Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets USP (SR) are chemically designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2 g/mol, and its molecular formula is C13H18ClNO∙HCl. The powder form of bupropion hydrochloride is white, crystalline, and highly soluble in water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa.

These extended-release tablets are available in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink), and are film-coated, sustained-release formulations. Each 100-mg tablet contains bupropion hydrochloride, USP, along with inactive ingredients including cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide. The 100-mg tablet also contains FD&C Blue No. 2 Lake; the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake; the 200-mg tablet contains Iron Oxide Red and Ferrosoferric Oxide.

Uses and Indications

Bupropion hydrochloride extended-release (SR) 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 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 increased 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 (SR) 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 seizure risk.

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release (SR) tablets should not be used within 14 days of stopping an MAOI or vice versa. Additionally, initiation of bupropion hydrochloride extended-release (SR) tablets is contraindicated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the ingredients in bupropion hydrochloride extended-release (SR) tablets is also a contraindication.

Warnings and Precautions

The use of bupropion requires careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors There is a significant warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including bupropion. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events Postmarketing reports have indicated that patients undergoing smoking cessation with bupropion may experience serious neuropsychiatric adverse events. These can include mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal ideation. It is essential to observe patients for these symptoms and instruct them to discontinue bupropion and seek immediate medical advice if such events occur.

Seizure Risk 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. If a seizure occurs, bupropion should be discontinued immediately.

Hypertension Bupropion hydrochloride extended-release (SR) tablets may elevate blood pressure. Therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment, and ongoing monitoring for symptoms of mania or hypomania is advised.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

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

Laboratory Tests Blood pressure should be monitored before the initiation of bupropion treatment and periodically during the course of therapy to ensure patient safety.

In the event of neuropsychiatric adverse events, patients must be advised to discontinue bupropion and contact their healthcare provider immediately. This proactive approach is essential for managing potential risks associated with the medication.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride extended-release (SR) tablets. 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 warranting caution include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors. Additionally, 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 been reported 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. Patients should also be monitored for hypertension, as bupropion can elevate blood pressure. Blood pressure should be assessed before initiating treatment and periodically during therapy.

Activation of mania or hypomania has been observed, necessitating screening for bipolar disorder and monitoring for these symptoms. Patients are advised to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in patients with a seizure disorder or a current or prior diagnosis of bulimia or anorexia nervosa. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs may also pose risks.

Bupropion hydrochloride extended-release (SR) tablets 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 a contraindication.

In cases of overdose, 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 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 an increase in the dosage of bupropion based on clinical response, ensuring that the maximum recommended dose is not exceeded.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain 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.

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

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

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

Increased risk of hypertensive reactions has been observed when bupropion hydrochloride extended-release (SR) tablets are used in conjunction with monoamine oxidase inhibitors (MAOIs). Caution should be exercised in such cases.

Additionally, it is important to note that bupropion hydrochloride extended-release (SR) tablets can lead to false-positive results in urine drug tests for amphetamines, which may have implications for drug screening processes.

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, the use of this medication in children, infants, and adolescents should be approached with caution. Further studies are necessary to determine appropriate dosing and potential 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 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 medication may be present in some older individuals.

Bupropion undergoes extensive hepatic metabolism to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to experience decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, careful consideration of renal function is essential 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 1-844-4056185 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 greater.

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 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 a possible association. 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, the Slone Epidemiology case-control study did not.

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 and greater. 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. 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

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 extended-release (SR) 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 prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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

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. These symptoms are particularly concerning in the context of multiple drug overdoses.

Fatalities linked to bupropion overdose have occurred, often following a series of uncontrolled seizures, bradycardia, and cardiac arrest. Given the potential severity of these reactions, immediate medical intervention is critical.

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and close medical supervision. It is imperative to ensure adequate airway management, oxygenation, and ventilation for affected patients. The induction of emesis is not recommended in cases of bupropion overdose due to the risk of further complications.

In the event of a suspected overdose, healthcare professionals are advised to consult a Certified Poison Control Center for expert guidance. The National Capital Poison Center can be reached at 1-800-222-1222 or through their website at www.poison.org for additional resources and support.

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 to rats, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male or female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males were treated for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately five 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 reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven 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, approximately two to seven 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 out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Postmarketing experience has revealed that some patients have reported changes in mood, including depression and mania, as well as various mental health issues such as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. These symptoms have been observed in individuals attempting to quit smoking while on bupropion.

Additionally, new or exacerbated mental health problems, including changes in behavior or thinking, aggression, hostility, agitation, depression, and suicidal thoughts or actions, have been documented. Some patients experienced these symptoms upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

Patients experiencing seizures while taking bupropion hydrochloride extended-release (SR) tablets are advised to discontinue use immediately and contact their healthcare provider. It is important to note that bupropion hydrochloride extended-release (SR) tablets should not be resumed if a seizure occurs.

Reports also indicate that some individuals may develop high blood pressure, which can be severe, while using bupropion hydrochloride extended-release (SR) tablets. The risk of elevated blood pressure may increase when combined with nicotine replacement therapies, such as nicotine patches.

Furthermore, some patients have experienced episodes of mania characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, and heightened happiness or irritability. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, and confusion, have also been reported.

Severe allergic reactions to bupropion hydrochloride extended-release (SR) tablets have been documented. Patients are advised to discontinue the medication and seek immediate medical attention if they experience symptoms such as rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing, as these may indicate a serious allergic reaction.

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, 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, sudden, 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 extended-release (SR) tablets if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare providers should inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should be advised to minimize or avoid alcohol consumption. Patients should take bupropion hydrochloride extended-release (SR) tablets in two divided doses, preferably with at least 8 hours between doses, to reduce the risk of seizures.

Patients should be made aware that taking bupropion hydrochloride extended-release (SR) tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. It is also important to inform patients that bupropion hydrochloride extended-release (SR) tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these tablets 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 extended-release (SR) tablets, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. They should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as interactions may affect drug metabolism.

Patients must inform their healthcare provider if they become pregnant or plan to become pregnant while on bupropion hydrochloride extended-release (SR) tablets. Proper storage instructions should be provided, advising patients to keep the tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and to keep them dry and out of light.

Patients should be instructed to swallow bupropion hydrochloride extended-release (SR) tablets whole, without chewing, dividing, or crushing them, to ensure the proper release rate of the medication. 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 should also be informed that bupropion hydrochloride extended-release (SR) tablets may have an odor and can be taken with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at room temperature, ideally between 20°C and 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F).

To ensure product integrity, it is essential to protect the product from light and moisture during storage and handling. Proper adherence to these conditions will help maintain the quality and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride, particularly for major depressive disorder (MDD) or other indications, should be closely monitored by families and caregivers for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of 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 associated with bupropion, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, presenting as skin rash, hives, and respiratory distress, necessitating immediate medical intervention. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, have been documented in association with bupropion use.

FDA Insert (PDF)

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

View full prescribing information (PDF)