Bupropion hydrochloride

Description

Bupropion hydrochloride tablets, USP, are chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The 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 powder form of bupropion hydrochloride is white, crystalline, and exhibits high solubility in water. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa.

Each bupropion hydrochloride tablet for oral administration contains either 75 mg or 100 mg of bupropion hydrochloride. The 75 mg tablet includes the following inactive ingredients: D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triacetin. The 100 mg tablet contains the following inactive ingredients: FD&C Red No. 40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triacetin.

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 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 adverse effects.

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

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride tablets should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride tablets. Additionally, bupropion should not be started in patients receiving linezolid or intravenous methylene blue.

Patients with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride tablets should not use this medication.

Warnings and Precautions

Neuropsychiatric adverse events have been reported during smoking cessation treatment with bupropion. Serious or clinically significant events may include 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. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and contact a healthcare provider immediately 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 maximum daily dose to 450 mg. If a seizure occurs, bupropion should be discontinued.

Bupropion hydrochloride tablets may elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to 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 advised.

Psychosis and other neuropsychiatric reactions may occur; patients should be instructed to contact a healthcare professional if they experience such reactions.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

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 of symptoms or emergence of suicidal thoughts and behaviors.

To ensure safe use, healthcare professionals should monitor blood pressure before starting treatment and periodically during treatment. Patients should be advised to seek emergency medical help if they experience psychosis or other neuropsychiatric reactions. Additionally, patients must be instructed to discontinue bupropion and contact their healthcare provider if they experience any neuropsychiatric adverse events.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. 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 adverse reactions warrant particular attention. A boxed warning highlights the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors. Neuropsychiatric adverse events may also occur, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, panic, and suicidal ideation, as well as suicide attempts and completed suicides.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 450 mg to minimize this risk. If a seizure occurs, discontinuation of treatment is advised. Additionally, bupropion hydrochloride tablets can lead to increased blood pressure, necessitating monitoring of blood pressure before and during treatment.

Patients should be screened for bipolar disorder due to the potential activation of mania or hypomania, and they should be monitored for these symptoms throughout treatment. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is crucial.

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

In cases of overdosage, seizures have been reported in approximately one-third of such instances. Other serious reactions associated with overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including conduction disturbances or arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths related to overdose have been documented, 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 bupropion based on clinical response. However, the dosage should not exceed the maximum recommended limit.

Bupropion is a known inhibitor of CYP2D6, which can lead to increased plasma concentrations of certain medications. This includes antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). It is advisable to consider dose reductions for these medications when co-administered with bupropion.

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

Caution is advised when prescribing bupropion hydrochloride tablets 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 tablets with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring.

There is an increased risk of hypertensive reactions when bupropion hydrochloride tablets are used in conjunction with monoamine oxidase inhibitors (MAOIs).

Lastly, it is important to note that bupropion hydrochloride tablets can cause false-positive results in urine tests for amphetamines, which should be considered in the context of drug screening.

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. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for additional information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

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 https://womensmentalhealth.org/research/pregnancyregistry/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. 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, 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 higher.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; however, 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.

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. Although the Registry was not designed to evaluate specific defects, it suggested a possible increase in cardiac malformations. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 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 a possible association. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m² basis) 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 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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to patients with reduced kidney function. Regular monitoring of renal function may be warranted in these patients, although specific guidelines are not outlined.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there is no information available regarding 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.

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. Healthcare professionals should be vigilant for serious reactions associated with bupropion overdose, which may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

Fatalities linked to bupropion overdose have occurred, often following a series of uncontrolled seizures, bradycardia, cardiac failure, and ultimately cardiac arrest. Given the severity of potential outcomes, it is critical to provide immediate and comprehensive medical attention.

Currently, there are no known antidotes for bupropion. Therefore, supportive care and close medical supervision are paramount in managing overdose cases. Healthcare providers are advised to consult a Certified Poison Control Center for specific guidance in the event of an overdose. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org.

It is important to note that the induction of emesis is not recommended in cases of bupropion overdose. Instead, healthcare professionals should ensure that the patient has an adequate airway, along with proper oxygenation and ventilation, to mitigate the risks associated with overdose.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of oral doses of bupropion up to 300 mg/kg/day to rats, which is approximately six times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male and female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males received the treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately four 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 of up to 300 mg/kg/day and 150 mg/kg/day, respectively, corresponding to approximately six 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, which is approximately two to six times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate that was two to three times higher than the control in two of five strains tested. Additionally, an increase in chromosomal aberrations was observed 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.

Additionally, some individuals may experience high blood pressure, which can be severe, while taking bupropion hydrochloride tablets. The risk of developing high blood pressure may be increased in patients who are also using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Reports have indicated that some patients may experience periods of mania while on bupropion hydrochloride tablets, characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and increased talkativeness. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been documented in some individuals.

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. In the event of a seizure while taking bupropion hydrochloride tablets, patients are advised to discontinue use and contact their healthcare provider immediately.

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 changes can be sudden. 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 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. 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 tablets if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Patients should be made aware that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride tablets can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be educated that bupropion hydrochloride tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN®, which is used for smoking cessation. Therefore, bupropion hydrochloride tablets should not be used in combination with ZYBAN® or any other medications containing bupropion.

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

Patients should be counseled to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride tablets may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with bupropion hydrochloride tablets.

Instructions for storage should include keeping bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and ensuring that the tablets remain dry and protected from light. Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, with doses 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 due to the dose-related risk of seizure.

Patients must be instructed to swallow bupropion hydrochloride tablets whole and not to crush, divide, or chew them. Bupropion hydrochloride tablets can be taken with or without food.

Storage and Handling

The tablets are supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP), equipped with a child-resistant closure. It is essential to keep the container tightly closed to maintain the integrity of the product.

For optimal storage, the tablets should be kept 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). Additionally, the tablets must be protected from light and moisture to ensure their efficacy and safety.

Additional Clinical Information

Patients receiving bupropion hydrochloride tablets should be closely monitored for neuropsychiatric symptoms, particularly by families and caregivers. It is essential to observe for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is crucial. Patients and caregivers should be advised to discontinue bupropion and seek medical attention if any atypical changes in mood or behavior occur, including suicidal ideation or behavior. Additionally, patients should contact a healthcare professional if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion, or if they develop allergic reactions like skin rash or difficulty breathing.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. These events include mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, with symptoms such as pruritus and dyspnea requiring medical intervention. Rare cases of severe skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been documented.

FDA Insert (PDF)

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

View full prescribing information (PDF)