Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (XL) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The chemical structure is designated as (±)-2-(tert-Butylamino)-3'-chloropropiophenone hydrochloride, with a molecular weight of 276.2 and an empirical formula of C₁₃H₁₈ClNO·HCl.

The active pharmaceutical ingredient, bupropion hydrochloride, is presented as a white or almost white crystalline powder that is soluble in water and has a bitter taste, producing a local anesthetic sensation on the oral mucosa. Bupropion hydrochloride extended-release tablets (XL) are formulated for oral administration, containing 450 mg of bupropion hydrochloride, USP, and are characterized as white to off-white extended-release tablets.

Each film-coated tablet includes the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients such as carboxymethyl cellulose sodium, colloidal silicon dioxide, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 8000, polyethylene oxide, polyvinyl pyrrolidone and polyvinyl acetate blend, stearic acid, talc, titanium dioxide, and triacetin. The imprint “BUP450” is printed on one side of the tablet using edible black ink.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of this formulation was established through two 4-week clinical trials, one 6-week trial utilizing the immediate-release formulation, and one maintenance trial involving the sustained-release formulation.

Healthcare professionals are advised to periodically re-evaluate the long-term usefulness of this medication for each individual patient to ensure continued appropriateness of therapy.

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL) as per the available data.

Dosage and Administration

Patients should take one tablet of bupropion hydrochloride extended-release tablets (XL) at a dosage of 450 mg once daily, without regard to food. The tablet must be swallowed whole; it should not be chewed, divided, or crushed.

It is important to note that treatment with bupropion hydrochloride extended-release tablets (XL) should not be initiated. For initial dose titration, another formulation of bupropion should be used.

Patients who have been receiving 300 mg/day of another bupropion formulation for a minimum of 2 weeks and require an increase to 450 mg/day may transition to bupropion hydrochloride extended-release tablets (XL). Additionally, patients currently treated with other bupropion products at a dosage of 450 mg/day can be switched to an equivalent dose of bupropion hydrochloride extended-release tablets (XL) administered once daily.

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. The concurrent use of other bupropion products is also contraindicated, as it may elevate the risk of adverse effects.

Bupropion is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may increase the risk of seizures.

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated, as it may precipitate seizures.

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

Known hypersensitivity to bupropion or any of the components of 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 Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including bupropion. It is imperative to monitor these patients closely for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking while using bupropion may experience serious neuropsychiatric adverse events. These can 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 any occur, bupropion should be discontinued immediately, and the patient should contact a healthcare provider.

Seizure Risk The risk of seizures associated with bupropion is dose-dependent. If a seizure occurs, the medication must be discontinued.

Hypertension Bupropion hydrochloride extended-release tablets (XL) have the potential to increase 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, and ongoing monitoring for symptoms of mania or hypomania is recommended.

Psychosis and Other Neuropsychiatric Reactions In the event of psychosis or other neuropsychiatric reactions, bupropion should be discontinued.

Angle-Closure Glaucoma There is a risk 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 treatment course to ensure patient safety.

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

Discontinuation Instructions Patients must stop taking bupropion if a seizure occurs or if they experience psychosis or other neuropsychiatric reactions, and they should contact their healthcare provider promptly.

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 warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients 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 closely monitored for these symptoms.

There is a dose-dependent risk of seizures associated with this medication; therefore, it should be discontinued if a seizure occurs. Additionally, bupropion hydrochloride extended-release tablets (XL) may 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. Psychosis and other neuropsychiatric reactions warrant discontinuation of the medication if they occur.

Patients with untreated anatomically narrow angles may be at risk for angle-closure glaucoma when treated with antidepressants.

In cases of overdose, particularly with doses of 30 grams or more, serious reactions have been reported. Approximately one third of overdose cases involved seizures, while other serious reactions included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Additional severe reactions, such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, have been noted, especially in the context of multiple drug overdoses. Deaths associated with bupropion overdoses have been reported, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest occurring prior to death in these patients.

