Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablet (SR) is an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. Its chemical structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2, with a molecular formula of C13H18ClNO•HCl.

The bupropion hydrochloride powder is characterized as white, crystalline, and highly soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. The extended-release tablets are formulated for oral administration and are available in strengths of 100 mg, 150 mg, and 200 mg. These tablets are white to off-white, film-coated, and designed for sustained release. Each tablet contains the specified amount of bupropion hydrochloride, USP, along with inactive ingredients including hydroxypropyl cellulose, saccharin, anhydrous lactose, colloidal silicon dioxide, talc, stearic acid, polyvinyl alcohol, titanium dioxide, and polyethylene glycol 3350.

The 100 mg strength meets USP dissolution test 7, while the 150 mg and 200 mg strengths comply with USP dissolution test 2.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder. The efficacy of bupropion in managing a major depressive episode has been established through two 4-week controlled trials involving depressed inpatients and one 6-week controlled trial involving depressed outpatients.

A major depressive episode, as defined by DSM-IV criteria, is characterized by the presence of either a depressed mood or a loss of interest or pleasure, along with at least five of the following symptoms occurring during the same 2-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

Additionally, the efficacy of bupropion hydrochloride extended-release tablets (SR) in maintaining an antidepressant response for up to 44 weeks following an initial 8-week treatment period has been demonstrated in a placebo-controlled trial. Physicians who choose to prescribe bupropion hydrochloride extended-release tablets (SR) for extended durations should periodically reevaluate the long-term usefulness of the medication for each individual patient.

Dosage and Administration

Bupropion hydrochloride extended-release tablets (SR) should be administered in a manner that minimizes the risk of seizure. A gradual escalation in dosage is essential to reduce the likelihood of agitation, motor restlessness, and insomnia. If these effects occur, they may be managed by temporarily reducing the dose or by the short-term administration of a sedative hypnotic. The tablets must be swallowed whole and should not be crushed, divided, or chewed.

For initial treatment, the usual adult target dose is 300 mg per day, administered as 150 mg twice daily. Treatment should begin with a single daily dose of 150 mg in the morning. If well tolerated, the dose may be increased to 300 mg per day (150 mg twice daily) as early as day 4, ensuring that there is an interval of at least 8 hours between successive doses.

If no clinical improvement is observed after several weeks at the 300 mg per day dosage, an increase to a maximum dosage of 400 mg per day, given as 200 mg twice daily, may be considered.

For maintenance treatment, it is important to note that acute episodes of depression may necessitate several months or longer of sustained pharmacological therapy. Patients should be periodically reassessed to determine the ongoing need for maintenance treatment and to adjust dosing as appropriate.

In patients with impaired hepatic function, bupropion should be used with extreme caution, particularly in those with severe hepatic cirrhosis, where the dosage should not exceed 100 mg daily or 150 mg every other day. For patients with mild-to-moderate hepatic cirrhosis, a reduced frequency and/or dose should be considered.

In patients with impaired renal function, bupropion should also be used with caution, and a reduced frequency and/or dose may be warranted based on the severity of the renal impairment.

Contraindications

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in the following situations:

Patients with a seizure disorder should not use bupropion hydrochloride extended-release tablets (SR) due to the risk of seizures. The use of these tablets is also contraindicated in individuals currently or previously treated with ZYBAN (bupropion hydrochloride) Sustained-release Tablets, bupropion hydrochloride tablets, the immediate-release formulation, bupropion hydrochloride extended-release tablets (XL), or any other medications containing bupropion, as the incidence of seizures is dose dependent.

Patients with a current or prior diagnosis of bulimia or anorexia nervosa are contraindicated for use, given the higher incidence of seizures observed in those treated for bulimia with the immediate-release formulation of bupropion. Additionally, bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives, including benzodiazepines, due to the increased risk of seizures.

The concurrent administration of bupropion hydrochloride extended-release tablets (SR) and a monoamine oxidase (MAO) inhibitor is contraindicated. A minimum of 14 days should elapse between the discontinuation of an MAO inhibitor and the initiation of treatment with bupropion hydrochloride extended-release tablets (SR).

Lastly, patients who have demonstrated an allergic response to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR) should not use this medication. If a patient experiences allergic or anaphylactoid/anaphylactic reactions during treatment, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath, they should discontinue use and consult a healthcare professional.

