Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinguished by its chemical structure, which is unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Its 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 C₁₃H₁₈CINO•HCl.

The compound appears as a white, crystalline powder that is highly soluble in water. It possesses a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Each tablet intended for oral administration contains either 75 mg or 100 mg of bupropion hydrochloride. The formulation includes several inactive ingredients: FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, hydroxypropyl methylcellulose, microcrystalline cellulose, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triethyl citrate.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder. The efficacy of bupropion hydrochloride has been established through three placebo-controlled trials, which included two studies of approximately three weeks’ duration involving depressed inpatients and one study of approximately six weeks’ duration involving depressed outpatients.

The depressive disorder in the studied patient population aligns closely with the Major Depression category as defined in the American Psychiatric Association's Diagnostic and Statistical Manual III. Major Depression is characterized by a prominent and relatively persistent depressed or dysphoric mood that typically interferes with daily functioning for nearly every day over a period of at least two weeks. This condition should also include at least four of the following eight symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decreased sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts.

The effectiveness of bupropion hydrochloride tablets for long-term use, defined as treatment extending beyond six weeks, has not been systematically evaluated in controlled trials.

Dosage and Administration

Bupropion hydrochloride tablets should be administered in a manner that minimizes the risk of seizure. Increases in dosage should not exceed 100 mg per day within a 3-day period. A gradual escalation in dosage is recommended to reduce the likelihood of agitation, motor restlessness, and insomnia. No single dose should exceed 150 mg. The tablets are to be taken three times daily, with a minimum interval of 6 hours between doses.

For adults, the usual starting dose is 200 mg per day, administered as 100 mg twice daily. After a minimum of 3 days, the dosage may be increased to 300 mg per day, given as 100 mg three times daily. If clinically indicated, the maximum dosage may be increased to 450 mg per day, divided into doses not exceeding 150 mg each. In this case, the 100 mg tablet should be taken four times daily, ensuring at least 4 hours between doses.

For patients with impaired hepatic function, particularly those with severe hepatic cirrhosis, the dosage should not exceed 75 mg once daily. Caution is advised for patients with mild-to-moderate hepatic cirrhosis, and consideration should be given to reducing the frequency and/or dose.

In patients with impaired renal function, caution is also warranted, and adjustments to the frequency and/or dose may be necessary based on individual patient assessment.

Contraindications

Bupropion hydrochloride tablets are contraindicated in the following situations:

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

Patients with a current or prior diagnosis of bulimia or anorexia nervosa are contraindicated for treatment with bupropion hydrochloride tablets due to an increased risk of seizures in this population. Additionally, the abrupt discontinuation of alcohol or sedatives, including benzodiazepines, is a contraindication for the use of bupropion hydrochloride tablets.

Concurrent administration of bupropion hydrochloride tablets with monoamine oxidase (MAO) inhibitors is contraindicated. A minimum of 14 days must elapse between the discontinuation of an MAO inhibitor and the initiation of bupropion treatment.

Lastly, bupropion hydrochloride tablets are contraindicated in patients who have demonstrated an allergic response to bupropion or any of the excipients in the formulation.

Warnings and Precautions

Patients diagnosed with major depressive disorder (MDD), including both adults and pediatric populations, may experience a worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), as well as unusual changes in behavior. This risk is present regardless of whether patients are currently taking antidepressant medications, and it may persist until significant remission is achieved.

Antidepressants, including bupropion, can contribute to the worsening of depression and the emergence of suicidality, particularly during the early phases of treatment. Therefore, it is imperative that all patients receiving antidepressants for any indication are monitored closely for clinical worsening, suicidality, and unusual behavioral changes. This monitoring should be especially vigilant during the initial months of therapy or during any dose adjustments.

Families and caregivers of patients undergoing treatment with antidepressants should be informed of the necessity to observe for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality. Any such symptoms should be reported to healthcare providers immediately.

Bupropion is associated with a risk of seizures in approximately 0.4% of patients treated at doses up to 450 mg/day, with the risk significantly increasing at higher doses. Consequently, bupropion hydrochloride tablets should be administered with extreme caution in patients with severe hepatic cirrhosis.

