Bupropion hydrochloride

Description

Bupropion Hydrochloride Extended-Release Tablets USP (SR) is chemically designated as (±)-1-(3-chlorophenyl)-2-(1, 1-dimethylethyl) amino-1­-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2 g/mol, and its molecular formula is C13H18ClNO•HCl. The bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa.

Bupropion Hydrochloride Extended-Release Tablets USP (SR) are available in strengths of 100 mg (light blue), 150 mg (purple), and 200 mg (pink) as film-coated, sustained-release tablets. Each 100-mg tablet contains inactive ingredients including colloidal silicon dioxide, hydroxypropyl cellulose, L-cysteine hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, povidone, talc, and titanium dioxide, along with FD&C blue No. 1 aluminum lake and FD&C blue No. 2 aluminum lake. The 150-mg tablet contains FD&C blue No. 2 aluminum lake and FD&C red No. 40 aluminum lake, while the 200-mg tablet contains FD&C red No. 40 aluminum lake.

Uses and Indications

Bupropion Hydrochloride Extended-Release Tablets (SR) are indicated for the treatment of major depressive disorder (MDD).

Limitations of Use: The safety and efficacy of Bupropion Hydrochloride Extended-Release Tablets (SR) have not been established in patients with a history of seizures or eating disorders, as these conditions may increase the risk of seizure. Additionally, no teratogenic or nonteratogenic effects have been reported in the available data.

Dosage and Administration

The recommended starting dose is 150 mg per day. To minimize the risk of seizures, the dose should be increased gradually. After an initial period of 3 days, the dose may be escalated to 300 mg per day, administered as 150 mg twice daily, with an interval of at least 8 hours between doses. The usual target dose is 300 mg per day, maintained as 150 mg twice daily.

For patients who do not respond adequately to the 300 mg per day regimen, the maximum dose may be increased to 400 mg per day, given as 200 mg twice daily. It is essential to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, in patients with renal impairment, a reduction in dose and/or frequency should also be considered.

Contraindications

Use of Bupropion Hydrochloride Extended-Release Tablets (SR) is contraindicated in the following situations:

Patients with a seizure disorder are at increased risk of seizures when using this medication.

The use of Bupropion Hydrochloride Extended-Release Tablets (SR) is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased seizure risk.

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is a contraindication, as it may elevate the risk of seizures.

Bupropion Hydrochloride Extended-Release Tablets (SR) should not be used in conjunction with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders, or within 14 days of discontinuing either treatment. Additionally, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any other components of Bupropion Hydrochloride Extended-Release Tablets (SR) is a contraindication for use.

Warnings and Precautions

Neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. 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. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare professionals closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and promptly contact a healthcare provider if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the daily dose to a maximum of 400 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) have the potential to elevate blood pressure. Therefore, 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 may activate mania or hypomania. Continuous monitoring for these symptoms is advised.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They must be instructed to contact a healthcare professional if such reactions occur.

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

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor for any worsening or emergence of suicidal thoughts and behaviors in these populations.

To ensure safe use of bupropion, healthcare professionals should monitor blood pressure before treatment initiation and periodically during treatment. Patients must be advised to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events or psychotic symptoms.

Side Effects

Patients receiving Bupropion Hydrochloride Extended-Release Tablets (SR) may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most common adverse reactions reported include headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitations, myalgia, sweating, rash, and anorexia. These reactions are generally mild to moderate in severity.

Serious adverse reactions warrant particular attention. A WARNING: 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 the emergence or worsening of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been observed 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. Patients should be instructed to contact a healthcare professional if any of these reactions occur.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, Bupropion Hydrochloride Extended-Release Tablets (SR) can increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Angle-closure glaucoma has also been noted in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. The use of Monoamine Oxidase Inhibitors (MAOIs) in conjunction with Bupropion Hydrochloride Extended-Release Tablets (SR) is contraindicated, as is the use of Bupropion Hydrochloride Extended-Release Tablets (SR) within 14 days of stopping an MAOI intended for psychiatric disorders. Known hypersensitivity to bupropion or other ingredients of the formulation is also a contraindication.

In cases of overdose, seizures were reported in approximately one-third of all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including conduction disturbances and arrhythmias), 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

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion based on clinical response, without exceeding the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications. This includes antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). It is advisable to consider a dose reduction of these medications when used concurrently with bupropion.

Additionally, bupropion may reduce plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy.

