Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake 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. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (XL) are supplied for oral administration as 150 mg and 300 mg creamy-white to pale yellow extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: povidone, cysteine hydrochloride monohydrate, colloidal anhydrous silica, glycerol dibehanate, magnesium stearate, ethyl cellulose, polyethylene glycol, colloidal hydrated silica, triethyl citrate, methacrylic acid - ethyl acrylate copolymer, shellac, iron oxide black, and propylene glycol.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, this medication is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL).

Dosage and Administration

The dosage and administration of the medication should be approached with caution, particularly in the context of seizure risk. It is recommended that healthcare professionals gradually increase the dose while periodically reassessing the patient's need for maintenance treatment.

For the management of Major Depressive Disorder, the starting dose is 150 mg administered once daily. After a period of 4 days, the dose may be increased to a usual target dose of 300 mg once daily.

In the case of Seasonal Affective Disorder, treatment should be initiated in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a potential increase to the usual target dose of 300 mg once daily after one week. Treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in the dose and/or frequency of dosing.

In patients with renal impairment, a reduction in the dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in the following situations:

Patients with a seizure disorder due to the increased risk of seizures associated with bupropion.

Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of seizures.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Serious neuropsychiatric adverse events have been reported in patients using bupropion hydrochloride extended-release tablets (XL) during smoking cessation. 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 reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare professionals closely monitor patients attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Patients should be instructed to discontinue the medication and seek immediate medical advice if they experience any of these adverse events.

The risk of seizures associated with bupropion hydrochloride XL is dose-dependent. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that the dose be increased gradually. Should a seizure occur, the medication must be discontinued immediately.

Bupropion hydrochloride XL has 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 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.

There is a risk of psychosis and other neuropsychiatric reactions. Patients should be instructed to contact a healthcare professional if they experience such reactions.

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 these patients for any worsening or emergence of suicidal thoughts and behaviors.

To ensure patient safety, healthcare providers should instruct patients to discontinue bupropion hydrochloride XL and contact a healthcare provider if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms. Regular monitoring of blood pressure is also recommended before and during treatment.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by seriousness and frequency.

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

A significant warning is associated with the increased risk of suicidal thoughts and behaviors 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.

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 advised to contact a healthcare professional if they experience any of these reactions.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride extended-release tablets (XL) may increase blood pressure, necessitating monitoring of blood pressure 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. Psychosis and other neuropsychiatric reactions may also occur, and patients should be instructed to seek medical advice if such reactions arise.

Angle-closure glaucoma has been noted in patients with untreated anatomically narrow angles who are treated with antidepressants, warranting caution in this population.

In cases of overdose, serious reactions have been reported, including seizures in approximately one third of all cases. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances or 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. However, it is important to ensure that the dosage does not exceed the maximum recommended limit.

Bupropion acts as an inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications. This includes antidepressants like venlafaxine and nortriptyline, antipsychotics such as haloperidol, beta-blockers including metoprolol, and Type 1C antiarrhythmics like propafenone. Clinicians should monitor patients for potential adverse effects associated with these increased drug levels.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (XL) alongside medications that may lower the seizure threshold. The risk of seizures may be heightened in such scenarios.

The concomitant use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic drugs, including levodopa and amantadine, may result in central nervous system (CNS) toxicity. Therefore, careful monitoring is recommended when these agents are used together.

Additionally, the combination of bupropion hydrochloride extended-release tablets (XL) with monoamine oxidase inhibitors (MAOIs) can increase the risk of hypertensive reactions. It is advisable to avoid this combination or to monitor blood pressure closely if co-administration is necessary.

Lastly, it should be noted that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines, which could lead to misinterpretation of 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 for bupropion hydrochloride extended-release tablets (XL). When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need for treatment.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6000 patients, of which 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 years and older participated in trials utilizing the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and their younger counterparts. 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 doses for geriatric patients. Monitoring renal function in elderly patients may also be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. 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. 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 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.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. In contrast, 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 in the indicated population is unknown. 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.

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%, which is similar to the background rate of 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 possible associations. In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day 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 ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, 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 (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly pronounced in cases involving multiple drug overdoses, which can complicate the clinical picture and necessitate more intensive management.

Fatalities linked to bupropion overdose have been observed, often occurring after multiple uncontrolled seizures. Other critical cardiovascular events, such as bradycardia, cardiac failure, and cardiac arrest, have also been noted in these severe cases.

Currently, there are no known antidotes for bupropion overdose. Therefore, the primary approach to management involves supportive care and close medical supervision. Healthcare professionals are advised to monitor the patient closely for any signs of deterioration.

In the event of a bupropion overdose, it is essential to consult a Certified Poison Control Center for expert guidance on the appropriate management strategies. This step is crucial to ensure the safety and well-being of the patient.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis; lower doses were not evaluated. 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.

In terms of mutagenicity, bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, bupropion was associated with an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

No evidence of impaired fertility was observed in a fertility study conducted in rats at doses up to 300 mg/kg/day.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide during attempts to quit smoking while taking bupropion hydrochloride extended-release tablets (XL). 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 documented. These symptoms have been observed in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been reported. Patients are advised to discontinue use and contact their healthcare provider immediately if they experience symptoms such as 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, as these may indicate a serious allergic reaction.

The incidence of seizures may increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some patients have experienced significant increases in blood pressure while taking this medication, with a heightened risk observed in those concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Periods of mania have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as markedly 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 also been noted, prompting patients to seek guidance from their healthcare provider.

Visual disturbances, including eye pain, changes in vision, and swelling or redness in or around the eye, have been documented in some cases.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) to understand the medication's use and potential risks. Healthcare providers should instruct patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial stages of antidepressant treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients closely for these symptoms on a daily basis, as changes can occur abruptly. Any severe or sudden onset of these symptoms, especially if they were not part of the patient’s initial presentation, should be reported to the 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, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

It is important to educate patients about the signs of hypersensitivity and instruct them to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Patients should also be advised to stop taking the medication and not to restart it if they experience a seizure during treatment.

Patients should be cautioned 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. Additionally, patients should be made aware that bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be informed that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride.

Healthcare providers should counsel patients that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks that require judgment or motor and cognitive skills. Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs.

Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant while on bupropion hydrochloride extended-release tablets (XL). It is essential to instruct patients to swallow the tablets whole to ensure the release rate is not altered and to avoid crushing, dividing, or chewing them.

If a patient misses a dose, they should not take an extra tablet to compensate for the missed dose but should instead take the next tablet at the regular scheduled time, due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food.

Storage and Handling

The product is supplied in well-closed containers to ensure integrity and stability. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to maintain its efficacy.

Additional Clinical Information

Patients and their caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention if they experience agitation, depressed mood, or any atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients receiving antidepressants for major depressive disorder or other indications should be vigilant in monitoring for signs of agitation, irritability, and other behavioral changes, reporting any concerning symptoms to healthcare providers promptly. Daily observation by families and caregivers is recommended.

Additionally, patients should be instructed to stop taking bupropion XL and consult a healthcare provider if they develop any allergic or anaphylactoid reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath. Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid reactions have also been reported, necessitating medical intervention, with rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)