Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, 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 276.21 g/mol, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride appears as a white to off-white crystalline powder and is highly soluble in water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride is supplied for oral administration as 75-mg (orange) and 100-mg (purple) film-coated tablets. Each 75-mg tablet contains colloidal silicon dioxide, crospovidone, FD&C Yellow #6 Aluminum Lake, fumaric acid granular, hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol, and titanium dioxide. Each 100-mg tablet contains colloidal silicon dioxide, crospovidone, D&C Red #7 Calcium Lake, fumaric acid granular, hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol, and titanium dioxide.

Uses and Indications

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

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The recommended starting dose is 200 mg per day, administered as 100 mg twice daily. 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, given as 100 mg three times daily, ensuring that there is an interval of at least 6 hours between doses. The usual target dose is 300 mg per day, maintained as 100 mg three times daily.

The maximum allowable dose is 450 mg per day, which can be administered as 150 mg three times daily. It is essential for healthcare professionals to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

For patients with moderate to severe hepatic impairment, the recommended dose is 75 mg once daily. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Similarly, for patients with renal impairment, a reduction in dose and/or frequency may be warranted.

Contraindications

Use of bupropion hydrochloride tablets is contraindicated in the following situations:

Patients with a seizure disorder are at increased risk of seizures when using this medication.

Bupropion is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased seizure risk.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs may precipitate seizures; therefore, bupropion should not be used in these circumstances.

The concurrent use of bupropion hydrochloride tablets with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. This includes use within 14 days of stopping either bupropion or an MAOI. Additionally, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of its components is a contraindication for the use of this medication.

Warnings and Precautions

Increased risk of suicidal thinking and behavior has been observed in children, adolescents, and young adults taking antidepressants. Healthcare professionals should closely monitor these populations for any worsening or emergence of suicidal thoughts and behaviors.

General Precautions

Neuropsychiatric adverse events may occur during smoking cessation, particularly in patients using bupropion. Postmarketing reports have documented serious or clinically significant neuropsychiatric events, including mood changes (such as depression and mania), 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 essential to observe patients attempting to quit smoking with bupropion for the occurrence of these symptoms. Patients should be instructed to discontinue bupropion and contact a healthcare provider if they experience any of these adverse events.

The risk of seizures is dose-related. To minimize this risk, healthcare providers should gradually increase the dose and limit the daily dose to a maximum of 450 mg. If a seizure occurs, bupropion should be discontinued immediately.

Bupropion hydrochloride tablets may increase blood pressure. Therefore, it is crucial to monitor blood pressure before initiating treatment and periodically throughout the treatment course.

Patients should be screened for bipolar disorder prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is recommended.

Psychosis and other neuropsychiatric reactions may occur. 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.

Laboratory Tests

Blood pressure should be monitored before initiating treatment with bupropion and periodically during the treatment to ensure patient safety.

Emergency Medical Help Instructions

Patients should be advised to seek immediate medical assistance if they experience psychosis or other neuropsychiatric reactions.

Discontinuation Instructions

Patients must be instructed to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events. Additionally, bupropion should be stopped if a seizure occurs.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride tablets. The most common adverse reactions reported include agitation, dry mouth, constipation, headache or migraine, nausea or vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbances.

Serious warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor patients for any worsening or emergence of suicidal thoughts and behaviors during treatment.

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.

There is a dose-related risk of seizures associated with bupropion hydrochloride. To minimize this risk, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride can increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is also important.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Other important considerations include a history of 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 hydrochloride should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders or within 14 days of stopping treatment with either bupropion hydrochloride or an MAOI. Known hypersensitivity to bupropion or any of its ingredients is also a contraindication.

In cases of overdosage, 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 (such as 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

Coadministration of bupropion hydrochloride tablets with certain drug classes may lead to significant interactions that require careful consideration and monitoring.

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 based on clinical response. However, the dosage should not exceed the maximum recommended limit.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6, which can lead to elevated plasma concentrations of drugs metabolized by this enzyme, including certain antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics. A dose reduction of these medications should be considered when used concurrently with bupropion.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely in patients receiving both medications to ensure therapeutic efficacy.

Drugs Lowering Seizure Threshold Caution is warranted when prescribing bupropion hydrochloride tablets in conjunction with other medications that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs Concomitant use of bupropion with dopaminergic agents such as levodopa and amantadine may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The use of bupropion alongside MAOIs can elevate the risk of hypertensive reactions. Close monitoring is essential when these drugs are used together.

Drug-Laboratory Test Interactions Bupropion hydrochloride tablets may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

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, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and outcomes in this demographic.

