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, with a molecular weight of 276.2 and a molecular formula of 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 these 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 for the medication is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, it is advised to increase the dose gradually. After an initial period of 3 days, the dose may be increased 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, administered in the same manner.

The maximum allowable dose is 450 mg per day, which should be given as 150 mg three times daily. It is important 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. Additionally, for patients with renal impairment, a reduction in dose and/or frequency may also 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 discontinuing bupropion hydrochloride tablets. Additionally, bupropion should not be started in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of its components is also a contraindication for use.

Warnings and Precautions

Neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. 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 promptly contact a healthcare provider if they experience any of these adverse events.

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

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 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 during treatment. In the event of psychosis or other neuropsychiatric reactions, patients should be instructed to contact a healthcare professional without delay.

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

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor these patients for any worsening of their condition or the emergence of suicidal thoughts and behaviors.

To ensure patient safety, blood pressure should be monitored before starting treatment and periodically during the course of therapy. Patients should be advised to discontinue bupropion and seek immediate medical assistance if they experience any neuropsychiatric adverse events or if a seizure occurs.

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 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. These reactions are generally mild to moderate in severity.

Serious adverse reactions warrant careful monitoring. A significant warning is the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have also been observed, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, panic, and suicidal ideation. Instances of suicide attempts and completed suicides have been reported, necessitating vigilant assessment of mood changes and mental health status.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride tablets may increase blood pressure, requiring monitoring before and 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 psychosis or other neuropsychiatric reactions occur is essential for safety.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, highlighting the need for caution in this population.

In cases of overdose, serious reactions such as seizures, hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation), arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been documented. Deaths associated with overdoses of bupropion alone have been reported, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Overall, healthcare professionals should remain vigilant in monitoring for these adverse reactions to ensure patient safety and well-being.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate a dose increase of the affected medication based on clinical response. However, it is important that the dosage does not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to increased concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). A dose reduction of these medications should be considered to mitigate potential adverse effects.

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

Caution is warranted when prescribing bupropion hydrochloride 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 of patients.

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

Lastly, it should be noted that bupropion hydrochloride tablets can cause false-positive results in urine drug tests for amphetamines, which may lead to unnecessary clinical interventions.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. 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 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 a pregnancy exposure registry indicates that there is ongoing monitoring of pregnancy outcomes in women exposed to antidepressants, including bupropion, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting the registry's website.

Epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an overall increased risk of congenital malformations. However, untreated depression during pregnancy poses risks to the mother and potentially to fetal outcomes. 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 fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and higher, with decreased fetal weights noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage in the general 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 longitudinal study of 201 pregnant women with a history of major depressive disorder found that those who discontinued antidepressants during pregnancy were more likely to relapse into major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks associated with untreated depression and the potential effects on the fetus when making decisions about antidepressant therapy during pregnancy and postpartum.

Human data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study involving 1,213 first trimester exposures did not demonstrate an increased risk for malformations overall. However, the registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations was observed overall, with a prospectively observed rate of 1.3% in pregnancies exposed to bupropion during the first trimester, which aligns with 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. Limitations in the studies include a small number of exposed cases and the potential for chance findings due to multiple comparisons.

In animal studies, bupropion administered orally to pregnant rats during organogenesis showed no evidence of fetal malformations. In contrast, pregnant rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose and higher. Decreased fetal weights were observed at doses of 50 mg/kg/day and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, a pre- and postnatal development study indicated that bupropion did not affect pup growth or development when administered to pregnant rats.

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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside 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 of these patients.

Hepatic Impairment

There is no available information regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the individual patient's liver status when prescribing this medication.

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 concerning in scenarios involving multiple drug overdoses, where the risk of severe complications is heightened.

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 may precede these outcomes, underscoring the importance of prompt medical intervention.

Currently, there are no known antidotes for bupropion overdose. Therefore, the management of such cases relies heavily on supportive care and vigilant medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for specific guidance in overdose situations. For assistance, they can contact 1-800-222-1222.

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 female rats prior to mating and continuing through Day 13 of gestation or lactation, as well as to male rats for 60 days prior to and during mating, did not result in any adverse effects on male and female fertility. However, doses of 200 mg/kg/day or greater caused 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. 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, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

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

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, and confusion, have also been reported among patients using bupropion hydrochloride tablets.

Severe allergic reactions to bupropion hydrochloride tablets have been documented, 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, and difficulty breathing.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. Instruct patients, their families, and/or caregivers to be vigilant for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening of depression and suicidal ideation, particularly during the initial phase of antidepressant treatment and when the dosage is adjusted.

Encourage families and caregivers to monitor for these symptoms on a daily basis, as changes may occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly. Inform patients that some individuals may experience mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal thoughts and actions when attempting to quit smoking while taking bupropion. Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience such symptoms.

Educate patients about the signs of hypersensitivity and advise them to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Instruct patients to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment. Advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should minimize or avoid alcohol consumption.

Patients should be informed that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. Educate patients that bupropion hydrochloride tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN®, which is used for smoking cessation, and that these tablets should not be used in conjunction with ZYBAN® or any other medications containing bupropion.

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 they are confident that bupropion hydrochloride tablets do not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

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

Instruct patients 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. Advise patients to 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 seizures. 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 seizures. Additionally, instruct patients 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 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 protected from light and moisture, within a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°F). Proper handling and storage conditions are crucial to ensure the efficacy and safety of the tablets.

Additional Clinical Information

Patients receiving bupropion hydrochloride tablets for major depressive disorder (MDD) or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion and seek medical attention if they experience agitation, mood changes, or suicidal thoughts. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, as well as anaphylactic shock, have also been reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)