A notable proportion of patients treated with bupropion hydrochloride tablets may experience increased restlessness, agitation, anxiety, and insomnia, particularly shortly after the initiation of treatment. Additionally, depressed patients receiving bupropion have been reported to exhibit various neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion. It is also important to note that antidepressants can precipitate manic episodes in patients with bipolar disorder during depressive phases and may activate latent psychosis in other susceptible individuals.

There are no specific laboratory tests recommended for monitoring patients on bupropion hydrochloride tablets. However, patients and caregivers should be advised to seek emergency medical assistance if the patient using bupropion for smoking cessation experiences agitation, a depressed mood, or any atypical changes in behavior or thinking, or if suicidal ideation or behavior develops.

Patients should discontinue the use of bupropion hydrochloride tablets 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 may experience a range of adverse reactions while receiving treatment. Common adverse reactions include agitation, dry mouth, insomnia, headache or migraine, nausea or vomiting, constipation, and tremor.

Serious adverse reactions have been reported, including neuropsychiatric disturbances occurring in 3.0% of patients, primarily characterized by agitation and abnormalities in mental status. Gastrointestinal disturbances, primarily nausea and vomiting, were noted in 2.1% of patients. Neurological disturbances, including seizures, headaches, and sleep disturbances, were observed in 1.7% of subjects. Additionally, dermatologic problems, primarily rashes, were reported in 1.4% of patients.

Cardiovascular adverse reactions include cardiac arrhythmias (5.3%), dizziness (22.3%), hypertension (4.3%), hypotension (2.5%), palpitations (3.7%), syncope (1.2%), and tachycardia (10.8%).

Dermatologic reactions such as pruritus were reported in 2.2% of patients, while rashes occurred in 8.0%. Gastrointestinal reactions included anorexia (18.3%), constipation (26.0%), diarrhea (6.8%), dyspepsia (3.1%), nausea or vomiting (22.9%), weight gain (13.6%), and weight loss (23.2%).

In the genitourinary system, impotence was reported in 3.4% of patients, menstrual complaints in 4.7%, urinary frequency in 2.5%, and urinary retention in 1.9%. Musculoskeletal adverse reactions included arthritis in 3.1% of subjects.

Neurological adverse reactions were prevalent, with dry mouth (27.6%), excessive sweating (22.3%), headache or migraine (25.7%), insomnia (18.6%), and sedation (19.8%) being the most common. Other neurological reactions included akathisia (1.5%), akinesia/bradykinesia (8.0%), impaired sleep quality (4.0%), and tremor (21.1%).

Neuropsychiatric reactions were also significant, with agitation reported in 31.9% of patients, anxiety in 3.1%, confusion in 8.4%, and hostility in 5.6%. Other notable reactions included decreased libido (3.1%), delusions (1.2%), and disturbed concentration (3.1%).

Nonspecific reactions such as fatigue and fever or chills were reported in 5.0% and 1.2% of patients, respectively. Respiratory adverse reactions included upper respiratory complaints in 5.0%.

Additional adverse reactions noted in postmarketing experiences include frequent occurrences of edema and nonspecific rashes, with infrequent reports of chest pain, ECG abnormalities, and shortness of breath. Rare reactions include flushing, pallor, myocardial infarction, and various gastrointestinal complications.

A boxed warning is included, indicating that antidepressants may increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders.

Drug Interactions

The metabolism of bupropion is significantly influenced by the coadministration of other drugs, particularly those that interact with the cytochrome P450 enzyme system. Bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme, which raises the potential for drug interactions with substances that are either substrates or inhibitors of this enzyme.

Pharmacokinetic Interactions:

• CYP2B6 Inhibitors: In vitro studies indicate that paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, ritonavir, and efavirenz may inhibit the hydroxylation of bupropion. Although clinical studies have not been conducted to confirm these findings, caution is advised when bupropion is coadministered with these agents.

• Cimetidine: A study involving 24 healthy volunteers demonstrated that cimetidine did not significantly affect the pharmacokinetics of bupropion and hydroxybupropion. However, it resulted in a 16% and 32% increase in the AUC and C_max of the combined moieties of threohydrobupropion and erythrohydrobupropion, respectively.