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, it is important to note that greater sensitivity to the drug 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 a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies of 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 fetal malformations were observed 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 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 general U.S. population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. 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 of untreated depression and potential effects on the fetus when contemplating the discontinuation or alteration of antidepressant therapy 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 with 1,213 first-trimester exposures did not demonstrate an overall increased risk for malformations. However, the Registry was not specifically designed to evaluate individual defects but suggested a possible increase in cardiac malformations. Notably, the observed rate of cardiovascular malformations in pregnancies exposed to bupropion during the first trimester was 1.3%, which aligns with the background rate of approximately 1%.

Findings regarding left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) in relation to bupropion exposure during the first trimester are inconsistent and do not permit definitive conclusions regarding potential associations. The United Healthcare database lacked sufficient power to evaluate these associations, while the National Birth Defects Prevention Study (NBDPS) indicated an increased risk for LVOTO, which was not corroborated by the Slone Epidemiology case-control study.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during organogenesis at doses of up to 450 mg and 150 mg/kg/day, respectively. No fetal malformations were observed in rats, while rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose and above. Decreased fetal weights were noted at doses of 50 mg/kg/day and higher, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, a pre-and postnatal development study in pregnant rats indicated that bupropion at doses up to 150 mg/kg/day had no adverse effects on pup growth or development.

Healthcare providers are encouraged to register patients exposed to any antidepressants during pregnancy with the National Pregnancy Registry for Antidepressants by calling 1-844-405-6185 or visiting National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

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, 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 tablets and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of bupropion overdose, significant clinical manifestations can occur, particularly with doses exceeding 30 grams. Seizures have been reported in approximately one-third of these cases, highlighting the potential for severe neurological complications.

Clinical Manifestations Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and various cardiac issues. It is important to note that fatalities have been documented, especially in patients who have ingested large quantities of the drug.

Management and Supportive Care Supportive care is critical in managing bupropion overdose. This includes close medical supervision, continuous monitoring of vital signs, and assessment of cardiac rhythm. Due to the absence of known antidotes for bupropion, the induction of emesis is not recommended in overdose situations.

Consultation and Guidance Healthcare professionals are advised to consult a Certified Poison Control Center for specific guidance in the event of a bupropion overdose. For assistance, they can contact the Poison Control Center at 1-800-222-1222.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered at doses up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 6 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 6 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 reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate 2 to 3 times higher than the control in 2 of 5 strains tested. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Regarding reproductive toxicity, no adverse effects on male or female fertility were observed when rats were administered oral doses of bupropion up to 300 mg/kg/day (approximately 6 times the MRHD on a mg/m² basis) prior to mating and continuing through Day 13 of gestation or lactation. Males were treated for 60 days prior to and through mating without any noted fertility issues. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) or higher resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects on the fertility, reproduction, or growth and development of male or female offspring.

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 individuals 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 tablets. Additionally, some patients have experienced significant elevations in blood pressure while on this medication.

Periods of mania have been reported in some individuals taking bupropion hydrochloride tablets, 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 been observed in some patients during treatment with bupropion hydrochloride tablets.

Severe allergic reactions to bupropion hydrochloride tablets have been reported, with symptoms 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

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important to 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 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 or sudden onset of such symptoms should be reported to the patient’s prescriber or healthcare professional promptly.

Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, or suicidal thoughts, especially when attempting to quit smoking while on bupropion.

Education on the symptoms of hypersensitivity is essential, and patients should discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, patients must be informed to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Healthcare providers should advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should minimize or avoid alcohol consumption.

Patients should be made aware that bupropion hydrochloride tablets can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals. It is also important to inform patients that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that they 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 tablets, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are certain that bupropion does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Healthcare providers should encourage patients to notify them if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride tablets may interact with other drugs. Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during therapy, as there is a pregnancy exposure registry that monitors outcomes in women exposed to bupropion during pregnancy.

Patients should be instructed to store bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), keeping them dry and protected from light. They should take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, ensuring that doses are separated by at least 6 hours to minimize the risk of seizure. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular time.

Finally, patients should be instructed that bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed, and that they can be taken with or without food.

Storage and Handling

The product is supplied in packaging that includes specific NDC numbers, which should be referenced for accurate identification. It is essential to store the product at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), with permissible excursions between 15ºC and 30ºC (59ºF to 86ºF) in accordance with USP Controlled Room Temperature guidelines.

To ensure product integrity, it must be protected from moisture. Additionally, the product should not be used if the blister is torn or broken, as this may compromise its safety and efficacy.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride tablets and contact a healthcare provider immediately 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 (MDD) or other indications should be vigilant for the emergence of agitation, irritability, and unusual behavioral changes, as well as suicidality, and report these symptoms to healthcare providers without delay.

Prescriptions for bupropion hydrochloride tablets should be limited to the smallest quantity necessary for effective patient management to minimize the risk of overdose. Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. While many cases reported resolution of symptoms following discontinuation, some patients experienced persistent symptoms, necessitating ongoing monitoring and supportive care until resolution occurs.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bupropion Hydrochloride as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)