Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (SR), are chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The structure of bupropion closely resembles that of diethylpropion and is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO•HCl.

The bupropion hydrochloride powder is a white powder that is soluble in 0.1N HCl, 96% alcohol, and water. It has a bitter taste and can produce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (SR), are available for oral administration in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each tablet is film-coated and contains the labeled amount of bupropion hydrochloride along with inactive ingredients, which include copovidone, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. The 100 mg tablet contains FD&C Blue No. 1 Brilliant Blue FCF Aluminium Lake, the 150 mg tablet contains FD&C Blue No. 2 Indigo Carmine Aluminium Lake and FD&C Red No. 40 Allura Red AC Aluminium Lake, and the 200 mg tablet contains FD&C Red No. 40 Allura Red AC Aluminium Lake.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder (MDD).

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

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 should be considered based on individual patient needs.

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, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (SR). Additionally, it is contraindicated in patients receiving linezolid or intravenous methylene blue.

• Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR).

Warnings and Precautions

Patients undergoing smoking cessation with bupropion should be closely monitored for neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including 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. Healthcare professionals are advised to observe these patients for the emergence of such symptoms and to instruct them to discontinue bupropion and seek immediate medical attention 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. In the event of a seizure, bupropion should be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) have been shown to potentially increase blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

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 also recommended.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional if they experience any 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 patient safety, it is imperative to monitor blood pressure before starting treatment and periodically during treatment. Patients should be advised to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs.

Side Effects

Patients may experience a range of adverse reactions while taking 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 medical attention include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening or emergence of suicidal ideation or behavior.

Neuropsychiatric adverse events have been observed during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should contact a healthcare professional promptly.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, 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 can increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Activation of mania or hypomania has been reported, necessitating screening for bipolar disorder and careful monitoring for these symptoms. Patients with untreated anatomically narrow angles may be at risk for angle-closure glaucoma when treated with antidepressants, including bupropion.

Other important considerations include the potential for serious reactions in patients with a seizure disorder, current or prior diagnoses of bulimia or anorexia nervosa, and those who abruptly discontinue alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping such treatment. It is also contraindicated 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, 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 dosage of the affected medication based on clinical response. However, it is important that the dosage does not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to elevated concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). Therefore, careful monitoring of these medications is advised when co-administered with bupropion.

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

Caution is advised when prescribing bupropion hydrochloride extended-release tablets (SR) to patients who are concurrently taking medications that lower the seizure threshold, as this 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 patient evaluation and monitoring.

Furthermore, the combination of bupropion hydrochloride extended-release tablets (SR) with monoamine oxidase inhibitors (MAOIs) can lead to an increased risk of hypertensive reactions, warranting close observation and potential dosage adjustments.

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) may cause false-positive results in urine tests for amphetamines, which should be considered when interpreting drug screening results.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

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 clinical trials utilizing 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 between these groups, it is important to note that greater sensitivity 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 elderly patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during 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 during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, no evidence of fetal malformations was observed at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were noted at doses approximately equal to the MRHD and greater, with decreased fetal weights observed at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown, although 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 approximately 2% to 4% and 15% to 20%, respectively.

A prospective longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those 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 associated with untreated depression and the potential effects on the fetus when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, along with a retrospective cohort study utilizing the United Healthcare database (1,213 first trimester exposures), did not demonstrate 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. Notably, no increased risk for cardiovascular malformations overall has been observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% for cardiovascular malformations, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and risks for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not permit definitive conclusions. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during organogenesis at doses of up to 450 mg and 150 mg/kg/day, respectively, with no evidence of fetal malformations in rats. However, in rabbits, non-dose-related increases in fetal malformations and skeletal variations were observed at the lowest tested dose of 25 mg/kg/day and higher, with decreased fetal weights noted at doses of 50 mg/kg/day and above. A pre-and postnatal development study in pregnant rats revealed that bupropion administered orally at doses up to 150 mg/kg/day from embryonic implantation through lactation had no adverse effects 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside 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

There is no information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing to patients with reduced kidney function.

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 can occur with significant clinical consequences. Reports indicate that overdoses of 30 grams or more have been documented, with seizures occurring in approximately one-third of these cases.

Clinical Manifestations Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as QRS prolongation. Additional symptoms reported in cases of overdose encompass sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. It is important to note that fatalities have been associated with bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac events often preceding death.

Management Recommendations There are currently no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are critical in managing these cases. In the event of an overdose, healthcare professionals should ensure that the patient has an adequate airway, oxygenation, and ventilation. Continuous monitoring of cardiac rhythm and vital signs is essential.

For further guidance, it is recommended to consult a Certified Poison Control Center when managing a suspected bupropion overdose. This resource can provide valuable assistance in the assessment and treatment of affected patients.

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, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male or female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males were treated 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, with a mutation rate that was two to three times higher than the control in two 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

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. It is advised that if patients, their families, or caregivers notice any unusual thoughts or behaviors, they should contact a healthcare provider immediately.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have been reported, with signs 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.

There is a risk of seizures associated with bupropion hydrochloride extended-release tablets (SR), particularly in individuals with certain medical conditions or those taking specific medications. The likelihood of seizures increases with higher doses of the medication.

Some patients may experience episodes of mania while on bupropion hydrochloride extended-release tablets (SR), characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech.

Reports of unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been noted in some patients taking bupropion hydrochloride extended-release tablets (SR). Additionally, visual disturbances such as eye pain, changes in vision, and swelling or redness in or around the eye have been reported, with some individuals potentially at risk for these issues.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. 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, particularly during the initial stages of antidepressant treatment and when adjusting the dose.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these may 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 when attempting to quit smoking while taking bupropion. Patients must be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity symptoms is essential, and patients should be advised to discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (SR) and not to restart if they experience a seizure during treatment.

Patients should be made aware that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures. Therefore, minimizing or avoiding alcohol use is recommended. It is also important to instruct patients to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, preferably with at least 8 hours between doses, especially when titrating to doses above 150 mg per day, to reduce the risk of seizures.

Patients should be informed 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. Furthermore, patients should be educated that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in combination with ZYBAN or any other medications containing bupropion.

Healthcare providers should counsel patients that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until patients are confident that bupropion does not adversely affect their performance, they should refrain from driving or operating complex machinery.

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

Storage instructions should be provided, advising patients to keep bupropion hydrochloride extended-release tablets (SR) at 20° to 25°C (68° to 77°F) in a tight, light-resistant container with a child-resistant closure, protecting it from light and moisture. Patients must be instructed to swallow the tablets whole to ensure the release rate is not altered and to avoid chewing, dividing, or crushing them.

If a patient misses a dose, they should be instructed not to take an extra tablet to compensate for the missed dose but to take the next tablet at the regular time, due to the dose-related risk of seizure. Patients should also be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and that they can be taken with or without food.

Storage and Handling

The product is supplied in a tight, light-resistant container equipped with a child-resistant closure, as required. 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. It is essential to protect the product from light and moisture to maintain its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)