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 ingredient, bupropion hydrochloride, appears as a white or almost white crystalline powder that is soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. The extended-release tablets are formulated for oral administration, each containing 450 mg of bupropion hydrochloride, USP, and are presented as white to off-white film-coated tablets.

Inactive ingredients include carboxymethyl cellulose sodium, colloidal silicon dioxide, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 8000, polyethylene oxide, a 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 (XL) 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 directly. For initial dose titration, another formulation of bupropion should be used.

For patients currently receiving 300 mg/day of another bupropion formulation for a minimum of two weeks, a dosage of 450 mg/day of bupropion hydrochloride extended-release tablets (XL) may be appropriate. Additionally, patients who are being treated with other bupropion products at a dosage of 450 mg/day can be transitioned 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.

• Individuals currently using other bupropion products, as this may lead to excessive dosing.

• Patients with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may increase the risk of seizures.

• Individuals who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, due to the potential for seizure risk.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated, as is use within 14 days of stopping either bupropion hydrochloride extended-release tablets (XL) or an MAOI. 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 ingredients in bupropion hydrochloride extended-release tablets (XL).

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 essential to monitor these patients closely for any worsening of symptoms or the 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, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Patients should be observed for these symptoms, and if they 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 should be discontinued without delay.

Hypertension Bupropion hydrochloride extended-release tablets (XL) have the potential to increase blood pressure. It is recommended that blood pressure be monitored prior to initiating treatment and periodically throughout the course of therapy.

Activation of Mania/Hypomania Patients with a history of bipolar disorder should be screened prior to treatment. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

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

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 Instructions 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 hydrochloride extended-release tablets (XL) if a seizure occurs or if they experience psychosis or other neuropsychiatric reactions, and they should contact their healthcare provider promptly.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of participants 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 warnings include an increased risk of suicidal thoughts and behaviors 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.

Postmarketing reports have indicated serious neuropsychiatric adverse events during smoking cessation, which may include 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, and treatment should be discontinued if such reactions occur.

There is a dose-dependent risk of seizures associated with the use of this medication; therefore, it is advised to discontinue treatment 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.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Furthermore, angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

In cases of overdose, particularly with doses of 30 grams or more, serious reactions have been documented. Approximately one third of these cases reported seizures, while other serious reactions included 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 associated with bupropion overdose have been reported, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

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 lead to central nervous system (CNS) toxicity.

Monoamine Oxidase Inhibitors (MAOIs) The risk of hypertensive reactions is increased when bupropion hydrochloride extended-release tablets (XL) are used alongside 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 studies 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 trials. However, while clinical experience has not identified significant differences in responses between these age groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

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

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at 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. 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 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, all pregnancies have 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. 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%. However, 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 lactating 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 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 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 were reported. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, alterations in mental status, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Additional symptoms may encompass clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

While the majority of patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, particularly in those who ingested large quantities. Reports indicate that these cases often involved multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for current guidance and recommendations. Healthcare professionals can reach the Poison Control Center at 1-800-222-1222 or visit www.poison.org for further assistance.

There are no known antidotes for bupropion; therefore, management of an overdose should focus on supportive care. This includes close medical supervision and monitoring of the patient. It is also essential to consider the possibility of a multiple drug overdose when assessing the situation.

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, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted 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 reported in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts in individuals 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 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, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

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

Patients should be cautioned 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 avoid alcohol altogether. It is also important to inform patients 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.

Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) found in ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with ZYBAN or any other medications 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 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.

Finally, patients should be counseled to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (XL) and other drugs may interact and affect each other’s metabolism.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain 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 immediately to healthcare providers, with daily observation recommended.

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 Upsher-Smith Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)