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 C13H18ClNO•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 bupropion hydrochloride tablet, formulated for oral administration, contains either 75 mg or 100 mg of bupropion hydrochloride. The tablets also include 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. It is essential to gradually escalate the dosage to mitigate potential side effects such as agitation, motor restlessness, and insomnia. Increases in dosage should not exceed 100 mg per day within a 3-day period, and no single dose should exceed 150 mg. The recommended administration schedule is three times daily, with at least 6 hours between doses.

For adults, the usual starting dose is 200 mg per day, divided into two doses of 100 mg each. After a minimum of 3 days, the dosage may be increased to 300 mg per day, administered as 100 mg three times daily. The maximum allowable dosage is 450 mg per day, which must be given in divided doses not exceeding 150 mg each. If the 100 mg tablet is used, it should be taken four times daily with at least 4 hours between doses.

In patients 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 dosage. Similarly, in patients with renal impairment, caution is warranted, and adjustments to frequency and/or dosage may be necessary.

Contraindications

Bupropion hydrochloride tablets are contraindicated in the following situations:

• Patients with a seizure disorder, due to the risk of seizures associated with bupropion use.

• Patients currently treated with ZYBAN (bupropion hydrochloride) Sustained-Release Tablets, Wellbutrin SR (sustained-release formulation), Wellbutrin XL (extended-release formulation), 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, as these conditions are associated with a higher incidence of seizures when treated with bupropion.

• Patients undergoing abrupt discontinuation of alcohol or sedatives, including benzodiazepines, due to the increased risk of seizures.

• Patients using monoamine oxidase inhibitors (MAOIs) for psychiatric disorders, or those who have stopped MAOIs within the past 14 days, as this combination increases the risk of hypertensive reactions. Additionally, starting bupropion in patients treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated.

• Patients with a known allergy to bupropion or any of the other ingredients in bupropion hydrochloride tablets.

Patients should discontinue use and consult a healthcare professional if they experience any allergic or anaphylactoid reactions during treatment.

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. 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 receiving antidepressants for any indication must be monitored closely for clinical worsening, suicidality, and unusual behavioral changes. This vigilance is especially critical during the initial months of treatment or when there are changes in dosage. Families and caregivers should be informed of the necessity to observe patients for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality, and they should be encouraged to report any concerning symptoms to healthcare providers immediately.

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

General precautions should be taken into account, as a substantial proportion of patients treated with bupropion hydrochloride tablets may experience increased restlessness, agitation, anxiety, and insomnia, particularly shortly after treatment initiation. Additionally, depressed patients may exhibit a range of neuropsychiatric symptoms, including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion. It is also important to recognize that antidepressants can precipitate manic episodes in patients with bipolar disorder during depressive phases and may activate latent psychosis in other susceptible individuals.

While there are no specific laboratory tests recommended for monitoring patients on bupropion hydrochloride tablets, healthcare providers should remain vigilant for any adverse effects. Patients and caregivers should be advised to seek emergency medical assistance if the patient using bupropion for smoking cessation experiences agitation, hostility, depressed mood, or any atypical changes in thinking or behavior, 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 undergoing treatment. Common adverse reactions include agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.

Serious adverse reactions have been reported, with neuropsychiatric disturbances occurring in approximately 3.0% of patients, primarily manifesting as 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 patients, while dermatologic problems, primarily rashes, occurred in 1.4% of patients.

In placebo-controlled clinical trials, the incidence of treatment-emergent adverse experiences varied across different systems. Cardiovascular events included 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 included pruritus (2.2%) and rash (8.0%). Gastrointestinal reactions were notably frequent, with anorexia (18.3%), constipation (26.0%), and nausea/vomiting (22.9%) being the most common. Other gastrointestinal issues included diarrhea (6.8%), dyspepsia (3.1%), weight gain (13.6%), and weight loss (23.2%).

Genitourinary adverse reactions included impotence (3.4%), menstrual complaints (4.7%), urinary frequency (2.5%), and urinary retention (1.9%). Musculoskeletal issues such as arthritis were reported in 3.1% of patients. Neurological adverse reactions were also significant, with akathisia (1.5%), akinesia/bradykinesia (8.0%), dry mouth (27.6%), excessive sweating (22.3%), headache/migraine (25.7%), insomnia (18.6%), and tremor (21.1%) being among the most frequently reported.

Neuropsychiatric reactions were prevalent, with agitation reported in 31.9% of patients, along with anxiety (3.1%), confusion (8.4%), and hostility (5.6%). Nonspecific reactions included fatigue (5.0%) and upper respiratory complaints (5.0%). Special senses were affected as well, with auditory disturbances (5.3%) and blurred vision (14.6%) reported.

