Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, 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 powder is white, soluble in 0.1N HCl, alcohol 96%, and in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (XL) are supplied for oral administration as 150 mg and 300 mg, white to pale yellow extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: colloidal silicon dioxide, copovidone, hydrochloric acid, hypromellose, magnesium stearate, methacrylic acid copolymer dispersion, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl alcohol, silicon dioxide, talc, and triethyl citrate.

Uses and Indications

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

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL).

Dosage and Administration

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

For 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 usual 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 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 (XL) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (XL).

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including but not limited to mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicide. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Patients should be instructed to discontinue the medication and seek immediate medical advice if they experience any of these adverse events.

The risk of seizures associated with bupropion hydrochloride XL is dose-dependent. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be made gradually. Should a seizure occur, the medication must be discontinued immediately.

Bupropion hydrochloride XL has 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 during treatment. Additionally, patients should be informed to report any signs of psychosis or other neuropsychiatric reactions to their healthcare provider promptly.

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 populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

To ensure patient safety, healthcare providers should instruct patients to discontinue bupropion hydrochloride XL and contact a healthcare professional if they experience any neuropsychiatric adverse events or if a seizure occurs. Regular blood pressure monitoring is also recommended to manage potential hypertension associated with the treatment.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride extended-release tablets (XL). These reactions can be categorized into common adverse reactions, serious warnings, and other significant risks.

Common adverse reactions reported by patients include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

A serious warning associated with the use of bupropion is the increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation during treatment.

Neuropsychiatric adverse events have been observed during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should be instructed to contact a healthcare professional immediately.

The risk of seizures is dose-related, and it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion can 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. There is also a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the contraindications for patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI.

In cases of overdose, serious reactions have been reported, including seizures in approximately one third of cases, hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with bupropion overdose have been documented, often following multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Drug Interactions

Coadministration of bupropion with CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in bupropion dosage. However, it is essential that the total dosage does not exceed the maximum recommended limit.

Bupropion acts as an inhibitor of CYP2D6, which can lead to elevated plasma concentrations of certain medications. This includes antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). In such cases, a dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects.

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

The use of bupropion hydrochloride extended-release tablets (XL) in conjunction with dopaminergic medications, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Therefore, careful monitoring is advised.

Additionally, there is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are administered with monoamine oxidase inhibitors (MAOIs).

It is important to note that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine drug screenings for amphetamines, which should be taken into consideration during testing.

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 6,000 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 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 between these groups, 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 elderly patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an increased risk of congenital malformations overall. However, there are inherent risks to the mother associated with untreated depression, which should be considered when evaluating treatment options during pregnancy.

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 the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Additionally, decreased fetal weights were noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background rate of birth defects, loss, or other adverse outcomes.

A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication. Therefore, it is crucial to consider the risks associated with untreated depression and the potential effects on the fetus when contemplating the discontinuation or alteration of antidepressant treatment 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 with 1,213 first trimester exposures, did not demonstrate an increased risk for malformations overall. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. However, no increased risk for cardiovascular malformations overall has been observed following bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with first trimester exposure to bupropion was 1.3%, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and risks for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions regarding these potential associations.

In summary, while animal studies indicate a lack of fetal malformations at certain doses, caution is warranted due to the observed effects in rabbits and the potential risks associated with untreated maternal depression. Healthcare professionals should carefully weigh the benefits and risks when prescribing bupropion to pregnant patients.

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.

The developmental and health benefits of breastfeeding should be weighed against 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

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 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 quantities 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 pronounced in cases involving multiple drug overdoses, which can complicate the clinical picture and necessitate more intensive management.

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 severity of the situation.

Currently, there are no known antidotes for bupropion overdose. Therefore, the cornerstone of management involves supportive care and vigilant medical supervision. Healthcare professionals are advised to monitor the patient closely and provide symptomatic treatment as necessary.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach out to the Poison Control Center at 1-800-222-1222 for assistance in managing the overdose effectively.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice, administering bupropion hydrochloride at doses 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 mg/kg/day 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. 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, indicating a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results 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.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide during attempts to quit smoking while taking bupropion. New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been observed. These symptoms may occur upon initiation of bupropion therapy, after several weeks of treatment, or following discontinuation of the medication.

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 in individuals who have had 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, to aid in smoking cessation.

Periods of mania, characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech, have been documented in some patients taking bupropion hydrochloride extended-release tablets (XL).

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported. Patients experiencing these symptoms are encouraged to contact their healthcare provider.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been noted, with symptoms including rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing. Patients experiencing any of these symptoms should discontinue use and seek immediate medical attention.

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, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial phase of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should monitor patients on a daily basis for any abrupt changes in behavior, as these can occur 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, and panic, along with suicidal thoughts or actions when attempting to quit smoking while taking bupropion.

Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience any concerning symptoms. They should also be educated about the signs of hypersensitivity and advised to stop taking bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. In the event of a seizure while on treatment, patients should discontinue the medication and not restart it.

It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should be encouraged to minimize or avoid alcohol consumption. Patients should be made aware 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 informed that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) as ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other products containing bupropion hydrochloride. Additionally, patients should be cautioned that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks that require judgment or motor and cognitive skills. Until they are certain that the medication 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 (XL) may interact with other drugs. They should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment. Communication with the patient’s pediatric healthcare provider regarding any infant exposure to bupropion through breast milk is essential, and patients should be instructed to contact the infant’s healthcare provider if they observe any concerning or persistent side effects in the infant.

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 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. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. 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) as outlined by USP guidelines. 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 seek immediate medical attention if they observe any signs of agitation, depressed mood, or atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers are encouraged to closely monitor patients treated with antidepressants for major depressive disorder or other indications for any emergence of agitation, irritability, or unusual behavioral changes, and to report these symptoms to healthcare providers promptly. Prescriptions for bupropion XL should be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use for smoking cessation, including mood changes, psychosis, hallucinations, and suicidal ideation. These events have been reported in both patients with and without pre-existing psychiatric conditions, with some experiencing exacerbation of their psychiatric illnesses. While many cases reported resolution of symptoms following discontinuation of bupropion, persistent symptoms were noted in some instances, necessitating ongoing monitoring and supportive care until resolution occurs. Additionally, symptoms of nicotine withdrawal, such as depressed mood, may occur in patients who have recently stopped smoking, even without medication.

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)