Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1 propanone hydrochloride. The molecular weight is 276.21, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white and soluble in water, with a bitter taste that produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablet USP (XL) is supplied for oral administration in strengths of 150 mg and 300 mg. These tablets are off-white to pale yellow in color. Each tablet contains the labeled amount of bupropion hydrochloride along with inactive ingredients, which include ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, glyceryl behenate, hydrophobic colloidal silica, hydroxypropyl cellulose, iron oxide black, L-cysteine hydrochloride monohydrate, methacrylic acid copolymer dispersion, polyvinyl alcohol, povidone, propylene glycol, shellac, and triethyl citrate.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

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

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual dose increase to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily, with the option to increase the dose to 300 mg after 4 days if clinically indicated.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a typical target dose of 300 mg once daily. After one week, the dose may be increased to 300 mg once daily, and treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in dose and/or frequency of administration.

In patients with renal impairment, a reduction in dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) 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 precipitate seizures.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with MAOIs or within 14 days of discontinuing either treatment.

• Patients receiving linezolid or intravenous methylene blue should not be initiated on bupropion hydrochloride extended-release tablets (XL) due to potential drug interactions.

• Known hypersensitivity to bupropion or any of the components of bupropion hydrochloride extended-release tablets (XL) is also a contraindication.

Warnings and Precautions

Increased risk of suicidal thinking and behavior has been observed in children, adolescents, and young adults taking antidepressants, including bupropion hydrochloride extended-release tablets (XL). Healthcare professionals should closely monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated serious or clinically significant neuropsychiatric adverse events associated with smoking cessation attempts using bupropion hydrochloride XL. These events may include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking should be observed for these symptoms, and if any occur, they should discontinue bupropion hydrochloride XL and contact a healthcare provider immediately.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, bupropion hydrochloride XL should be discontinued.

Hypertension Bupropion hydrochloride XL has the potential to increase blood pressure. It is essential 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 have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

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

Patients should be advised to discontinue bupropion hydrochloride XL and seek immediate medical assistance if they experience any neuropsychiatric adverse events.

Side Effects

Common adverse reactions observed in clinical trials, occurring in at least 5% of participants and at a rate greater than twice that of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions warranting attention 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.

Neuropsychiatric adverse events have been reported during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

Additional important safety information includes a dose-related risk of seizures, which can be minimized by limiting the daily dose to 450 mg and gradually increasing it. Discontinuation of treatment is advised if a seizure occurs. Bupropion hydrochloride extended-release tablets (XL) may also increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment. Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania.

Psychosis and other neuropsychiatric reactions have been reported, and patients are advised to contact a healthcare professional if such reactions occur. Angle-closure glaucoma has been noted in patients with untreated anatomically narrow angles who are treated with antidepressants.

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, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), mental status changes, 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, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest occurring prior to death.

Drug Interactions

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

Bupropion is known to inhibit CYP2D6, which can lead to elevated 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).

When prescribing bupropion hydrochloride extended-release tablets (XL), caution is warranted in patients taking other medications that may lower the seizure threshold. Additionally, the concomitant use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity.

There is also an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are used in conjunction with monoamine oxidase inhibitors (MAOIs). Furthermore, it should be noted that bupropion hydrochloride extended-release tablets (XL) can produce false-positive results in urine tests for amphetamines.

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 of bupropion hydrochloride extended-release tablets (XL) in the pediatric population have not been established. When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks against the clinical need for treatment.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 and older participated in clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No significant differences in safety or effectiveness were observed between elderly patients and younger subjects in these studies. However, it is important to note that while clinical experience has not identified distinct differences in responses between elderly and younger patients, a greater sensitivity in some older individuals cannot be excluded.

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, there is an increased risk of adverse reactions in this population. Therefore, careful consideration of renal function is essential when selecting a dose for geriatric patients. Monitoring of renal function may be beneficial to ensure safe and effective use of bupropion in this demographic.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to 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 National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for 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. A prospective, longitudinal study indicated that women 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 to the mother 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 greater.

The estimated background risk for major birth defects and miscarriage in the U.S. general population is 2% to 4% and 15% to 20%, respectively. The international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures did not show an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall has been observed. 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 possible associations. In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day 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 ten 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, to bupropion and its active metabolites 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 tablets (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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 can occur with significant consequences, particularly at doses of 30 grams or more, where seizures have been reported in approximately one third of cases. Healthcare professionals should be vigilant for serious reactions associated with bupropion overdose, which may include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes.

In addition to these severe symptoms, other manifestations of bupropion overdose may present as mental status changes, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. It is important to note that fatalities have been documented in association with bupropion overdose, particularly in instances involving large doses, where multiple uncontrolled seizures and cardiac complications were observed prior to death.

Currently, there are no known antidotes for bupropion overdose. Therefore, the recommended approach involves providing supportive care and ensuring close medical supervision of the patient. In the event of a bupropion overdose, it is crucial to consult a Certified Poison Control Center for expert guidance on management and treatment protocols.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 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 of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded a negative result in another assay. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility. No information is available regarding teratogenic effects or animal pharmacology and toxicology.

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 in some 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.

Patients experiencing a seizure while taking bupropion hydrochloride extended-release tablets (XL) are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride extended-release tablets (XL) is contraindicated following a seizure.

Instances of severe hypertension have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL), with an increased risk noted in those concurrently using nicotine replacement therapy, such as nicotine patches, for smoking cessation.

Some individuals may experience episodes of mania while on bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been reported by some patients taking bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been observed in some individuals. Signs of a serious allergic reaction may include rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL). It is essential to counsel patients, their families, and caregivers on the appropriate use of this medication.

Providers should instruct patients and their support systems to read the Medication Guide thoroughly and assist them in comprehending its contents. Patients should be encouraged to discuss the information within the Medication Guide and to ask any questions they may have.

Healthcare providers must inform patients about the potential emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual behavioral changes, as well as worsening depression and suicidal ideation, particularly during the initial stages of treatment or when dosage adjustments occur. Families and caregivers should be advised to monitor for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient's prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and possible medication adjustments.

Patients should be educated on the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be informed to stop taking the medication and not to restart it if they experience a seizure during treatment.

Providers should caution patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can elevate the risk of seizures, and patients should minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these medications should not be used concurrently. Furthermore, patients should be advised that any central nervous system-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks requiring judgment or motor and cognitive skills.

Healthcare providers should encourage patients to notify them of any prescription or over-the-counter medications they are currently taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL). Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole to ensure the release rate is not altered. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to continue with the next scheduled dose, due to the dose-related risk of seizure. Lastly, patients should be informed that they may notice an inert matrix in their stool, which is normal, as the active medication has already been absorbed by the time they see the inert matrix tablet.

Storage and Handling

The product is supplied in a packaging configuration of 30 units per blister pack. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if they observe any agitation, depressed mood, or atypical changes in behavior or thinking, including suicidal ideation or behavior. Additionally, patients should seek medical advice if they experience any allergic or anaphylactoid reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath during treatment.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes (depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts or actions. Anaphylactoid and anaphylactic reactions have also been reported, presenting with symptoms like pruritus, urticaria, angioedema, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion have been documented.

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)