Bupropion hydrochloride

Description

Bupropion Hydrochloride Extended-release Tablets, USP (SR) is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.2, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water, with a bitter taste and the ability to produce a sensation of local anesthesia on the oral mucosa.

Bupropion Hydrochloride Extended-release Tablets, USP (SR) are supplied for oral administration as 100 mg, 150 mg, and 200 mg white to off-white, film-coated, extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with the following inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, and magnesium stearate. The film coating includes lactose monohydrate, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol.

Uses and Indications

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

There are no teratogenic or nonteratogenic effects associated with the use of this medication as per 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 a minimum interval of 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 allowable dose is 400 mg per day, which should be 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 may also be warranted.

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

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 course of therapy.

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.

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 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 may experience a range of adverse reactions while using the medication. 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 warnings associated with the use of this medication include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation.

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. It is crucial for healthcare professionals to instruct patients to report any such reactions immediately.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dosage and limit the daily dose to 400 mg. If a seizure occurs, the medication should be discontinued. Additionally, bupropion hydrochloride extended-release tablets (SR) may increase blood pressure, necessitating monitoring of blood pressure before and during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Furthermore, angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

In cases of overdose, serious reactions such as seizures, hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation), arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been documented. Notably, deaths associated with bupropion overdose have been reported, 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 a dose increase of the affected medication based on clinical response. However, the dosage should not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to increased plasma 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). A dose reduction of these medications should be considered to mitigate potential adverse effects.

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

Caution is warranted 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 monitoring of patients.

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

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) can cause false-positive results in urine drug tests for amphetamines, which may lead to unnecessary clinical interventions.

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 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 suggest that women with a history of major depressive disorder who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue 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.

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. However, the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% in pregnancies exposed to bupropion, which is similar to the background rate of approximately 1%.

Findings regarding left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) associated with bupropion exposure during the first trimester are inconsistent and do not allow for definitive conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, the Slone Epidemiology case-control study did not find an increased risk for LVOTO or VSD.

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, while pregnant rabbits exhibited non-dose–related increases in fetal malformations and skeletal variations at the lowest tested dose of 25 mg/kg/day and greater, with decreased fetal weights observed 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, 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

There are no specific dosing adjustments, monitoring requirements, or precautions indicated for patients with renal impairment. The prescribing information does not provide details regarding the management of patients with reduced kidney function, including any changes in clearance or creatinine clearance thresholds. Healthcare professionals should consider this lack of information when prescribing to patients with renal impairment.

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

In cases of bupropion overdose, significant clinical manifestations can occur, necessitating immediate medical intervention. Reports indicate that overdoses of 30 grams or more have been documented, with seizures occurring in approximately one-third of these instances.

Symptoms of Overdosage

Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as conduction disturbances. 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 failure being significant contributors to mortality.

Management of Overdosage

There are currently no known antidotes for bupropion; therefore, supportive care and close medical supervision are critical in managing an overdose. In the event of an overdose, healthcare professionals should ensure the maintenance of an adequate airway, oxygenation, and ventilation, while also closely monitoring cardiac rhythm and vital signs.

It is advisable to consult a Certified Poison Control Center for further guidance in managing bupropion overdose. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org. Induction of emesis is not recommended in cases of bupropion overdose, emphasizing the need for careful and supportive management.

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, 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

Some patients have reported experiencing changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation and suicide during attempts 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 also been noted in 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.

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. Additionally, 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.

Instances of high blood pressure, which can be severe, have been reported in some patients taking bupropion hydrochloride extended-release tablets (SR). The risk of developing high blood pressure may be heightened in individuals concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation. Some patients have experienced 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, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been documented in some individuals taking bupropion hydrochloride extended-release tablets (SR). Reports of visual disturbances, such as eye pain, changes in vision, and swelling or redness in or around the eye, have also been noted.

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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms may occur, particularly during the initial stages of antidepressant treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can be significant. Any severe, sudden, or previously unreported symptoms should be communicated 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 should be instructed to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare 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 patients should be advised to minimize or avoid alcohol consumption. During the initial titration phase, particularly when increasing the dose above 150 mg/day, patients should 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 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 also 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 should not be used in combination with ZYBAN® or any other medications 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. They should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as interactions may affect drug metabolism.

Patients must inform their healthcare provider if they become pregnant or plan to become pregnant while undergoing therapy with bupropion hydrochloride extended-release tablets (SR). Proper storage of the medication at 20° to 25°C (68° to 77°F) should be emphasized.

Patients should be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole, without chewing, dividing, or crushing them, to ensure the correct release rate of the medication. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular scheduled time due to the dose-related risk of seizure. It should also be noted that bupropion hydrochloride extended-release tablets (SR) may have an odor, and they can be taken with or without food.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature.

It is essential to protect the product from light and moisture to maintain its integrity and efficacy. Proper storage conditions must be observed to ensure optimal performance.

Additional Clinical Information

Patients receiving treatment with bupropion 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 develop suicidal thoughts or behaviors. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Postmarketing reports indicate that serious neuropsychiatric adverse events, including mood changes, psychosis, and suicidal ideation, have occurred in patients taking bupropion for smoking cessation. While some patients may experience symptoms of nicotine withdrawal, including depression, it is important to note that these symptoms can also arise in patients taking bupropion who continue to smoke. In many cases, symptoms resolved after discontinuation of the medication; however, persistent symptoms have been noted, necessitating ongoing monitoring and supportive care until resolution.

FDA Insert (PDF)

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

View full prescribing information (PDF)