Additional adverse reactions noted in postmarketing experiences included frequent edema and infrequent occurrences of chest pain, ECG abnormalities, and shortness of breath. Rare events included flushing, pallor, and myocardial infarction. Dermatologic reactions such as nonspecific rashes were frequent, while alopecia and dry skin were infrequent. Gastrointestinal issues like dysphagia and liver damage were infrequent, with rare occurrences of gastrointestinal bleeding and intestinal perforation.

Patients should be aware of the boxed warning regarding suicidality and antidepressant drugs, as there is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults. Monitoring for clinical worsening, suicidality, or unusual changes in behavior is advised. Additionally, patients may experience clinical worsening and emergence of suicidal ideation when treating psychiatric disorders. Serious neuropsychiatric symptoms have also been reported in patients taking bupropion for smoking cessation.

Seizures have been associated with bupropion, occurring in approximately 0.4% of patients treated at doses up to 450 mg/day, with an increased risk at higher doses.

Drug Interactions

The coadministration of bupropion with other medications may significantly influence its clinical efficacy due to its extensive metabolism. Bupropion is primarily metabolized to hydroxybupropion via the CYP2B6 isoenzyme, which presents a potential for drug interactions with other agents that are substrates, inhibitors, or inducers of this enzyme.

Pharmacokinetic Interactions

CYP2B6 Inhibitors In vitro studies indicate that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir may inhibit the hydroxylation of bupropion. However, clinical studies to confirm these findings are lacking.

Cimetidine The pharmacokinetics of bupropion and its active metabolites were unaffected by cimetidine in a study involving 24 healthy volunteers. Nevertheless, there were observed increases of 16% and 32% in the AUC and C_max, respectively, for the combined moieties of threohydrobupropion and erythrohydrobupropion.

Inducers of CYP2B6 Ritonavir (at doses of 100 mg or 600 mg twice daily), as well as ritonavir combined with lopinavir (KALETRA), significantly reduced the exposure of bupropion and its metabolites by approximately 20% to 80%, depending on the dosage. Similarly, efavirenz (600 mg once daily) reduced bupropion exposure by about 55%. These interactions suggest that patients receiving these medications may require increased doses of bupropion, although the maximum recommended dose should not be exceeded. Other drugs that may induce bupropion metabolism include carbamazepine, phenobarbital, and phenytoin.

Lamotrigine Multiple oral doses of bupropion did not significantly affect the pharmacokinetics of a single dose of lamotrigine in a study involving 12 healthy volunteers.

Pharmacodynamic Interactions

Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs with bupropion is contraindicated due to the increased risk of hypertensive reactions, as bupropion inhibits the reuptake of dopamine and norepinephrine.

Levodopa and Amantadine Limited clinical data suggest a higher incidence of adverse effects when bupropion is used with levodopa or amantadine. Caution is advised when administering bupropion to patients on these medications, with recommendations for small initial doses and gradual dose increases.

Seizure Threshold Lowering Agents 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.

Alcohol Interaction

Post-marketing reports have indicated rare neuropsychiatric events and reduced alcohol tolerance in patients consuming alcohol while on bupropion. Therefore, it is advisable to minimize or avoid alcohol consumption during treatment.

Urine Drug Screening

Patients taking bupropion may experience false-positive results on urine immunoassay screening tests for amphetamines due to the lack of specificity of some tests. Confirmatory testing, such as gas chromatography/mass spectrometry, is recommended to differentiate bupropion from amphetamines, even after discontinuation of therapy.

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

Geriatric Use

Clinical trials involving approximately 6,000 patients, including 275 individuals aged 65 and older and 47 aged 75 and older, have been conducted with bupropion sustained-release tablets for the treatment of depression and smoking cessation. The data indicate no overall differences in safety or effectiveness between elderly patients and younger subjects. However, it is important to note that greater sensitivity to the drug may be present in some older individuals, which cannot be entirely ruled out.

Pharmacokinetic studies have shown that the disposition of bupropion and its metabolites in elderly subjects is comparable to that of younger subjects. Nonetheless, findings from another pharmacokinetic study, which included both single and multiple doses, suggest that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites.

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 may be beneficial 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 significantly higher than the maximum recommended human dose (MRHD). While no clear evidence of teratogenic activity was observed in these studies, rabbits exhibited slightly increased incidences of fetal malformations and skeletal variations at the lowest tested dose of 25 mg/kg/day, which is approximately equal to the MRHD on a mg/m² basis. Additionally, decreased fetal weights were noted at doses of 50 mg/kg/day and higher.