Warnings and Precautions

Patients with major depressive disorder (MDD), both adult and pediatric, are at risk for worsening depression and the emergence of suicidal ideation and behavior (suicidality), as well as unusual changes in behavior, regardless of whether they are receiving antidepressant medications. This risk may persist until significant remission is achieved. It is important to note that antidepressants can contribute to the worsening of depression and the emergence of suicidality, particularly during the early phases of treatment.

All patients undergoing treatment with antidepressants for any indication must be monitored closely for clinical worsening, suicidality, and unusual behavioral changes. This monitoring is especially critical during the initial months of therapy or when there are changes in dosage. Symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania have been reported in patients receiving antidepressants.

In cases where a patient's depression worsens persistently, or if they exhibit emergent suicidality or symptoms that may precede worsening depression or suicidality, consideration should be given to modifying the therapeutic regimen, which may include discontinuation of the medication. Families and caregivers should be informed of the importance of monitoring patients for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality, and they should report any such symptoms to healthcare providers immediately.

Prescriptions for bupropion should be written for the smallest quantity of tablets necessary for effective patient management to minimize the risk of overdose.

Bupropion must be used with extreme caution in patients with severe hepatic cirrhosis, necessitating a reduced frequency and/or dosage. All patients with hepatic impairment should be closely monitored for potential adverse effects that may indicate elevated drug and metabolite levels.

While there are no specific laboratory tests recommended for monitoring, it is crucial for patients and caregivers to be vigilant. Patients using bupropion for smoking cessation should be advised to discontinue the medication and seek immediate medical attention if they experience agitation, hostility, depressed mood, or any atypical changes in thinking or behavior, including suicidal ideation or behavior.

Patients should also be instructed to stop taking bupropion and consult a healthcare provider if they experience any allergic or anaphylactoid/anaphylactic reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath during treatment.

Side Effects

Patients receiving treatment with bupropion should be closely monitored for adverse reactions, particularly those related to suicidality and neuropsychiatric symptoms. A boxed warning highlights that antidepressants, including bupropion, may increase the risk of suicidal thinking and behavior in children, adolescents, and young adults. Patients of all ages should be observed for clinical worsening, suicidality, or unusual changes in behavior.

In clinical trials, patients with major depressive disorder (MDD) have reported worsening depression and the emergence of suicidal ideation and behavior. Additionally, serious neuropsychiatric symptoms such as mood changes, psychosis, hallucinations, paranoia, delusions, hostility, agitation, and suicidal ideation have been documented in patients taking bupropion for smoking cessation.

Common adverse reactions observed in controlled trials include headache (26% for 300 mg/day), dry mouth (17%), nausea (13%), insomnia (11%), and dizziness (7%). Other notable reactions include agitation (3%), abdominal pain (3%), and rash (5%). The incidence of these events was compared to placebo, with some reactions occurring at similar or lower rates in the treatment group.

Infrequent adverse reactions reported include chills, facial edema, musculoskeletal chest pain, and photosensitivity. Rare events include malaise, syncope, and bronchospasm. Patients may also experience cardiovascular effects such as postural hypotension, tachycardia, and vasodilation.

Gastrointestinal disturbances such as abnormal liver function, bruxism, gastric reflux, and increased salivation have been noted, along with metabolic changes like hyperglycemia and hypoglycemia. Hematological reactions include ecchymosis, anemia, and leukopenia.

Musculoskeletal symptoms may manifest as leg cramps, muscle rigidity, or weakness. Neurological effects can include abnormal coordination, decreased libido, emotional lability, and suicidal ideation. Rare neurological events such as amnesia and ataxia have also been reported.

Respiratory adverse reactions include pneumonia and, rarely, bronchospasm. Skin reactions may range from alopecia to angioedema, while urogenital effects can include impotence, urinary incontinence, and abnormal ejaculation.

Overall, the safety profile of bupropion necessitates careful monitoring for both common and serious adverse reactions, particularly in vulnerable populations.

Drug Interactions

Bupropion exhibits several potential drug interactions that may affect its metabolism and clinical efficacy.

Pharmacokinetic Interactions

Bupropion is primarily metabolized by the CYP2B6 isoenzyme to its active metabolite, hydroxybupropion. Concomitant use of drugs that are substrates or inhibitors of CYP2B6, such as orphenadrine, thiotepa, and cyclophosphamide, may lead to altered bupropion levels. In particular, the following drugs have been identified as inhibitors of bupropion hydroxylation: paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, ritonavir, and efavirenz. Clinicians should consider monitoring bupropion levels and adjusting dosages accordingly when these agents are coadministered.