• CYP2D6 Substrates: Coadministration of bupropion with drugs metabolized by the CYP2D6 isoenzyme, including certain antidepressants (e.g., 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), should be approached with caution. It is recommended to initiate these medications at the lower end of their dosing range. If bupropion is added to a regimen that includes a CYP2D6 substrate, consideration should be given to reducing the dose of the original medication, especially for those with a narrow therapeutic index.

• Inducers of Metabolism: Certain drugs, such as carbamazepine, phenobarbital, and phenytoin, may induce the metabolism of bupropion, potentially leading to decreased efficacy.

Pharmacodynamic Interactions:

• Seizure Threshold: Coadministration of bupropion with agents that lower the seizure threshold, including antipsychotics, other antidepressants, theophylline, and systemic steroids, should be conducted with extreme caution. It is advisable to start with low initial doses and to increase gradually.

• Levodopa and Amantadine: Limited clinical data suggest an increased incidence of adverse experiences when bupropion is used concurrently with levodopa or amantadine. Caution is warranted, and small initial doses with gradual increases are recommended.

• MAO Inhibitors: Animal studies indicate that the acute toxicity of bupropion may be enhanced by the MAO inhibitor phenelzine.

• Alcohol Consumption: Post-marketing reports have indicated rare neuropsychiatric events and reduced alcohol tolerance in patients consuming alcohol while on bupropion. Therefore, alcohol intake should be minimized or avoided during treatment.

In summary, careful consideration of potential drug interactions is essential when prescribing bupropion, particularly with respect to drugs that affect CYP2B6 and CYP2D6 metabolism, as well as those that may lower seizure thresholds. Monitoring and dosage adjustments may be necessary to ensure patient safety and therapeutic efficacy.

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 tablets in the pediatric population have not been established. Healthcare professionals considering the use of this medication in children or adolescents must carefully weigh the potential risks against the clinical need for treatment.

Geriatric Use

Clinical trials involving bupropion sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 and older, and 47 were aged 75 and older. No overall differences in safety or effectiveness were observed between these elderly patients and younger subjects. However, it is important to note that greater sensitivity to the drug may be present in some older individuals, although this has not been definitively established in reported clinical experiences.

Pharmacokinetic studies indicate that the disposition of bupropion and its metabolites in elderly subjects is similar to that of younger individuals. Nonetheless, other studies have suggested that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites, particularly with single and multiple dosing regimens.

Additionally, the risk of toxic reactions to bupropion may be heightened in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection in this population. It is advisable to monitor renal function to mitigate potential risks associated with bupropion therapy in geriatric patients.

Pregnancy

Pregnant patients should be aware that bupropion is classified as Pregnancy Category C. In animal studies, bupropion was administered orally to rats and rabbits during the period of organogenesis at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively, which are approximately 11 and 7 times the maximum recommended human dose (MRHD) on a mg/m² basis. 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 tested dose of 25 mg/kg/day (approximately equal to the MRHD on a mg/m² basis) 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 (approximately 7 times the MRHD on a mg/m² basis) 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 1,213 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 or bupropion outside of the first trimester. However, these results have not been corroborated.

Bupropion hydrochloride tablets should be prescribed during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Lactation

Bupropion hydrochloride tablets and its metabolites are secreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, lactating mothers should consider whether to discontinue nursing or to discontinue the drug. This decision should take into account the importance of bupropion to the mother’s health and well-being.

Renal Impairment

Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced dose and/or frequency is required, as peak bupropion levels, as well as the area under the curve (AUC), are substantially increased, leading to a higher likelihood of accumulation. The maximum recommended dose for patients with severe hepatic cirrhosis should not exceed 75 mg once daily.

Hepatic Impairment

Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. In this population, a reduced dose and/or frequency is required due to significantly increased peak bupropion levels and area under the curve (AUC) levels, which may lead to accumulation in these patients to a greater extent than usual. Therefore, the dose should not exceed 75 mg once a day for patients with severe hepatic impairment. Regular monitoring of liver function is recommended to assess the safety and efficacy of treatment in these individuals.

