Bupropion hydrochloride

Description

Bupropion Hydrochloride USP is an antidepressant belonging to the aminoketone class, which is chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its chemical designation is (±)-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 substance appears as a white, crystalline powder that is highly soluble in water, has a bitter taste, and induces a sensation of local anesthesia on the oral mucosa.

Bupropion Hydrochloride Extended-Release Tablets USP (XL) are formulated for oral administration and are available in strengths of 150 mg and 300 mg. These tablets are white to pale yellow in color and contain the labeled amount of bupropion hydrochloride along with the following inactive ingredients: cysteine hydrochloride, ethylcellulose, methacrylic acid copolymer dispersion, lecithin, magnesium stearate, polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, talc, triethyl citrate, and titanium dioxide.

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 of the medication should be increased gradually to minimize the risk of seizures. Healthcare professionals are advised to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After an initial period of 4 days, the dose may be increased to a usual target 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 usual target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily, and it is recommended to continue treatment 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, consideration should be given to reducing the dose and/or frequency of administration.

In patients with renal impairment, it is advisable to consider a reduction in the dose and/or frequency of dosing based on the severity of the impairment.

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.

• 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).

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and aggressive behaviors. Notably, there have been instances of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion hydrochloride XL for these symptoms. Patients should be instructed to discontinue the medication and seek immediate medical attention if they experience any of these adverse events.

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

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. Additionally, patients should be informed about the possibility of psychosis and other neuropsychiatric reactions, and they should be encouraged 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 hydrochloride XL.

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 populations for any worsening or emergence of suicidal thoughts and behaviors.

In summary, healthcare providers should ensure that patients are well-informed about the potential risks associated with bupropion hydrochloride XL, including the need for regular monitoring of blood pressure and vigilance for neuropsychiatric symptoms. Patients should be instructed to discontinue the medication and contact their healthcare provider if they experience any concerning symptoms.

Side Effects

Patients may experience a range of adverse reactions while taking bupropion hydrochloride extended-release tablets (XL). These reactions can be categorized into common adverse reactions, serious warnings, and other important considerations.

Common adverse reactions reported in clinical trials include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash. These effects were observed among participants and may vary in frequency and severity.

A significant warning associated with bupropion is the 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 during treatment.

Neuropsychiatric adverse events have been noted during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should seek immediate medical attention.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised.

Bupropion hydrochloride extended-release tablets (XL) may also lead to increased blood pressure. It is essential to monitor blood pressure before 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. Additionally, patients should be instructed to contact a healthcare professional if they experience any psychotic symptoms or other neuropsychiatric reactions.

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

Other important considerations include the presence of a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of 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 treatment with either bupropion or an MAOI. Additionally, patients with known hypersensitivity to bupropion or any of its components should avoid this medication.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (XL) with certain drug classes may lead to significant interactions that require careful consideration.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, an increase in bupropion dosage may be necessary to maintain clinical exposure. However, any dosage adjustment should not exceed the maximum recommended dose.

CYP2D6 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including:

• Antidepressants: venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline.

• Antipsychotics: haloperidol, risperidone, and thioridazine.

• Beta-blockers: metoprolol.

• Type 1C antiarrhythmics: propafenone and flecainide.

When these medications are used concurrently with bupropion, a dose reduction of the affected drugs should be considered to mitigate the risk of adverse effects.

Seizure Threshold Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) in conjunction with other medications that may lower the seizure threshold, as this combination can increase the risk of seizures.

CNS Toxicity The concomitant use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Hypertensive Reactions The use of bupropion hydrochloride extended-release tablets (XL) in combination with monoamine oxidase inhibitors (MAOIs) can lead to an increased risk of hypertensive reactions. Close monitoring of blood pressure is advised in patients receiving this combination.

Urine Drug Testing It is important to note that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines. This should be taken into account 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 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 6,000 patients, of whom 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 clinical trials utilizing the immediate-release formulation of bupropion hydrochloride 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 in some older individuals cannot be ruled out.

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, and monitoring of renal function may 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 involving pregnant women exposed to bupropion during the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. In a prospective, longitudinal study, women with a history of major depressive disorder 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 of untreated depression and 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. Conversely, in pregnant rabbits, 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; however, all pregnancies carry a background rate 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.

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 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 after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, similar to the background rate of approximately 1%.

Findings regarding the risk of 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 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

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 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 considered as part of standard clinical practice.

Overdosage

Overdoses of bupropion have been documented, with instances involving amounts 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.

Potential Symptoms of Overdosage

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.

Management of Overdosage

There have been reports of fatalities linked to bupropion overdose, often characterized by multiple uncontrolled seizures and cardiac arrest prior to death. Given the severity of these potential outcomes, immediate medical intervention is critical.

Currently, there are no known antidotes for bupropion. Therefore, the primary approach to managing an overdose 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 resource can provide valuable information tailored to the specific circumstances of the overdose.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with 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, 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, the mouse study did not demonstrate similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion exhibited 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, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

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. These symptoms have been observed in some patients upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

The incidence of seizures has been reported to increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some individuals may experience significant increases in blood pressure while on this medication.

Periods of mania have been reported in some patients taking bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as markedly 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 also been reported among patients using bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been documented, with signs including 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

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. Healthcare providers should instruct patients, their families, and/or 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 are particularly important to monitor during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may occur suddenly. Any severe, abrupt, 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 significant 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 essential to educate patients about the signs of hypersensitivity and to 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 bupropion hydrochloride extended-release tablets (XL) and not to restart the medication 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. Therefore, minimizing or avoiding alcohol consumption is recommended.

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. Additionally, it should be noted that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) found in ZYBAN, which is used for smoking cessation. Consequently, bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be informed 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. 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 the metabolism of bupropion hydrochloride extended-release tablets (XL) and other drugs.

Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride extended-release tablets (XL). It is important to instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole to ensure the release rate is not altered. 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.

Finally, patients should be instructed that bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed with or without food, and they should not be crushed, divided, or chewed.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as outlined by USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep the product out of reach of children to ensure safety.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention if they observe any signs of agitation, depressed mood, or 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 the emergence of agitation, irritability, and other concerning symptoms, reporting any such changes to healthcare providers promptly. It is recommended that prescriptions for bupropion XL be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been reported, presenting with symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson Syndrome, and anaphylactic shock have also been documented, along with reports of delayed hypersensitivity symptoms like arthralgia and fever with rash.

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)