Caution is advised when prescribing bupropion hydrochloride extended-release tablets (SR) alongside medications that lower the seizure threshold, as this combination may increase the risk of seizures.

The concomitant use of bupropion hydrochloride extended-release tablets (SR) with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring.

There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are used in conjunction with monoamine oxidase inhibitors (MAOIs).

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) can lead to false-positive results in urine tests for amphetamines, which should be considered in the context of drug screening.

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. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for further information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

Geriatric Use

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

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, it is important to note that some older individuals may exhibit greater sensitivity to the medication.

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

Pregnancy

There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any 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 during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 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, with decreased fetal weights noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies carry a background risk 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.

Clinical considerations must include the disease-associated maternal and/or embryo/fetal risk. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued treatment. Therefore, it is essential 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.

Human 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 increased risk for malformations overall. Although the Registry was not designed or powered to evaluate specific defects, it suggested a possible increase in cardiac malformations. However, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3%, which is similar to the background rate of cardiovascular malformations (approximately 1%). Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding a possible association.

In animal studies, bupropion was administered orally to pregnant rats and rabbits 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. However, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater, with decreased fetal weights noted at doses of 50 mg/kg/day and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less. Additionally, 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 10 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. The relationship between bupropion exposure and these seizures remains unclear.

When considering the use of bupropion hydrochloride extended-release tablets (SR) in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for the medication and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Renal Impairment

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

Hepatic Impairment

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

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one-third of these cases, seizures have been reported, highlighting the potential neurological risks associated with significant overdosage.

Serious adverse reactions may manifest in the event of a bupropion overdose. These can include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes, notably QRS prolongation. Such symptoms necessitate immediate medical attention, as they indicate severe toxicity.

Fatalities linked to bupropion overdose have been observed, particularly in patients who have ingested large quantities. These cases often involve multiple uncontrolled seizures and subsequent cardiac failure, underscoring the critical nature of managing overdose situations promptly and effectively.

Currently, there are no known antidotes for bupropion. Therefore, the cornerstone of management in overdose cases is supportive care, which should be accompanied by close medical supervision. Healthcare professionals are advised to monitor the patient’s vital signs and neurological status continuously.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center by calling 1-800-222-1222 or by visiting www.poison.org for additional resources and information.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day to rats did not adversely affect male and female fertility. This dosing regimen, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, was applied to females prior to mating and continued either through Day 13 of gestation or through lactation. Males received the same treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately five times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven and two times the 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, approximately two to seven times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, yielding a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports include changes in mood, such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, instances of suicidal ideation, suicide attempts, and completed suicides have been documented.

Neuropsychiatric adverse events have occurred in patients both with and without pre-existing psychiatric conditions, with some individuals experiencing a worsening of their psychiatric illnesses. In many cases, resolution of symptoms following the discontinuation of bupropion has been reported; however, in some instances, symptoms persisted. Therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

Patient Counseling

Healthcare providers should inform patients that the use of antidepressants has been associated with an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults during short-term trials. It is important to note that these trials did not indicate an increased risk in individuals over the age of 24, and there was a reduction in risk observed in patients aged 65 and older.

Providers should emphasize the necessity of close monitoring for all patients initiating antidepressant therapy, regardless of age. This includes vigilance for any worsening of symptoms or the emergence of suicidal thoughts and behaviors. Healthcare providers should advise families and caregivers about the importance of maintaining open communication with the prescriber and the need for close observation of the patient.

Patients receiving antidepressants for major depressive disorder (MDD) or other indications, whether psychiatric or nonpsychiatric, should be monitored for signs of agitation, irritability, and any unusual changes in behavior. Families and caregivers should be alerted to report any concerning symptoms, including the emergence of suicidality, to healthcare providers immediately.

Additionally, when prescribing bupropion hydrochloride extended-release tablets (SR), providers should write prescriptions for the smallest quantity of tablets necessary for effective patient management. This practice is intended to minimize the risk of overdose.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°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

Bupropion hydrochloride extended-release tablets (SR) should be administered whole, without crushing, dividing, or chewing, and can be taken with or without food. Clinicians are advised to counsel families and caregivers to closely monitor patients for signs of agitation, irritability, unusual behavioral changes, and any emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and prescriptions should be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation. These events include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, and aggressive behaviors, as well as suicidal ideation, suicide attempts, and completed suicides.

FDA Insert (PDF)

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

View full prescribing information (PDF)