Cimetidine has been shown to have no significant effect on the pharmacokinetics of bupropion and hydroxybupropion; however, it does increase the AUC and C_max of the metabolites threohydrobupropion and erythrohydrobupropion by 16% and 32%, respectively.

Conversely, drugs that induce CYP2B6 metabolism, such as carbamazepine, phenobarbital, and phenytoin, may decrease bupropion levels, necessitating potential dosage adjustments.

Bupropion and its metabolite hydroxybupropion are also in vitro inhibitors of the CYP2D6 isoenzyme. Caution is advised when bupropion is coadministered with drugs metabolized by CYP2D6, including nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, thioridazine, metoprolol, propafenone, and flecainide. Notably, daily doses of bupropion have been shown to increase the C_max, AUC, and half-life of desipramine by approximately 2-, 5-, and 2-fold, respectively.

Pharmacodynamic Interactions

The concurrent use of bupropion with agents that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids, should be approached with extreme caution. It is recommended to initiate treatment with low doses and to increase dosages gradually.

Limited clinical data indicate a higher incidence of adverse experiences when bupropion is used alongside levodopa or amantadine. Therefore, caution is advised, particularly with small initial doses and gradual dose increases.

Additionally, the acute toxicity of bupropion may be enhanced by the MAO inhibitor phenelzine.

There have been rare reports of adverse neuropsychiatric events and reduced alcohol tolerance in patients consuming alcohol during bupropion treatment. It is advisable to minimize or avoid alcohol consumption during therapy.

In summary, careful consideration of potential drug interactions is essential when prescribing bupropion, with appropriate monitoring and dosage adjustments as necessary.

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 for bupropion. Healthcare professionals considering the use of bupropion in children or adolescents must carefully balance the potential risks against the clinical need for treatment.

Geriatric Use

Clinical trials involving bupropion hydrochloride extended-release tablets included approximately 6,000 patients, of whom 275 were aged 65 and older, and 47 were aged 75 and older. Additionally, several hundred patients aged 65 and over participated in trials using the immediate-release formulation of bupropion. No overall differences in safety or effectiveness were observed between these elderly patients and younger subjects. However, it is important to note that while clinical experience has not identified significant differences in responses between elderly and younger patients, greater sensitivity in some older individuals cannot be ruled out.

Pharmacokinetic studies have shown that the disposition of bupropion and its metabolites in elderly subjects is similar to that of younger subjects. Nonetheless, another study indicated that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites. Given that bupropion is extensively metabolized in the liver to active metabolites, which are further processed and excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function.

Elderly patients are more likely to experience decreased renal function; therefore, careful consideration should be given to dose selection in this population. It may be beneficial to monitor renal function in elderly patients to mitigate potential risks associated with bupropion therapy.

Pregnancy

Bupropion is classified as Pregnancy Category C. In animal studies, bupropion was administered orally to rats and rabbits during the organogenesis period at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively. These studies did not demonstrate clear evidence of teratogenic activity; however, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day) and higher. Additionally, decreased fetal weights were observed at doses of 50 mg/kg/day and above. In a separate study involving rats, administration of bupropion at doses up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation did not reveal any apparent adverse effects on offspring development.

A retrospective managed-care database study involving pregnant women assessed the risk of congenital malformations, including cardiovascular malformations, following first trimester exposure to bupropion compared to other antidepressants. This study included 7,005 infants with antidepressant exposure during pregnancy, of which 1,213 were exposed to bupropion in the first trimester. The findings indicated no greater risk for congenital malformations overall or specifically for cardiovascular malformations following first trimester exposure to bupropion compared to exposure to other antidepressants in the same period or to bupropion outside of the first trimester. However, these results have not been corroborated by further studies.

Given the potential risks, bupropion should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Lactation

Bupropion and its metabolites are secreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, a decision should be made regarding whether to discontinue nursing or to discontinue bupropion hydrochloride extended-release tablets (SR). This decision should consider the importance of the medication to the lactating mother.

Renal Impairment

Patients with severe hepatic cirrhosis should use bupropion with extreme caution due to the potential for significantly increased peak levels and area under the curve (AUC) concentrations, which may lead to accumulation. In this population, it is recommended to reduce the frequency and/or dose of bupropion. The maximum dose should not exceed 100 mg daily or 150 mg every other day to mitigate the risk of adverse effects associated with elevated drug levels. Regular monitoring of these patients is advised to ensure safety and efficacy.