In a 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 7,005 infants assessed the risk of congenital malformations, including cardiovascular malformations, following exposure to bupropion in the first trimester. Among these, 1,213 infants were exposed to bupropion during this critical period. The study found no increased risk for congenital malformations overall or specifically for cardiovascular malformations when comparing first trimester exposure to bupropion with exposure to other antidepressants in the same timeframe, as well as bupropion exposure outside of the first trimester. However, it is important to note that the results of this study have not been corroborated.

Bupropion hydrochloride tablets should be prescribed during pregnancy only if the potential benefits to the mother 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, lactating mothers should consider whether to discontinue breastfeeding or to discontinue the drug, weighing the importance of the medication to the mother against the potential risks to the nursing infant.

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 greater accumulation of the drug than typically observed. For patients with severe hepatic impairment, the dose should not exceed 75 mg once daily. Close monitoring of these patients is recommended to assess for potential adverse effects and to ensure safe use of the medication.

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, severe 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, fatalities have been associated with bupropion overdoses, particularly in those who ingested large quantities. Reports indicate that patients who succumbed to overdose experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of an overdose, it is crucial 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 management 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-dependent risk of seizures associated with bupropion hydrochloride tablets, hospitalization should be considered following any suspected overdose. Based on animal studies, seizures should be treated with intravenous benzodiazepines and other supportive measures as deemed appropriate.

It is important to consider the potential for multiple drug involvement when managing an overdose. Physicians are encouraged to contact a poison control center for further guidance on the treatment of any overdose. 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 mg/kg/day and 150 mg/kg/day, respectively, during the period of organogenesis. No clear evidence of teratogenic activity was observed in either species. However, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day), which is approximately equal to the maximum recommended human dose (MRHD) on a mg/m² basis, and at higher doses. Decreased fetal weights were noted at doses of 50 mg/kg/day and above.

When rats were administered bupropion at oral doses of up to 300 mg/kg/day, approximately seven 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.

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 to bupropion outside of the first trimester. These results 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 mg/kg/day and 150 mg/kg/day, respectively. 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; lower doses were not tested. The potential for these lesions to serve as precursors to neoplasms of the liver remains unresolved. No similar liver lesions were noted in the mouse study, and no increase in malignant tumors of the liver or other organs was observed 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 the control. Additionally, 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. These events include, but are not limited to, depression, suicidal ideation, suicide attempts, and completed suicides. In the postmarketing experience, symptoms such as agitation, hostility, depressed mood, and suicide-related events—including ideation, behavior, and attempts—have been observed in some patients attempting to quit smoking while using ZYBAN.

Most reported symptoms occurred during treatment with ZYBAN; however, some cases were noted following the discontinuation of the medication. These events have been documented in patients both with and without pre-existing psychiatric conditions, with some individuals experiencing a worsening of their psychiatric illnesses. Notably, patients with serious psychiatric disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, were not included in the premarketing studies of ZYBAN.

In many instances, resolution of symptoms was reported after discontinuation of ZYBAN, although in some cases, symptoms persisted. Therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

Patient Counseling

Patients, their families, and caregivers should be informed about the risks of suicidality and clinical worsening associated with the use of bupropion hydrochloride, particularly during the initial treatment period and when doses are adjusted. It is essential for healthcare providers to monitor patients for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior.

Families and caregivers should be advised to observe patients closely for any changes in mood or behavior and to report any concerning symptoms to the healthcare provider immediately. For patients using bupropion for smoking cessation, it is important to instruct them to stop taking the medication and contact a healthcare provider if they experience agitation, hostility, depressed mood, or any changes in thinking or behavior that are not typical for them, or if they develop suicidal ideation or behavior.

Patients should be informed that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in combination with ZYBAN or any other medications containing bupropion. They should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day to minimize the risk of seizure. Additionally, patients should be advised that bupropion hydrochloride tablets should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be cautioned that bupropion hydrochloride tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills, and they should refrain from driving or operating complex machinery until they are certain of how the medication affects them. It is also advisable for patients to minimize or avoid alcohol consumption while taking bupropion hydrochloride tablets, as excessive use or abrupt discontinuation of alcohol may alter the seizure threshold.

Finally, patients should be encouraged to inform their healthcare provider about all medications they are taking, including prescription and over-the-counter drugs, as well as any plans 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. Care must be taken to protect the product from light and moisture to ensure 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 potential, 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)