Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (SR) serve as a non-nicotine aid for smoking cessation. Bupropion is chemically distinct from nicotine and other agents utilized in nicotine addiction treatment. Originally developed as an antidepressant, it is marketed under the names WELLBUTRIN and WELLBUTRIN SR. This compound is also unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressants.

The chemical designation of bupropion 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. Bupropion hydrochloride appears as a white powder, soluble in 0.1N hydrochloric acid, alcohol (96.0%), and water. It possesses a bitter taste and induces a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets, USP (SR) are formulated for oral administration, available in 150-mg film-coated, sustained-release tablets that are purple in color. Each tablet contains the specified amount of bupropion hydrochloride USP along with inactive ingredients, including copovidone, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide, FD&C Blue No. 2 Lake, and FD&C Red No. 40 Lake. Additionally, the flavoring agent comprises dextrose, ethyl alcohol, gum arabic, propylene glycol, and silicon dioxide. Bupropion hydrochloride extended-release tablets, USP (SR) comply with USP dissolution Test 2.

Uses and Indications

Bupropion hydrochloride extended-release tablets, USP (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 first three days. Dosing should commence one week prior to the designated quit day. Following the initial 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 within 14 days of stopping an MAOI, nor should it be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Postmarketing surveillance has identified serious neuropsychiatric adverse events associated with the use of Bupropion hydrochloride extended-release tablets, USP (SR). These events may include significant mood alterations such as depression and mania, as well as psychotic symptoms including hallucinations, paranoia, delusions, and aggression. Healthcare professionals should closely observe patients who are attempting to quit smoking while on this medication for any emergence of these symptoms. Patients should be instructed to discontinue the use of Bupropion hydrochloride extended-release tablets, USP (SR) and seek immediate medical advice if they experience any neuropsychiatric adverse events, including suicidal ideation, suicide attempts, or completed suicide.

The risk of seizures is dose-dependent. To mitigate this risk, it is recommended that the dosage be gradually increased, with a maximum daily limit of 300 mg. Should a seizure occur, the medication must be discontinued promptly.

Bupropion hydrochloride extended-release tablets (SR) have the potential to elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy, particularly in patients who are also using nicotine replacement therapies.

Patients should be screened for bipolar disorder prior to treatment, as Bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is advised during treatment.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be encouraged to contact a healthcare professional if they experience any such reactions.

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

It is critical to note the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including Bupropion. Healthcare providers should monitor these populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors throughout the treatment period.

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 observed, particularly neuropsychiatric events. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, necessitating careful monitoring for the emergence or worsening of these symptoms. Neuropsychiatric adverse events may include 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 are advised to contact a healthcare professional if any of these reactions occur.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 300 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride extended-release tablets (SR) can increase blood pressure, and blood pressure should be monitored before and during treatment, especially in patients using nicotine replacement therapies.

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

Patients with a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, or those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs should exercise caution. The use of monoamine oxidase inhibitors (MAOIs) is contraindicated with bupropion hydrochloride extended-release tablets (SR) or within 14 days of stopping treatment with either medication.

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 consideration.

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

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of drugs metabolized by this enzyme. This includes various antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), 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 both medications.

Drugs Lowering Seizure Threshold Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (SR) in conjunction with drugs that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs The concomitant use of bupropion hydrochloride extended-release tablets (SR) with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion hydrochloride extended-release tablets (SR) with MAOIs can heighten the risk of hypertensive reactions. Caution is advised when these agents are used together.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (SR) may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

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 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 geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies indicate that bupropion is classified as Pregnancy Category C. The risk summary suggests that exposure to bupropion during the first trimester does not appear to increase the overall 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. In reproductive developmental studies conducted in rats and rabbits, no clear evidence of teratogenic activity was observed; however, rabbits exhibited 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 noted at doses three times the MRHD and higher. Therefore, bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical considerations suggest that pregnant smokers should be encouraged to attempt cessation through educational and behavioral interventions prior to considering pharmacological approaches. 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. 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%.

