Bupropion hydrochloride

Description

Bupropion hydrochloride, USP 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 276.2, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride, USP appears as a white or almost white crystalline powder. It is freely soluble in water, soluble in alcohol and 0.1N HCl, has a bitter taste, and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (SR) are supplied for oral administration in strengths of 100 mg, 150 mg, and 200 mg as film-coated, extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Red #40/Allura Red AC Aluminum Lake, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid, titanium dioxide, and triacetin.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) 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 150 mg per day. 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, administered as 150 mg twice daily, with an interval of at least 8 hours between doses. The usual target dose is 300 mg per day, maintained as 150 mg twice daily.

For patients who do not respond adequately to the 300 mg per day regimen, the maximum dose may be increased to 400 mg per day, given as 200 mg twice daily. It is essential to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, in patients with renal impairment, a reduction in dose and/or frequency should also be considered.

Contraindications

Use of bupropion hydrochloride extended-release tablets (SR) 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 (SR) should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (SR). Additionally, it is contraindicated to start bupropion in patients receiving linezolid or intravenous methylene blue.

• Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR).

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. It is imperative that healthcare professionals 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 daily dose to a maximum of 400 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) have 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.

The occurrence of psychosis and other neuropsychiatric reactions necessitates that patients be instructed to contact a healthcare professional if such reactions arise.

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

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

To ensure safe use of bupropion, healthcare professionals should monitor blood pressure before treatment initiation and periodically during treatment. Patients should be advised to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events or psychotic symptoms.

Side Effects

Patients may experience a range of adverse reactions while taking bupropion hydrochloride extended-release tablets (SR). The most common adverse reactions reported include headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitations, myalgia, sweating, rash, and anorexia.

Serious adverse reactions have been noted, including an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for the emergence or worsening of these thoughts and behaviors during treatment. Neuropsychiatric events, such as mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides, have also been reported, particularly during smoking cessation.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion can increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been observed, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions.

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 extended-release tablets (SR) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either medication. Known hypersensitivity to bupropion or 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 (including 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 following multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in dosage 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 plasma 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 lower plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy and safety.

Caution is advised when prescribing bupropion hydrochloride extended-release tablets (SR) alongside medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

The concomitant use of bupropion hydrochloride extended-release tablets (SR) with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity, necessitating careful monitoring of patients.

Furthermore, there is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are used in conjunction with monoamine oxidase inhibitors (MAOIs).

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) can cause false-positive results in urine drug tests for amphetamines, which may lead to unnecessary clinical concerns.

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 these age groups.

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 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 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. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 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. 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.

Clinical considerations suggest that women with a history of major depressive disorder who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue treatment. Therefore, it is essential to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. However, the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, similar to the background rate of approximately 1%.

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. The United Healthcare database lacked sufficient power to evaluate these associations, while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, and the Slone Epidemiology case-control study did not find an increased risk for LVOTO or VSD.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while pregnant rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day and higher, with no maternal toxicity evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day had no effect on pup growth or development.

Lactation

Bupropion is excreted in breast milk. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 4 times the maximum recommended human dose on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

Lactating mothers should be aware of the potential for bupropion to be present in breast milk and consider the benefits and risks of treatment while breastfeeding. There is limited data on the effects of bupropion on breastfed infants; therefore, healthcare providers should monitor infants for any adverse effects if the mother is taking this medication.

Renal Impairment

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

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, necessitating immediate medical intervention. Reports indicate that overdoses of 30 grams or more have been documented, with seizures occurring in approximately one-third of these instances.

Clinical Symptoms Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as conduction disturbances. Additional symptoms reported in overdose cases encompass sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Notably, fatalities have been linked to bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac failure often preceding death.

Management Recommendations There are currently no known antidotes for bupropion; therefore, supportive care and close medical supervision are critical in managing overdose cases. In the event of an overdose, it is imperative to ensure an adequate airway, oxygenation, and ventilation, while continuously monitoring cardiac rhythm and vital signs. The induction of emesis is not recommended for bupropion overdose.

Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in managing overdose situations. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day (approximately 7 times the maximum recommended human dose MRHD on a mg/m² basis) to female rats prior to mating, and either through Day 13 of gestation or through lactation, as well as to male rats for 60 days prior to and during mating, did not result in any effects on male or female fertility. However, doses of 200 mg/kg/day (approximately 5 times the MRHD on a mg/m² basis) or higher caused transient ataxia or behavioral changes in adult female rats. Additionally, 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, which correspond to approximately 7 and 2 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 (approximately 2 to 7 times the MRHD on a mg/m² basis), while 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 2 to 3 times that of the control in 2 of 5 strains tested. Furthermore, an increase in chromosomal aberrations was reported 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, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts in individuals attempting to quit smoking while on bupropion therapy. These events were reported voluntarily or identified through surveillance programs.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important for patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, unusual changes in behavior, worsening of depression, and suicidal ideation, particularly during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should monitor patients on a daily basis for any abrupt changes in behavior, as these symptoms can manifest suddenly. Any severe or unexpected symptoms should be reported 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, panic, and suicidal thoughts when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion and contact a healthcare professional immediately.

Education on hypersensitivity symptoms is essential, and patients should discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (SR) and not to restart if they experience a seizure during treatment.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption. During the initial titration phase, particularly at doses above 150 mg/day, patients should take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures.

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. It is also important to inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in conjunction with ZYBAN or any other bupropion-containing medications.

Patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks that require 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.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (SR) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Storage instructions for bupropion hydrochloride extended-release tablets (SR) should include keeping the tablets at room temperature, between 20° and 25°C (68° to 77°F), and ensuring they remain dry and protected from light. Patients should be instructed to swallow the tablets whole, without chewing, dividing, or crushing them, to maintain the intended release rate of the medication.

If patients miss a dose, they should not take an extra tablet to compensate for the missed dose but should instead take the next tablet at the regular scheduled time, due to the dose-related risk of seizure. Patients should also be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and can be taken with or without food.

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 should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its integrity and efficacy.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants, including bupropion hydrochloride for major depressive disorder (MDD) and other indications, should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop.

Clinicians should also instruct patients to report any neuropsychiatric symptoms, such as delusions, hallucinations, or confusion, and to discontinue the medication if allergic reactions, including skin rash or difficulty breathing, occur. Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in smoking cessation contexts, including mood changes, psychosis, and suicidal ideation. Additionally, anaphylactoid reactions have been reported, necessitating medical intervention, with rare cases of severe skin reactions and anaphylactic shock documented.

FDA Insert (PDF)

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

View full prescribing information (PDF)