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, 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, there are no teratogenic or nonteratogenic effects 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. Similarly, in patients with renal impairment, a reduction in dose and/or frequency may be warranted based on individual patient assessment.

Contraindications

Use of Bupropion Hydrochloride Extended-Release Tablets (SR) 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 (SR) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any other components of Bupropion Hydrochloride Extended-Release Tablets (SR).

Warnings and Precautions

Serious 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, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicide. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and contact their healthcare provider immediately 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. If a seizure occurs, bupropion should be discontinued.

Bupropion hydrochloride extended-release tablets (SR) may elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

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 advised.

Psychosis and other neuropsychiatric reactions may occur; patients should be instructed to contact a healthcare professional if they experience such reactions.

There is a risk of angle-closure glaucoma 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 these patients for any worsening or emergence of suicidal thoughts and behaviors.

To ensure safe use, blood pressure should be monitored before starting treatment and periodically during therapy. Patients should be advised to seek emergency medical help if they experience psychosis or other neuropsychiatric reactions. Additionally, patients must be instructed to discontinue bupropion and contact their healthcare provider if they experience any neuropsychiatric adverse events.

Side Effects

Patients may experience a range of adverse reactions while using Bupropion Hydrochloride Extended-Release Tablets (SR). The 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.

Serious adverse reactions warranting immediate attention include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for the emergence or worsening of these thoughts and behaviors. Neuropsychiatric events, such as mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides, have also been reported, particularly during smoking cessation.

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

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Psychosis and other neuropsychiatric reactions may occur, and patients are advised to contact a healthcare professional if such symptoms arise. Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles receiving antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnoses 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 or in patients receiving linezolid or intravenous methylene blue.

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, and ECG changes such as conduction disturbances or arrhythmias. Severe outcomes, including fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, have been noted, particularly in the context of multiple drug overdoses. Fatalities 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, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). A dose reduction of these concomitant medications should be considered.

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

Caution is warranted 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 may require further investigation.

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.

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 their antidepressant treatment. Therefore, healthcare providers should 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, which included 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% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%).

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 (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis). 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, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m² basis) and greater, with no maternal toxicity 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 (approximately 4 times the MRHD on a mg/m² basis) 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 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, 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.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for bupropion hydrochloride extended-release tablets (SR) 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 not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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. Healthcare professionals should be vigilant for serious reactions associated with bupropion overdose, which may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as conduction disturbances.

Fatalities linked to bupropion overdose have occurred, particularly in patients who have ingested large quantities. These cases often involve multiple uncontrolled seizures and cardiac failure, underscoring the severity of the situation.

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and close medical supervision. It is crucial to ensure adequate airway management, oxygenation, and ventilation. The induction of emesis is not recommended in these situations.

In the event of a bupropion overdose, healthcare professionals are advised to consult a Certified Poison Control Center for further guidance. The National Capital Poison Center can be reached at 1-800-222-1222 or through their website at www.poison.org for additional resources and support.

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 was 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, indicating a potential concern, although the relationship of these lesions to neoplasms remains unresolved. No similar liver lesions were detected in the mouse study, and there was no increase in malignant tumors in either species. Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with 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 noted in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented in some individuals using bupropion for smoking cessation. These symptoms were more frequently observed in patients with a prior history of mental health disorders compared to those without such a history.

Patients experiencing a seizure while on bupropion hydrochloride extended-release tablets (SR) are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride extended-release tablets (SR) is contraindicated following a seizure.

Instances of severe hypertension have been reported in some individuals taking bupropion hydrochloride extended-release tablets (SR). Additionally, some patients may experience episodes of mania characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been reported by some patients during treatment with bupropion hydrochloride extended-release tablets (SR).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have also been documented. Patients should discontinue use and seek immediate medical attention if they experience symptoms such as rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they are well-informed about their treatment. It is important to 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 stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can occur suddenly. Any severe or unexpected symptoms should be reported to the patient's prescriber or healthcare professional promptly. Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts, particularly when attempting to quit smoking while taking bupropion. Patients experiencing such symptoms should discontinue bupropion and contact a healthcare professional immediately.

Healthcare providers should educate patients about the signs of hypersensitivity and instruct them to discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking bupropion hydrochloride extended-release tablets (SR) and not to restart if they experience a seizure during treatment. It is crucial 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.

As the dosage is increased during the initial titration phase to levels above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures. Patients should also be made aware that taking bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

It is important to inform patients that bupropion hydrochloride extended-release tablets (SR) 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. Patients should be counseled that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks that require judgment or motor and cognitive skills.

Patients should 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 (SR) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients should be instructed to store bupropion hydrochloride extended-release tablets (SR) at room temperature, between 68°F and 77°F (20°C to 25°C), keeping the tablets dry and protected from light. They should swallow the tablets whole to avoid altering the release rate and should not chew, divide, or crush them. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next tablet at the regular scheduled time due to the dose-related risk of seizure. Lastly, patients should be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and can be taken with or without food.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the United States Pharmacopeia (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

Patients receiving bupropion hydrochloride should be closely monitored for the emergence of agitation, irritability, and unusual behavioral changes, as well as symptoms of suicidality. Families and caregivers are advised to conduct daily observations and report any concerning symptoms to healthcare providers immediately. Patients should discontinue bupropion and seek medical attention if they experience agitation, changes in mood or behavior, or suicidal thoughts. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, as well as anaphylactic shock, have also been reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)