However, findings regarding the association between bupropion exposure during the first trimester and specific cardiovascular malformations, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), are inconsistent. The United Healthcare database lacked sufficient power to evaluate the association with LVOTO, while the National Birth Defects Prevention Study (NBDPS) reported an increased risk for LVOTO (adjusted OR = 2.6; 95% CI: 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. For VSD, the Slone Epidemiology Study indicated an increased risk following first trimester exposure (adjusted OR = 2.5; 95% CI: 1.3, 5.0), while the NBDPS and United Healthcare database did not find an association. The limitations of these studies, including small sample sizes and inconsistent findings, should be considered when interpreting these results.

Animal studies have shown that bupropion, administered orally during the organogenesis period in rats and rabbits, did not provide clear evidence of teratogenicity. However, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at the lowest tested dose (25 mg per kg per day, approximately two times the MRHD on a mg per m² basis) and higher doses. Decreased fetal weights were observed at doses of 50 mg per kg and greater. In contrast, when rats were administered bupropion at doses up to 300 mg per kg per day (approximately ten times the MRHD on a mg per m² basis) prior to mating and throughout pregnancy and lactation, no adverse effects on offspring development were apparent.

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, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

Caution is advised when administering bupropion hydrochloride extended-release tablets (SR) to lactating mothers.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 were reported as a significant adverse effect. Other serious reactions associated with bupropion overdoses include hallucinations, loss of consciousness, alterations in mental status, and sinus tachycardia. Additionally, electrocardiogram (ECG) changes such as conduction disturbances, including QRS prolongation and arrhythmias, have been observed. Neuromuscular symptoms such as clonus, myoclonus, and hyperreflexia may also occur.

In more severe cases, particularly when bupropion is involved in multiple drug overdoses, symptoms can escalate to include fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. While most patients have recovered without lasting effects, there have been reports of fatalities associated with bupropion overdoses, particularly in those who ingested large quantities of the drug. In these cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

Healthcare professionals are advised to monitor patients closely for these symptoms in the event of a suspected overdose. Immediate medical intervention is critical, and supportive care should be initiated as necessary.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered 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. 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 the Ames bacterial mutagenicity assay, with a mutation rate 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. Additionally, instances of suicidal ideation and suicide have been noted in individuals attempting to quit smoking while using bupropion hydrochloride extended-release tablets (SR). It is advised that patients discontinue the use of bupropion hydrochloride extended-release tablets (SR) and seek guidance from a healthcare professional if they encounter any of these symptoms.

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 stages 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. If such symptoms arise, especially if they are severe, sudden, or not part of the patient’s initial presentation, they should be reported 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, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion hydrochloride extended-release tablets (SR). In the event that patients experience any of these symptoms, they should discontinue the medication and contact a healthcare professional immediately.

It is essential to educate patients about the signs of hypersensitivity and to instruct them to discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients should 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. Furthermore, patients should be made aware that bupropion hydrochloride extended-release tablets (SR) can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals.

Healthcare providers should inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient (bupropion hydrochloride) found in WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL, which are used to treat depression. Patients should not use bupropion hydrochloride extended-release tablets (SR) in conjunction with any other medications that contain bupropion.

Patients should also be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks that require judgment or motor and cognitive skills. Until patients are confident that bupropion does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Finally, patients should be counseled to notify their healthcare provider 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 and affect each other's metabolism.

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° to 25°C (68° 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.

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, and report these symptoms to healthcare providers promptly. Prescriptions for Bupropion hydrochloride extended-release tablets (SR) 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 hydrochloride extended-release tablets (SR), particularly in patients using the medication for smoking cessation. Reported events include mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal ideation. The incidence of these events was higher in the psychiatric cohort compared to the non-psychiatric cohort, and the composite endpoint was more frequent with Bupropion hydrochloride extended-release tablets (SR) than with placebo. While some patients experienced resolution of symptoms after discontinuation, others continued to have 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 ScieGen Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)