Hepatic Impairment

Bupropion should be used with extreme caution in patients with severe hepatic cirrhosis. In this population, a reduced frequency and/or dose is required due to significantly increased peak bupropion levels and area under the curve (AUC) levels, which may lead to greater accumulation than typically observed. Specifically, the dose of bupropion in patients with severe hepatic impairment should not exceed 100 mg per day or 150 mg every other day. Close monitoring of these patients is recommended to mitigate the risk of adverse effects associated with elevated drug levels.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 g or more. In approximately one-third of these cases, seizures were reported. Other serious adverse reactions associated with bupropion overdoses include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances (including QRS prolongation) and arrhythmias. Additionally, symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have primarily been observed in cases involving multiple drug overdoses.

While most patients have recovered without lasting effects, there have been reports of fatalities linked to bupropion overdoses, particularly in individuals who ingested large quantities of the drug. In these cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

Management of bupropion overdose requires immediate attention to ensure an adequate airway, oxygenation, and ventilation. Continuous monitoring of cardiac rhythm and vital signs is essential, and EEG monitoring is recommended for the first 48 hours following ingestion. General supportive and symptomatic measures should be implemented, while the induction of emesis is not advised.

Activated charcoal should be administered as part of the treatment protocol. There is currently no established experience with forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the context of bupropion overdoses, and no specific antidotes for bupropion are available.

Given the dose-related risk of seizures associated with bupropion, hospitalization should be considered following any suspected overdose. Based on animal studies, it is advisable to treat seizures with intravenous benzodiazepines and to provide other supportive measures as necessary.

In cases of overdose, it is crucial to consider the potential for multiple drug involvement. Physicians are encouraged to contact a poison control center for further guidance on the management of any overdose. Contact information for certified poison control centers can be found in the Physicians’ Desk Reference (PDR).

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice 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, 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 demonstrate similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion exhibited a positive response in the Ames bacterial mutagenicity test, showing 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/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation, including depression, suicidal ideation, suicide attempts, and completed suicides. Patients undergoing treatment with bupropion for smoking cessation should be closely monitored for neuropsychiatric symptoms, which may include changes in behavior, hostility, agitation, depressed mood, and suicide-related events, encompassing ideation, behavior, and attempts.

In the postmarketing experience, these symptoms, along with the exacerbation of pre-existing psychiatric conditions and completed suicides, have been documented in individuals attempting to quit smoking while using ZYBAN. While most reported symptoms occurred during treatment with ZYBAN, some cases were noted following the discontinuation of the medication.

These events have been observed in both patients with and without a history of psychiatric disorders, with some individuals experiencing a worsening of their psychiatric conditions. In numerous postmarketing cases, a resolution of symptoms was reported after discontinuation of ZYBAN; however, in certain instances, symptoms persisted. Therefore, ongoing monitoring and supportive care are recommended until symptoms fully resolve.

Patient Counseling

Patients, their families, and caregivers should be informed about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (SR) and should receive counseling on its appropriate use. A Medication Guide is available that covers important topics such as “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)?” Patients should be advised to read this Medication Guide and should be assisted in understanding its contents.

Patients should be encouraged to remain vigilant for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening of depression and suicidal ideation, particularly during the initial stages of treatment and when doses are adjusted. Families and caregivers should also be advised to monitor for these symptoms on a daily basis, as changes may occur abruptly, and to report any concerning symptoms to the patient’s prescriber or health professional.

It is important to inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride extended-release tablets (SR) should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride. Patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to minimize the risk of seizures. If a patient experiences a seizure while on treatment, they should discontinue bupropion and not restart it.

Patients should be made aware 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. They should refrain from driving or operating complex, hazardous machinery until they are confident that the medication does not adversely affect their performance. Additionally, patients should be advised to minimize or avoid alcohol consumption, as excessive use or abrupt discontinuation of alcohol or sedatives may alter the seizure threshold.

Patients should inform their physicians of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (SR) may interact with other drugs. They should also notify their physicians if they become pregnant or intend to become pregnant during therapy. Finally, patients should be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole, without chewing, dividing, or crushing them, to ensure the proper release rate of the medication.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

There are no specific laboratory tests recommended for patients. Additionally, there is no further information available regarding abuse, route, method, and frequency of administration, patient counseling, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)