Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (SR) are chemically unrelated to nicotine or other agents currently used in the treatment of nicotine addiction. Its structure closely resembles that of diethylpropion and is related to phenylethylamines. The chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO•HCl. The bupropion hydrochloride powder is white, crystalline, and highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (SR) are supplied for oral administration as 150 mg white to off-white, film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including colloidal silicon dioxide, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and stearic acid. The film-coating consists of hydroxypropyl cellulose, lactose monohydrate, polyethylene glycol, and titanium dioxide.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) are indicated as an aid to smoking cessation treatment.

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 for the initial three days of treatment. Dosing should commence one week prior to the designated quit day. Following the first three days, the dose may be increased to 300 mg per day, administered as 150 mg twice daily, with a minimum interval of 8 hours between doses.

For patients with moderate to severe hepatic impairment, the dosing regimen should be adjusted to 150 mg every other day. In cases of mild hepatic impairment, healthcare professionals should consider reducing the dose and/or frequency of administration. Additionally, for patients with renal impairment, a reduction in dose and/or frequency should also be considered to ensure safety and efficacy.

It is essential to increase the dose gradually to minimize the risk of seizures.

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 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 started on bupropion hydrochloride extended-release tablets (SR) due to potential interactions.

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

Warnings and Precautions

Neuropsychiatric adverse events have been reported in postmarketing surveillance, including serious and clinically significant changes in mood such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion hydrochloride extended-release tablets (SR) for the emergence of these symptoms. Patients should be instructed to discontinue the medication and contact a healthcare provider immediately if they experience any of these adverse events.

The risk of seizures is dose-related; therefore, it is essential to minimize this risk by gradually increasing the dosage and limiting the maximum daily dose to 300 mg. If a seizure occurs, the medication should be discontinued.

Bupropion hydrochloride extended-release tablets (SR) may elevate blood pressure. It is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course, particularly in patients using nicotine replacement therapies.

Patients should be screened for bipolar disorder prior to treatment, as bupropion can activate mania or hypomania. Continuous monitoring for these symptoms is recommended. In the event of psychosis or other neuropsychiatric reactions, patients should be advised to contact a healthcare professional.

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

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 imperative to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

To ensure safe use, healthcare professionals should instruct patients to monitor for neuropsychiatric reactions and to seek emergency medical help if such reactions occur. Patients should also be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and contact their healthcare provider if they experience any neuropsychiatric adverse events. Regular blood pressure monitoring is recommended before and during treatment, especially in conjunction with nicotine replacement therapies.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (SR) may experience a range of adverse reactions. The most common adverse reactions reported include insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia.

Serious adverse reactions have been identified, including an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor patients for any worsening or emergence of suicidal thoughts and behaviors. Neuropsychiatric adverse events may also occur, such as changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients should be instructed to contact a healthcare professional if any of these reactions occur.

The risk of seizures is dose-related, and it is recommended to gradually increase the dose while limiting the daily dose to 300 mg. 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, especially if the patient is using nicotine replacement therapy.

Activation of mania or hypomania has been reported, necessitating screening for bipolar disorder and careful monitoring for these symptoms. Angle-closure glaucoma has also been observed in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnoses of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of 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 overdosage, seizures were reported in approximately one-third of all cases. 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

Coadministration of bupropion hydrochloride extended-release tablets (SR) with certain drug classes may lead to significant interactions that require careful management.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, an increase in bupropion dosage may be necessary based on clinical response. However, the dosage should not exceed the maximum recommended limit.

CYP2D6 Inhibitors 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, risperidone), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). A dose reduction of these medications should be considered when used concurrently with bupropion.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely in patients receiving this combination.

Seizure Threshold Caution is warranted when prescribing bupropion in conjunction with drugs that lower the seizure threshold, as this may increase the risk of seizures.

CNS Toxicity The concomitant use of bupropion with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system toxicity. Monitoring for adverse effects is recommended.

MAOIs The use of bupropion with monoamine oxidase inhibitors (MAOIs) can heighten the risk of hypertensive reactions. Close monitoring is essential when these agents are used together.

Urine Drug Testing Bupropion hydrochloride extended-release tablets (SR) may cause false-positive results in urine tests for amphetamines. This should be taken into consideration when interpreting drug screening results.

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 is advised when considering the use of this medication in children, infants, and adolescents. 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 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 some older individuals may exhibit greater sensitivity to the medication.

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, 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

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester indicate no overall increased risk of congenital malformations. It is important to note that all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. Reproductive developmental studies in rats and rabbits did not demonstrate clear teratogenic activity; however, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at doses approximately two times the maximum recommended human dose (MRHD) and greater. Additionally, decreased fetal weights were observed at doses three times the MRHD and higher.

Bupropion hydrochloride extended-release tablets (SR) should be prescribed during pregnancy only if the potential benefits justify the potential risks to the fetus. Pregnant smokers are encouraged to attempt cessation through educational and behavioral interventions prior to considering pharmacological options.

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 reveal an increased risk for malformations overall. Specifically, the 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%. Furthermore, studies from the United Healthcare database and the National Birth Defects Prevention Study (NBDPS) did not find an increased risk for cardiovascular malformations following bupropion exposure during the first trimester.

However, findings regarding the association between bupropion exposure and left ventricular outflow tract obstruction (LVOTO) are inconsistent. The NBDPS identified an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), while the United Healthcare database lacked sufficient power to evaluate this association, and the Slone Epidemiology case-control study did not find an increased risk. Similarly, findings related to ventricular septal defect (VSD) are also inconsistent. The Slone Epidemiology Study reported an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0), while the NBDPS and United Healthcare database studies did not find an association. Limitations in these studies, including small sample sizes and inconsistent findings, may affect the reliability of these associations.

