risk noted in those concurrently using nicotine replacement therapies, such as nicotine patches, to aid in smoking cessation.

Episodes of mania, characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech, have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL). Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been documented. Patients experiencing these symptoms are encouraged to contact their healthcare provider.

Visual disturbances, such as eye pain, changes in vision, and swelling or redness in or around the eye, have been reported, although only a subset of patients may be at risk for these issues. An eye examination may be warranted to assess risk and consider preventative treatment.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they are well-informed about their treatment. It is important to instruct patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly concerning during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can occur suddenly. Any severe or unexpected symptoms should be reported to the patient’s prescriber or healthcare professional promptly. Patients should be informed that some individuals may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and suicidal thoughts, 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 concerning symptoms. They should also be educated about the signs of hypersensitivity and advised to stop taking the medication if they experience a severe allergic reaction. In the event of a seizure while on treatment, patients should discontinue bupropion hydrochloride extended-release tablets (XL) and not restart the medication.

It is crucial 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 be advised to minimize or avoid alcohol consumption. Patients should also be made aware that bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals.

Patients should be educated that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride. Additionally, patients should be cautioned that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks that require judgment or 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.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs. They should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to maintain the proper release rate. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular scheduled time due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed with or without food.

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), with permissible excursions between 15º to 30ºC (59º to 86ºF) as defined by USP Controlled Room Temperature guidelines.

Proper storage conditions are essential to maintain the integrity of the product. It is recommended that the product be kept in a suitable container that protects it from environmental factors that may compromise its quality. Special handling requirements should be observed to ensure that the product remains within the specified temperature range throughout its storage period.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention if they observe any signs of agitation, depressed mood, or 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 the emergence of agitation, irritability, and other concerning symptoms, reporting any such changes to healthcare providers promptly. 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, presenting with symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been documented, along with reports of delayed hypersensitivity symptoms like arthralgia and fever with rash.

FDA Insert (PDF)

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

View full prescribing information (PDF)