Drug Interactions

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

CYP2B6 Inhibitors The use of ticlopidine or clopidogrel may increase the exposure to bupropion. Therefore, the coadministration of bupropion XL with these agents is not recommended.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, a dose increase of bupropion may be necessary based on clinical exposure. However, the dosage should not exceed the maximum recommended limit.

Drugs Metabolized by CYP2D6 Bupropion is a known inhibitor of CYP2D6 and may elevate the concentrations of various medications 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). A dose reduction of these medications should be considered when used in conjunction with bupropion.

Drugs That Lower Seizure Threshold Bupropion hydrochloride extended-release tablets (XL) should be used with extreme caution in patients taking other medications that lower the seizure threshold.

Dopaminergic Drugs Concomitant use of bupropion XL with dopaminergic drugs such as levodopa and amantadine may result in central nervous system (CNS) toxicity.

Monoamine Oxidase Inhibitors (MAOIs) The risk of hypertensive reactions is increased when bupropion XL is used in conjunction with MAOIs.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines, which should be taken into account during laboratory evaluations.

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 geriatric patients and younger subjects. However, while clinical experience has not identified significant differences in responses, it is important to note that greater sensitivity to the drug may be present in some elderly 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

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 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. In contrast, when administered 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, all pregnancies carry a background rate of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data from the international bupropion Pregnancy Registry, which included 675 first-trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first-trimester exposures, did not show an increased risk for malformations overall. The registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, 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 a possible drug association. 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 MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside the mother’s clinical need for bupropion hydrochloride extended-release tablets (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available 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 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 approximately one third of these cases, seizures were reported. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances or arrhythmias. Additionally, severe symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have primarily been observed in cases involving multiple drug overdoses.

While most patients have recovered without lasting effects, there have been fatalities linked to bupropion overdose, particularly in individuals who ingested large quantities of the drug. Reports indicate that these patients experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a bupropion overdose, it is crucial to consult a Certified Poison Control Center for the most current guidance and recommendations. Healthcare professionals can reach out to certified poison control centers by calling 1-800-222-1222 or visiting www.poison.org.

There are currently 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 possibility of a multiple drug overdose when assessing the patient.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using 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.

In terms of mutagenicity, 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, bupropion was associated with an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

No evidence of impaired fertility was noted in a fertility study conducted in rats at doses up to 300 mg/kg/day. There is no information available regarding teratogenic effects.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts occurring in the context of smoking cessation efforts while on bupropion therapy. These events were identified through voluntary reports and surveillance programs.

Patient Counseling

Advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL). It is important to counsel patients, their families, and caregivers on the appropriate use of this medication.

Instruct patients, their families, and caregivers to read the Medication Guide thoroughly and assist them in understanding its contents. Encourage patients to discuss the information within 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 the dosage is adjusted. Families and caregivers should monitor patients closely for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Inform patients that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal ideation when attempting to quit smoking while taking bupropion. Patients should be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience such symptoms.

Educate patients about the signs of hypersensitivity and instruct them to discontinue the medication if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking bupropion hydrochloride extended-release tablets (XL) and not to restart if they experience a seizure during treatment.

Advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should avoid alcohol while on this medication.

Patients should be informed that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. Patients may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure if necessary.

Educate patients 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 conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

Advise patients that bupropion hydrochloride extended-release tablets (XL) 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.

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

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants for major depressive disorder (MDD) or other indications should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. It is crucial that any concerning symptoms are reported to healthcare providers immediately. Daily observation by families and caregivers is recommended to ensure patient safety.

Prescriptions for bupropion hydrochloride extended-release tablets (XL) should be limited to the smallest quantity necessary for effective patient management to minimize the risk of overdose. Additionally, postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use for smoking cessation, including mood changes, psychosis, and suicidal ideation. While many patients experienced resolution of symptoms upon discontinuation, some required ongoing monitoring and supportive care until symptoms fully resolved.

FDA Insert (PDF)

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

View full prescribing information (PDF)