In animal studies, bupropion was administered orally during the organogenesis period at doses up to 450 mg/kg/day in rats and 150 mg/kg/day in rabbits, which are approximately 15 and 10 times the MRHD on a mg/m² basis, respectively. No clear evidence of teratogenic activity was observed in either species; however, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at the lowest tested dose of 25 mg/kg/day (approximately 2 times the MRHD on a mg/m² basis) and higher. Decreased fetal weights were recorded at doses of 50 mg/kg and above. In studies where rats were administered bupropion at doses up to 300 mg/kg/day (approximately 10 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, no apparent adverse effects on offspring development were observed.

Lactation

Bupropion and its metabolites are present 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 per kg, was found to be 2% of the maternal weight-adjusted dose. Therefore, caution is advised when administering bupropion hydrochloride extended-release tablets (SR) to lactating mothers.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function 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 have been documented, with instances involving doses of 30 grams or more. In approximately one-third of these cases, seizures have been reported, highlighting the potential neurological risks associated with excessive intake.

Potential Symptoms of Overdosage Serious adverse reactions following bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and significant electrocardiogram (ECG) changes, such as conduction disturbances. These symptoms indicate a severe impact on both neurological and cardiovascular systems. Furthermore, fatalities have been associated with bupropion overdose, particularly in cases where patients have ingested large quantities, leading to multiple uncontrolled seizures and cardiac failure.

Management of Overdosage Currently, there are no known antidotes for bupropion. Therefore, the management of overdose primarily involves supportive care and close medical supervision. Healthcare professionals are advised to monitor the patient closely for any signs of complications and to provide appropriate interventions as necessary.

In the event of a bupropion overdose, it is crucial to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center by calling 1-800-222-1222 or visiting www.poison.org. This resource can offer valuable assistance in managing the overdose effectively.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice, administering bupropion at doses of up to 300 mg per kg per day and 150 mg per kg per day, respectively. These doses correspond to approximately 10 and 2 times the maximum recommended human dose (MRHD) on a mg per 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 per kg per day, which is approximately 3 to 10 times the MRHD on a mg per m² basis. Lower doses were not evaluated in this study. The potential for these lesions to serve as precursors to neoplasms of the liver remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors of the liver or other organs in either species.

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

A fertility study conducted in rats at doses up to 300 mg per kg per day indicated no evidence of impaired fertility.

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 using bupropion hydrochloride extended-release tablets (SR).

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, and suicidal thoughts or actions, have been documented in some individuals taking bupropion hydrochloride extended-release tablets (SR) for smoking cessation. Symptoms of mania associated with the use of this medication may include significantly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, and increased talkativeness.

Reports have also indicated that some patients experienced unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion while on bupropion hydrochloride extended-release tablets (SR).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have been reported, with symptoms that 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.

There is a risk of seizures (convulsions) associated with bupropion hydrochloride extended-release tablets (SR), particularly in individuals with certain medical conditions or those taking specific medications. The likelihood of seizures increases with higher doses of the medication.

Additionally, some individuals may experience significant increases in blood pressure while taking bupropion hydrochloride extended-release tablets (SR), especially if they are also using nicotine replacement therapy.

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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly critical to monitor during the initial phase of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may occur suddenly. Any severe, abrupt, 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 significant 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 hydrochloride extended-release tablets (SR). If patients experience any of these symptoms, they should discontinue the medication and contact a healthcare professional immediately.

Education on hypersensitivity symptoms is essential, and patients should be instructed to discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients must be advised to stop taking the medication and not to restart it 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. It is also important to inform patients that bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as WELLBUTRIN® and should not be used in conjunction with any other medications containing bupropion. Furthermore, patients should be counseled that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks requiring judgment or motor and cognitive skills.

Healthcare providers should encourage patients to notify them if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (SR) and other drugs may interact with each other. Patients should also be advised to inform their healthcare provider if they become pregnant or intend to become pregnant during therapy, as bupropion hydrochloride extended-release (SR) is present in human milk in small amounts.

Storage instructions should be provided, advising patients to keep bupropion hydrochloride extended-release tablets (SR) at room temperature, between 68°F and 77°F (20°C to 25°C), and to keep the tablets dry and out of light. Patients should be instructed to swallow the tablets whole to ensure the release rate is not altered, and they should not chew, divide, or crush the tablets.

For patients taking more than 150 mg per day, it is important to instruct them to take bupropion hydrochloride extended-release tablets (SR) in two doses at least 8 hours apart to minimize the risk of seizures. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next tablet at the regular time due to the dose-related risk of seizure.

Finally, patients should be informed that bupropion hydrochloride extended-release tablets (SR) can be taken with or without food and may have an odor.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. 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. Proper handling and storage conditions are crucial for ensuring the quality of the product throughout its shelf life.

Additional Clinical Information

Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (SR) 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. Families and caregivers of patients receiving antidepressants for major depressive disorder (MDD) or other indications should be vigilant for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality, and report these symptoms to healthcare providers without delay.

Prescriptions for bupropion hydrochloride extended-release tablets (SR) should be limited to the smallest quantity necessary for effective patient management to minimize the risk of overdose. Postmarketing experience has revealed serious neuropsychiatric adverse events associated with the use of bupropion hydrochloride extended-release tablets (SR) for smoking cessation, including mood changes, psychosis, and suicidal behaviors. While many cases reported resolution of symptoms following discontinuation, some patients experienced persistent symptoms, necessitating ongoing monitoring and supportive care until resolution occurs.

FDA Insert (PDF)

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

View full prescribing information (PDF)