Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (XL) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. 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 pharmaceutical ingredient is presented as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and a local anesthetic effect on the oral mucosa. Bupropion hydrochloride extended-release tablets (XL) are formulated for oral administration, each containing 300 mg of bupropion hydrochloride. The tablets are white to off-white in appearance and include inactive ingredients such as alcohol, ethylcellulose, hydrochloric acid, hydroxypropyl cellulose, hypromellose, methacrylic acid and ethyl acrylate copolymer, polyethylene glycol, povidone, purified water, silicon dioxide, stearic acid, and talc.

The tablets are printed with edible black ink composed of ferrosoferric oxide, hypromellose, propylene glycol, and purified water. 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, 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 (XL).

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For 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 dose 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 starting dose is also 150 mg once daily, with a typical target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily, and it is advised to continue treatment 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, consideration should be given to reducing the dose and/or frequency of administration.

In patients with renal impairment, it is recommended to evaluate the need for dose reduction and/or adjustment of dosing frequency based on the severity of the impairment.

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

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

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI or started in patients currently receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (XL).

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 XL and seek immediate medical attention if such adverse events occur.

The risk of seizures is dose-related; therefore, it is crucial 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 XL has the potential to elevate blood pressure. Consequently, 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 may activate mania or hypomania. Continuous monitoring for these symptoms is recommended during treatment.

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

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

A critical warning pertains to the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. It is essential to monitor these populations for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion hydrochloride XL, healthcare providers should emphasize the importance of monitoring blood pressure before and during treatment. Patients should be instructed to discontinue the medication and contact their healthcare provider if they experience any neuropsychiatric adverse events or if they develop psychosis or other concerning symptoms.

Side Effects

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

Postmarketing reports have identified serious neuropsychiatric adverse events 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. Patients attempting to quit smoking with bupropion hydrochloride extended-release tablets (XL) should be observed for these symptoms, and they should be instructed to discontinue the medication and contact a healthcare provider if such events occur.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride extended-release tablets (XL) may increase blood pressure, necessitating monitoring before and during treatment.

Patients should be screened for bipolar disorder due to the potential activation of mania or hypomania. In the event of psychosis or other neuropsychiatric reactions, patients are advised to contact a healthcare professional.

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

Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either medication. Additionally, known hypersensitivity to bupropion or any of the ingredients in bupropion hydrochloride extended-release tablets (XL) is a 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, 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. 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, 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 poses an increased risk of hypertensive reactions. Close monitoring is warranted if these agents are used together.

Drug-Laboratory Test Interactions Bupropion XL may interfere with urine drug screening tests, potentially resulting in false-positive results for amphetamines. This should be taken into account when interpreting test results.

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 trials utilizing the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses between these groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

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

Pregnancy

Pregnancy Category C. 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) should be prescribed during pregnancy only if the potential benefits outweigh the potential risks to the fetus. Clinical considerations must include the risk of untreated depression when contemplating the discontinuation or alteration of antidepressant therapy 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, no increased risk for cardiovascular malformations was observed following bupropion exposure in the first trimester, with a prospectively observed rate of 1.3% (9 cardiovascular malformations out of 675 exposures), consistent with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and left ventricular outflow tract obstruction (LVOTO) have been reported. The United Healthcare database lacked sufficient power to evaluate this association, while the National Birth Defects Prevention Study (NBDPS) indicated an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. Similarly, findings regarding the risk for ventricular septal defect (VSD) are inconsistent, with the Slone Epidemiology Study reporting an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0), while the NBDPS and United Healthcare database studies did not find an association. Limitations in these studies include small sample sizes, inconsistent results, 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.

Caution is advised when administering bupropion hydrochloride extended-release tablets (XL) to 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 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 been observed, particularly 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 patients experienced 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 access the 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 supportive care, which 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 significant 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 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, 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. 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 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.

Providers should ensure that patients are aware of the available Medication Guide, which includes critical information regarding “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and other important details about bupropion hydrochloride extended-release tablets (XL). Patients, along with their families and caregivers, should be instructed to read the Medication Guide thoroughly and be supported in understanding its contents. They should also be given the opportunity to discuss the guide and ask any questions they may have.

Healthcare providers should advise patients to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial stages of treatment or when doses are adjusted. Families and caregivers should be encouraged to monitor patients closely for these symptoms, as changes can occur abruptly. Any severe or sudden onset of these symptoms should be reported 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.

Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal ideation when attempting to quit smoking while on bupropion. If such symptoms arise, patients should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

Healthcare providers should 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) if they experience a seizure during treatment. It is important to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

Patients should also be made aware that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. Furthermore, it should be communicated that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride.

Providers should caution 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.

Lastly, healthcare providers should encourage patients to notify them if they are taking or plan to take any prescription or over-the-counter medications, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL) and other drugs.

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 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by the United States Pharmacopeia (USP) guidelines. It is essential to protect the product from light to maintain its integrity and efficacy.

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 Zhejiang Jutai Pharamceutical Co. , Ltd. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)