Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (XL) contain bupropion hydrochloride, an antidepressant belonging to the aminoketone class, which is chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressants. The chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO•HCl.

The active ingredient is presented as a white, crystalline powder that is highly soluble in water and has a bitter taste, producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration and are available in dosages of 150 mg and 300 mg. These tablets are creamy-white to pale yellow, round, and coated, with one side imprinted with black ink and the other side plain.

Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including ethyl alcohol, ethylcellulose, glyceryl dibehenate, isopropyl alcohol, methacrylic acid and ethyl acrylate copolymer dispersion, polyethylene glycol, polyvinyl alcohol, povidone, silicon dioxide, and triethyl citrate. The black ink used for printing contains ferrosoferric oxide, hypromellose, isopropyl alcohol, and propylene glycol. Notably, the insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is excreted in the feces. The FDA-approved dissolution test specifications for this formulation differ from those established by the USP.

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 dosage and the necessity for maintenance therapy.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily, with the option to increase the dosage 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 initial dose is also 150 mg once daily, with a target dose of 300 mg once daily. After one week, the dosage 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 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 is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the heightened risk of seizures associated with these conditions.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs can increase the risk of seizures; therefore, bupropion should not be used in these circumstances.

The concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders with bupropion is contraindicated. Bupropion should not be initiated in patients currently receiving linezolid or intravenous methylene blue, nor should it be used within 14 days of stopping an MAOI.

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

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and aggressive behaviors. Notably, there have been instances of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients for these symptoms and instruct them to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical advice if such adverse events occur.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to a maximum of 450 mg and to increase the dosage gradually. Should a seizure occur, the medication must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (XL) may also elevate blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy to ensure patient safety.

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

Additionally, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional if they experience any such reactions.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor these populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion hydrochloride extended-release tablets (XL), healthcare providers should implement regular blood pressure monitoring before and during treatment. Patients should be advised to discontinue the medication and contact their healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (XL) may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of patients and at least twice the rate of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions warranting attention include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for the emergence or worsening of these thoughts and behaviors.

Neuropsychiatric adverse events have been reported during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

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

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 symptoms arise.

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

Other important considerations include the contraindication of bupropion in 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. 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 have been reported in approximately one third of 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

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

Pharmacokinetic Interactions

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

• CYP2D6 Substrates: Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of drugs metabolized by this enzyme, including 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.

Pharmacodynamic Interactions

• Drugs that Lower Seizure Threshold: Caution is advised when prescribing bupropion XL with other medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

• Dopaminergic Drugs: The concurrent use of bupropion XL with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

• Monoamine Oxidase Inhibitors (MAOIs): The combination of bupropion XL with MAOIs can heighten the risk of hypertensive reactions. Close monitoring is warranted if these agents are used together.

Drug-Laboratory Test Interactions

Bupropion XL may interfere with laboratory tests, specifically causing false-positive results for amphetamines in urine drug screenings. This potential interaction should be communicated to healthcare providers conducting such tests.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness 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 and older participated in trials with 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, careful consideration of renal function is essential in dose selection for this population. Monitoring renal function may be beneficial, as the risk of adverse reactions could be heightened in patients with impaired renal function.

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 involving pregnant women exposed to bupropion during the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. In a prospective, longitudinal study, women with a history of major depressive disorder 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 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 higher.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown; however, 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 with 1,213 first-trimester exposures did not show an overall increased risk for malformations. The registry was not specifically designed to evaluate individual defects but suggested a possible increase in cardiac malformations. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion during 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 of left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations.

In summary, while data suggest that bupropion does not significantly increase the risk of congenital malformations overall, careful consideration of the risks associated with untreated maternal depression is essential when managing treatment 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

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 outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution and consider the overall clinical context when prescribing this medication to patients with hepatic impairment.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In these cases, seizures occurred in approximately one third of the patients.

Symptoms of Overdosage

Serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, and alterations in mental status. Additional symptoms may manifest as sinus tachycardia, electrocardiogram (ECG) changes such as conduction disturbances or arrhythmias, clonus, myoclonus, and hyperreflexia. In cases where bupropion was part of a multiple drug overdose, further complications such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported.

Management of Overdosage

While most patients have recovered without lasting effects, there have been fatalities associated with bupropion overdose, particularly in those who ingested large quantities. Reports indicate that patients who succumbed to overdose experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Healthcare professionals are advised to monitor patients closely for these symptoms and to initiate appropriate medical interventions as necessary. Immediate supportive care and symptomatic treatment are critical in managing bupropion overdose cases.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. The 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 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, and homicidal ideation. Instances of aggression, hostility, agitation, anxiety, and panic have also been documented. Furthermore, there have been reports of suicidal ideation and suicide in patients attempting to quit smoking while on bupropion therapy. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to 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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly critical to monitor during the initial phase of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may 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 have experienced significant 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 and actions 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 is essential; patients should be made aware of the symptoms of severe allergic reactions and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if such reactions occur. Additionally, patients should be advised to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare providers should inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should be encouraged 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 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 medications should not be used together or with any other products containing bupropion hydrochloride.

Furthermore, patients should be advised 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 patients are confident that the medication does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Lastly, patients should be counseled to notify 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 and affect their metabolism.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as outlined by USP Controlled Room Temperature guidelines.

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. It is crucial for them to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion XL and seek medical attention if they observe any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, patients should stop taking the medication and consult a healthcare provider if they experience any allergic reactions, such as skin rash, hives, or difficulty breathing.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. Reports have included mood changes, psychosis, and suicidal ideation, among other serious effects. Furthermore, anaphylactoid and anaphylactic reactions have been documented, characterized by symptoms such as pruritus and dyspnea, necessitating medical intervention. Rare cases of severe skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have also been reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)