Overdosage

In cases of bupropion overdosage, significant clinical manifestations can occur, particularly with doses of 30 g or more. Seizures have been reported in approximately one-third of these cases. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances and arrhythmias. Additionally, symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been observed, particularly in instances of multiple drug overdoses.

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

Management Recommendations

Immediate management of bupropion overdose should focus on ensuring an adequate airway, oxygenation, and ventilation. Continuous monitoring of cardiac rhythm and vital signs is essential. It is advisable to conduct EEG monitoring for the first 48 hours following ingestion to assess for seizure activity. General supportive and symptomatic measures should be implemented, while the induction of emesis is not recommended.

Activated charcoal should be administered to limit further absorption of the drug. There is currently no established experience with forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the context of bupropion overdose, and no specific antidotes are available.

Given the dose-dependent risk of seizures associated with bupropion hydrochloride tablets, hospitalization should be considered following any suspected overdose. Treatment for seizures should involve the administration of intravenous benzodiazepines and other supportive measures as necessary.

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

Nonclinical Toxicology

In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively, during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were noted at doses of 50 mg/kg and higher.

When rats were administered bupropion at oral doses of up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation, there were no 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 exposure to bupropion in the first trimester. 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 first trimester or bupropion outside of the first trimester. The results of this study have not been corroborated. Bupropion hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study, there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower doses were not tested. The question of whether such lesions may be precursors of neoplasms of the liver remains unresolved. Similar liver lesions were not observed in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion produced a borderline positive response in some strains in the Ames bacterial mutagenicity test, with a mutation rate 2 to 3 times that of control. A high oral dose of 300 mg/kg, but not 100 or 200 mg/kg, resulted in a low incidence of chromosomal aberrations in rats. The relevance of these findings in estimating the risk of human exposure to therapeutic doses is unknown.

A fertility study conducted in rats revealed no evidence of impairment of fertility at oral doses up to 300 mg/kg/day.

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 have been observed in individuals attempting to quit smoking while using ZYBAN, with reports indicating that such events can occur in patients both with and without pre-existing psychiatric conditions. Some patients have experienced a worsening of their psychiatric illnesses during treatment.

While most reported symptoms occurred during the course of treatment with ZYBAN, there have been instances where symptoms emerged following the discontinuation of the medication. In many cases, resolution of symptoms was noted after stopping ZYBAN; however, there are reports of persistent symptoms in some individuals. Therefore, it is recommended that ongoing monitoring and supportive care be provided 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 and should be counseled on its appropriate use. A patient Medication Guide is available, which 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 Tablets?” Patients should be advised to read this Medication Guide and should be assisted in understanding its contents.

Patients should be encouraged to be alert to 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 early stages of antidepressant treatment and when the dose is adjusted. Families and caregivers should also be advised to monitor for these symptoms on a day-to-day basis, as changes may occur abruptly, and to report any concerning symptoms to the patient’s prescriber or health professional.

Patients should be informed that quitting smoking, whether using ZYBAN or not, may be associated with nicotine withdrawal symptoms, including depression or agitation, or may exacerbate pre-existing psychiatric conditions. They should be advised to stop taking bupropion and contact a healthcare provider immediately if they experience agitation, hostility, depressed mood, or any atypical changes in thinking or behavior, or if they develop suicidal ideation or behavior.

Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day to minimize the risk of seizure. They should be informed that bupropion hydrochloride tablets should be discontinued and not restarted if they experience a seizure while on treatment. Additionally, patients should be advised to minimize or avoid alcohol consumption during treatment with bupropion hydrochloride tablets.

Patients should be made aware that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. They should refrain from driving or operating complex machinery until they are reasonably certain that bupropion hydrochloride tablets do not adversely affect their performance. Furthermore, patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs, as bupropion hydrochloride tablets and other medications may affect each other’s metabolism. Lastly, patients should notify their physicians if they become pregnant or intend to become pregnant during therapy.

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 20º to 25ºC (68º to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light and moisture to maintain its integrity and efficacy.

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 Contract Pharmacy Services-PA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)