Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its chemical structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2, with a molecular formula of C₁₃H₁₈ClNO·HCl.

The compound appears as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (XL), are formulated for oral administration, containing 150 mg of bupropion hydrochloride. These tablets are peach and white to off-white bilayer extended-release formulations.

Each tablet comprises the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including hydroxypropyl cellulose, saccharin, lactose monohydrate, colloidal silicon dioxide, talc, stearic acid, microcrystalline cellulose, crospovidone, FD&C yellow 6 Lake, polyvinyl alcohol, polyethylene glycol, polysorbate 80, ethyl cellulose aqueous dispersion, methacrylic acid copolymer, triethyl citrate, sodium bicarbonate, sodium lauryl sulfate, and dibutyl sebacate. The tablets are printed with edible black ink, which contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, isopropyl alcohol, and ammonium hydroxide. Biologically inert fragments of the coating may remain intact and be eliminated in feces. The USP dissolution test for this formulation is pending.

Uses and Indications

Bupropion hydrochloride extended-release tablets, USP (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, these tablets are indicated for the prevention of seasonal affective disorder (SAD).

Healthcare professionals are advised to periodically reevaluate 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, USP (XL).

Dosage and Administration

The dosage and administration of the medication should be approached with caution, particularly in the context of seizure risk. It is recommended that healthcare professionals gradually increase the dose while periodically reassessing the patient's need for maintenance treatment.

For the management of Major Depressive Disorder, the 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 be initiated 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 dose and/or frequency of administration.

In patients with renal impairment, a reduction in dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in the following situations:

• Patients with a seizure disorder due to the risk of seizure exacerbation.

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

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

• Co-administration with 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, bupropion should not be initiated 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.

Warnings and Precautions

Increased risk of suicidal thoughts and behaviors has been observed in children, adolescents, and young adults taking antidepressants, including bupropion hydrochloride extended-release tablets (XL). Healthcare professionals should closely monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

During smoking cessation, patients may experience serious or clinically significant neuropsychiatric adverse events. Postmarketing reports have indicated changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. It is essential to observe patients attempting to quit smoking with bupropion hydrochloride XL for the occurrence of such symptoms. Patients should be instructed to discontinue the medication and contact a healthcare provider immediately if they experience any of these adverse events.

The risk of seizures is dose-related with bupropion hydrochloride XL. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose as clinically appropriate. If a seizure occurs, the medication should be discontinued.

Bupropion hydrochloride XL may also increase blood pressure. Therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course. Additionally, patients should be screened for bipolar disorder, as the activation of mania or hypomania can occur. Continuous monitoring for these symptoms is advised.

Patients should be informed about the potential for psychosis and other neuropsychiatric reactions. If such reactions occur, patients must be instructed to contact a healthcare professional promptly. Furthermore, angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, necessitating caution in these individuals.

To ensure safe use of bupropion hydrochloride XL, healthcare professionals should conduct regular blood pressure monitoring before and during treatment. Patients should be advised to discontinue the medication and seek medical attention if they experience any neuropsychiatric adverse events.

Side Effects

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

Common adverse reactions reported in clinical trials include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash. These reactions were observed with varying frequencies among participants.

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

Neuropsychiatric adverse events have been noted during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should be advised to contact a healthcare professional immediately.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised.

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

Other serious reactions include the potential for angle-closure glaucoma in patients with untreated anatomically narrow angles. Patients should be informed of this risk and advised to seek medical attention if they experience symptoms.

It is important to note that bupropion should not be used in patients with a seizure disorder, current or prior diagnoses of bulimia or anorexia nervosa, or those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Furthermore, bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with an MAOI. Patients receiving linezolid or intravenous methylene blue should also avoid starting bupropion. Known hypersensitivity to bupropion or any of its components is another contraindication for use.

Drug Interactions

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

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

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of drugs metabolized by this enzyme. This includes 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.

Drugs That Lower Seizure Threshold Caution is advised when prescribing bupropion XL in conjunction with other medications that may lower the seizure threshold. Close monitoring of the patient is recommended to prevent potential seizure activity.

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 warranted in patients receiving this combination.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion XL with MAOIs poses an increased risk of hypertensive reactions. It is essential to avoid this combination or to monitor blood pressure closely if coadministration is unavoidable.

