Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinguished by its chemical structure, which is unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitors, or other known antidepressant agents. Its chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.21 and a molecular formula of C13H18ClNO•HCl.

The compound appears as a white powder that is soluble in water and possesses a bitter taste, which can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets for oral administration, available in dosages of 150 mg and 300 mg. These tablets are off-white to pale yellow in color and contain the labeled amount of bupropion hydrochloride along with several inactive ingredients, including 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. The tablets are printed with edible black ink.

The extended-release tablet's insoluble shell may remain intact during gastrointestinal transit and is excreted in the feces. The drug product meets the USP Dissolution Test 20 standards.

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 Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily. After a period of 4 days, the dose may be increased to 300 mg once daily 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 usual target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily. It is recommended to continue treatment 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, consideration should be given to reducing the dose and/or frequency of administration.

In patients with renal impairment, it is advisable to consider a reduction in the dose and/or frequency of dosing 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 associated with bupropion use.

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 initiated in patients currently receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (XL) is also a contraindication.

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events Postmarketing reports have indicated serious or clinically significant neuropsychiatric adverse events associated with bupropion hydrochloride XL. These events may 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 attempting to quit smoking while on bupropion hydrochloride XL should be observed for these symptoms. If any adverse events occur, patients should be instructed to discontinue the medication and contact a healthcare provider immediately.

Seizure Risk The risk of seizure is dose-related. 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, the medication should be discontinued.

Blood Pressure Monitoring Bupropion hydrochloride XL can elevate blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Bipolar Disorder Screening Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for the activation of mania or hypomania symptoms is also advised.

Psychosis and Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any signs of psychosis or other neuropsychiatric reactions.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in these patients.

Emergency Instructions Patients should be advised to discontinue bupropion hydrochloride XL and seek immediate medical assistance if they experience any neuropsychiatric adverse events.

In summary, thorough monitoring and patient education are critical components of the safe use of bupropion hydrochloride extended-release tablets (XL). Regular assessments, particularly regarding blood pressure and neuropsychiatric symptoms, are essential to mitigate risks associated with this medication.

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 safety information includes 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. Patients should also be monitored for hypertension, as bupropion hydrochloride extended-release tablets (XL) can elevate blood pressure; monitoring should occur before and periodically during treatment.

The potential for activation of mania/hypomania necessitates screening for bipolar disorder and ongoing monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions. Additionally, there is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

In cases of overdosage, seizures were reported 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, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest occurring prior to death.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (XL) with certain drug classes may necessitate careful monitoring and potential dosage adjustments due to significant interactions.

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 required to maintain clinical efficacy. However, the total dosage should not exceed the maximum recommended limit.

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 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 for seizure activity is recommended.

Dopaminergic Drugs The concurrent use of bupropion XL with dopaminergic agents such as levodopa and amantadine may increase the risk of central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is warranted.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion XL with MAOIs can elevate the risk of hypertensive reactions. It is essential to avoid this combination or to monitor blood pressure closely if coadministration is necessary.

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 in patients receiving 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 for treatment.

Geriatric Use

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

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects in these studies. 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 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. Data from epidemiological studies involving pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are inherent risks to the mother associated with untreated depression, which should be considered when evaluating treatment options.

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, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Additionally, decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background rate of birth defects, loss, or other adverse outcomes.

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication. Therefore, it is crucial to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures did not show an overall increased risk for malformations. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. However, no increased risk for cardiovascular malformations overall has been observed following bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion during this period was 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions regarding possible associations. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 mg and 150 mg/kg/day, respectively. No evidence of fetal malformations was observed in rats, while in rabbits, non-dose-related increases in fetal malformations and skeletal variations were noted at the lowest tested dose of 25 mg/kg/day, with decreased fetal weights observed at doses of 50 mg/kg/day and greater. Notably, 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 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, 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

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 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 considered as part of standard clinical practice.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In these cases, seizures occurred in approximately one third of the patients. Other serious adverse reactions associated with bupropion overdoses include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Additionally, mental status changes, clonus, myoclonus, and hyperreflexia have been reported.

In situations where bupropion was part of a multiple drug overdose, further complications such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been observed. While most patients have recovered without lasting effects, there have been fatalities linked to overdoses of bupropion alone, particularly in those who ingested large quantities. Reports indicate that multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted in patients who succumbed to these overdoses.

In the event of a bupropion overdose, it is crucial to provide supportive care, which includes close medical supervision and monitoring of the patient. There are no known antidotes for bupropion, and healthcare professionals should consider the possibility of a multiple drug overdose when assessing the patient. For up-to-date guidance and advice, it is recommended to consult a Certified Poison Control Center by calling 1-800-222-1222 or visiting 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 two out of five 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 one of three 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

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 informed about the contents of the 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 "What Other Important Information Should I Know About bupropion hydrochloride extended-release tablets (XL)?" Patients should be encouraged to discuss the Medication Guide and ask any questions they may have.

Healthcare providers should 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, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly concerning during the initial treatment phase and when dosage adjustments occur. Families and caregivers should monitor for these changes on a daily basis, as they may appear suddenly. Any severe or abrupt symptoms that were not part of the patient's initial presentation 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 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) can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. It is important to inform patients that this medication contains the same active ingredient (bupropion) found in ZYBAN, which is used for smoking cessation, and that it should not be used in combination with ZYBAN or any other bupropion-containing medications.

Furthermore, 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.

Lastly, patients should be encouraged 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) may interact with other drugs, affecting their metabolism.

Storage and Handling

The product is supplied in two packaging configurations: a blister pack containing 30 units and a plastic bottle also containing 30 units.

For optimal storage, the product should be maintained at a temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants, including bupropion hydrochloride extended-release tablets (XL), should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion XL and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop. Additionally, patients should stop taking the medication and consult a healthcare provider if they experience any allergic reactions, such as skin rash, pruritus, or respiratory difficulties.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. These events include mood changes, psychosis, and suicidal ideation, among others. Anaphylactoid and anaphylactic reactions have also been reported, necessitating medical intervention, with rare cases of severe skin reactions and anaphylactic shock noted in spontaneous reports.

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)