Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1 propanone hydrochloride. The molecular weight is 276.21, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white and soluble in water, with a bitter taste that produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablet USP (XL) is supplied for oral administration as 150 mg and 300 mg, off-white to pale yellow extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, glyceryl behenate, hydrophobic colloidal silica, hydroxypropyl cellulose, iron oxide black, L-cysteine hydrochloride monohydrate, methacrylic acid copolymer dispersion, polyvinyl alcohol, povidone, propylene glycol, shellac, and triethyl citrate.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with this medication.

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 adverse effects.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may precipitate seizures.

• 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, nor should an MAOI be initiated within 14 days of discontinuing bupropion hydrochloride extended-release tablets (XL). Additionally, bupropion should not be started 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).

Warnings and Precautions

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

General Precautions

Neuropsychiatric adverse events have been reported during smoking cessation attempts with bupropion hydrochloride extended-release tablets (XL). These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Patients attempting to quit smoking should be observed for these symptoms, and they should be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider if any of these adverse events occur.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, bupropion hydrochloride extended-release tablets (XL) should be discontinued immediately.

Bupropion hydrochloride extended-release tablets (XL) may also increase blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

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

Instruct patients to report any occurrences of psychosis or other neuropsychiatric reactions to a healthcare professional promptly.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution should be exercised in these patients.

Laboratory Tests

Blood pressure should be monitored before initiating treatment with bupropion hydrochloride extended-release tablets (XL) and periodically during the treatment to ensure patient safety.

Emergency Medical Help Instructions

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

Stop Taking and Call Your Doctor Instructions

Patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (XL) and contact their healthcare provider if they experience any neuropsychiatric adverse events.

Side Effects

Patients may experience a range of adverse reactions while using this medication, categorized by seriousness and frequency.

Common adverse reactions, occurring in 5% or more of patients and at least twice the rate of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions warrant particular attention. A WARNING regarding suicidal thoughts and behaviors is indicated, as there is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported 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.

Additional important notes include a dose-related seizure risk, which can be minimized by limiting the daily dose to 450 mg and gradually increasing it. Discontinuation of the medication is advised if a seizure occurs. The medication may also lead to hypertension, necessitating blood pressure monitoring before and during treatment.

Patients with a history of bipolar disorder should be screened and monitored for the activation of mania or hypomania. Instruct patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

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

In cases of overdosage, serious reactions have been reported, including seizures in approximately one third of all cases. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), mental status changes, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

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

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 exposure. However, any dosage adjustment should not exceed the maximum recommended dose.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6, which can lead to elevated 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 when used with bupropion.

Drugs Lowering Seizure Threshold Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) in conjunction with other medications that may lower the seizure threshold, as this combination may increase the risk of seizures.

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

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion hydrochloride extended-release tablets (XL) with MAOIs poses an increased risk of hypertensive reactions. Caution is warranted, and monitoring for hypertensive symptoms should be implemented.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness of bupropion hydrochloride extended-release tablets (XL) in the pediatric population have not been established. When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks against the clinical need for treatment.

Geriatric Use

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

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

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting doses 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 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 indicated that women 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 to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; 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%.

Inconsistent findings have been reported regarding the association between bupropion exposure during the first trimester and specific cardiovascular malformations, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). The NBDPS found an increased risk for LVOTO, while the Slone Epidemiology case-control study did not find an increased risk for LVOTO or any other cardiovascular malformations studied. The studies were limited by the small number of exposed cases and the potential for chance findings from multiple comparisons.

In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while in rabbits, non-dose-related increases in fetal malformations and skeletal variations were observed at the lowest dose tested and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less. In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day 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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

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 have been reported.

Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, tachycardia, and changes in ECG. Additionally, patients may exhibit alterations in mental status, clonus, myoclonus, and hyperreflexia. Other symptoms that have been observed in cases of overdose encompass fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

Fatalities linked to bupropion overdose have been recorded, typically occurring in the context of large doses and multiple uncontrolled seizures. These cases may also involve bradycardia, cardiac failure, and cardiac arrest prior to death.

Currently, there are no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are essential in managing such cases. Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in the event of an overdose. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org.

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 of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded a negative result 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. No information is available regarding teratogenic effects or animal pharmacology and toxicology.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs associated with bupropion hydrochloride extended-release tablets (XL).

Patients have reported experiencing changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, particularly during attempts to quit smoking. Additionally, new or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, and suicidal thoughts or actions, have been noted in individuals using bupropion for smoking cessation.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been documented in some patients taking bupropion XL. Furthermore, severe allergic reactions to bupropion XL have been reported, with symptoms including rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

The potential for seizures (convulsions) has been recognized, particularly in individuals with certain medical conditions or those taking specific medications. The risk of seizures may increase with higher doses of bupropion XL. Additionally, some patients have experienced episodes of mania characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Lastly, instances of elevated blood pressure, which can be severe, have been reported in patients taking bupropion XL, with an increased risk noted in those concurrently using nicotine replacement therapy for smoking cessation.

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 contents of the Medication Guide, which includes critical information about antidepressant medicines, depression, serious mental illnesses, and the potential for suicidal thoughts or actions. Patients should be encouraged to discuss the Medication Guide and ask any questions they may have.

Healthcare providers must 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, hypomania, mania, unusual changes in behavior, worsening depression, and suicidal ideation, particularly during the initial treatment phase or when adjusting the dose. Families and caregivers should monitor for these symptoms daily, as changes can occur abruptly. Any severe or sudden onset of these symptoms should be reported to the prescriber, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

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 inform 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 made aware 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 inform patients that this medication contains the same active ingredient as ZYBAN, which is used for smoking cessation, and that it 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 or motor and cognitive skills. Until patients are confident that the medication does not adversely affect their performance, they should refrain from driving or operating complex machinery.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect drug metabolism. Additionally, patients should inform their provider if they become pregnant or plan to become pregnant during treatment.

Instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to ensure the proper release rate. If a dose is missed, patients should not take an extra tablet but should continue with the next scheduled dose, as this can help mitigate the dose-related risk of seizure. The medication should be taken in the morning and can be consumed with or without food. Patients may notice an inert matrix in their stool, which is normal, as the active medication has already been absorbed.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. 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 outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets (XL) for major depressive disorder or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion XL and seek medical attention if they observe any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, any signs of allergic reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath, warrant immediate consultation with a healthcare provider.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, characterized by symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been documented in association with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)