Laboratory Test Interactions Bupropion XL may interfere with urine drug screening tests, potentially resulting in false-positive results for amphetamines. Clinicians should be aware of this possibility when interpreting test results in patients taking bupropion.

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.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 years and older participated in clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients in these studies. 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, careful consideration of renal function is essential when selecting a dose for geriatric patients. Monitoring of renal function may be beneficial to ensure safe and effective use of bupropion in this demographic.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester indicate no overall increased risk of congenital malformations. The background rate for major malformations in all pregnancies is approximately 2% to 4%, with a pregnancy loss rate of 15% to 20%. Reproductive developmental studies in rats and rabbits did not demonstrate clear teratogenic activity; however, rabbits exhibited slightly increased incidences of fetal malformations and skeletal variations at doses around the maximum recommended human dose (MRHD) and higher. Additionally, decreased fetal weights were noted at doses twice the MRHD and above.

Bupropion hydrochloride extended-release tablets (XL) are classified as Pregnancy Category C, indicating that they should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Clinical considerations must include the risk of untreated depression when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum.

Human data from an international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study utilizing the United Healthcare database with 1,213 first trimester exposures, did not reveal an increased risk for malformations overall. Specifically, the observed rate of cardiovascular malformations in pregnancies with first trimester bupropion exposure was 1.3% (9 cases), which aligns with the background rate of approximately 1%.

Inconsistent findings have been reported regarding the association between first trimester bupropion exposure and left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). The United Healthcare database lacked sufficient power to evaluate the LVOTO association, while the National Birth Defects Prevention Study (NBDPS) identified an increased risk for LVOTO (adjusted odds ratio OR = 2.6; 95% confidence interval CI 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. For VSD, the Slone Epidemiology Study reported an increased risk following first trimester exposure (adjusted OR = 2.5; 95% CI: 1.3, 5), while the NBDPS and United Healthcare database studies did not find an association. Limitations in these studies include small sample sizes, inconsistent findings, and the potential for chance findings due to multiple comparisons.

Animal studies involving oral administration of bupropion in rats and rabbits during organogenesis showed no clear evidence of teratogenic effects. However, in rabbits, increased incidences of fetal malformations and skeletal variations were observed at doses starting from 25 mg/kg/day (approximately equal to the MRHD on a mg/m² basis) and higher, with decreased fetal weights noted at doses of 50 mg/kg and above. In rats, administration of bupropion at doses up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

Lactation

Bupropion and its metabolites are present 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.

Exercise caution when administering bupropion hydrochloride extended-release tablets (XL) to lactating mothers.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one third of these cases, seizures 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 the majority of patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, particularly in individuals who ingested large quantities of the drug. 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 the most current guidance and recommendations. Healthcare professionals can find contact information for certified poison control centers in the Physicians' Desk Reference (PDR) or 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 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. In contrast, 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, as well as psychosis, hallucinations, paranoia, delusions, and homicidal ideation. Additional symptoms noted include aggression, hostility, agitation, anxiety, panic, suicidal ideation, and suicide, particularly during attempts to quit smoking while using bupropion hydrochloride extended-release tablets (XL). It is advised that patients discontinue the medication and consult a healthcare professional if they encounter any of these symptoms.

Patient Counseling

Healthcare providers should 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 essential to counsel patients, their families, and caregivers on the appropriate use of this medication.

Patients should be instructed to read the Medication Guide, which includes critical information about antidepressant medicines, depression, serious mental illnesses, and the potential for suicidal thoughts or actions. Providers should ensure that patients have the opportunity to discuss the contents of the Medication Guide and address any questions they may have.

Healthcare providers must inform patients and their 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 behavioral changes. Worsening depression and suicidal ideation should also be monitored, particularly during the initial treatment phase and when dosage adjustments occur. Families and caregivers should observe for these symptoms daily, as changes can be abrupt, and any severe or sudden onset symptoms should be reported to the prescriber.

Patients should be educated about the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue and not restart the medication. Providers should advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures and recommend minimizing or avoiding alcohol consumption.

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. It is also important to note that this medication contains the same active ingredient as ZYBAN*, used for smoking cessation, and should not be used in combination with ZYBAN* or any other bupropion-containing medications.

Healthcare providers should counsel patients that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment, 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 machinery.

Finally, patients should be encouraged to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (XL) 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 should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° and 30°C (59° and 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)