Bupropion hydrochloride

Description

Bupropion hydrochloride 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 compound appears as a white or almost white crystalline powder, exhibiting high solubility in water. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated in tablet form for oral administration, available in dosages of 75 mg and 100 mg. Each tablet contains inactive ingredients including anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid, titanium dioxide, and triacetin. The 75 mg tablets also contain synthetic red iron oxide and synthetic yellow iron oxide, while the 100 mg tablets include FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder. The efficacy of bupropion has been established through three placebo-controlled trials, which included two studies of approximately 3 weeks’ duration involving depressed inpatients and one study of approximately 6 weeks’ duration involving depressed outpatients. The depressive disorder in the studied populations 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, occurring nearly every day for at least 2 weeks. This condition should 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 for long-term use, defined as treatment extending beyond 6 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 medication should be administered three times daily, with at least 6 hours between successive doses.

For adults, the usual starting dose is 200 mg per day, divided into two doses of 100 mg each. Based on clinical response, this dose may be increased to 300 mg per day, administered as 100 mg three times daily, no sooner than 3 days after initiating therapy.

If there is no clinical improvement after several weeks at the 300 mg per day dosage, an increase up to a maximum of 450 mg per day may be considered. This higher dosage can be achieved using either the 75 mg or 100 mg tablets, with the 100 mg tablet requiring administration four times daily, ensuring at least 4 hours between doses.

For patients with severe hepatic cirrhosis, the dosage should not exceed 75 mg once daily. Caution is advised in patients with hepatic impairment, and a reduced frequency and/or dose should be considered. Similarly, in patients with renal impairment, caution is warranted, and adjustments to frequency and/or dosage may be necessary.

Contraindications

Bupropion is contraindicated in the following situations:

• Patients with a seizure disorder, as the use of bupropion may increase the risk of seizures.

• Patients currently receiving treatment with ZYBAN (bupropion hydrochloride) Sustained-Release Tablets, WELLBUTRIN SR (bupropion hydrochloride), WELLBUTRIN XL (bupropion hydrochloride), or any other medications containing bupropion, due to the dose-dependent incidence of seizures.

• 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.

• Concurrent administration with monoamine oxidase (MAO) inhibitors is contraindicated; a minimum of 14 days should elapse between discontinuation of an MAO inhibitor and initiation of bupropion treatment.

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

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

Warnings and Precautions

Antidepressants have been associated with an increased risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults aged 18 to 24 who are diagnosed with major depressive disorder (MDD) and other psychiatric disorders. It is imperative that patients of all ages who initiate antidepressant therapy are monitored closely for any clinical worsening, emergence of suicidality, or unusual changes in behavior.

Patients with MDD may experience a worsening of their condition or the emergence of suicidal ideation and behavior, regardless of whether they are receiving antidepressant treatment. Therefore, all patients undergoing treatment with antidepressants for any indication should be closely observed, particularly during the initial months of therapy or following any dose adjustments. Families and caregivers play a crucial role in this monitoring process and should be informed of the need to watch for signs of agitation, irritability, or any unusual behavioral changes. Immediate reporting of such symptoms to healthcare providers is essential.

In the context of bupropion, serious neuropsychiatric events, including depression, suicidal ideation, suicide attempts, and completed suicides, have been reported among patients using this medication for smoking cessation. Patients and caregivers should be advised to discontinue bupropion and seek immediate medical attention if they observe any signs of agitation, hostility, depressed mood, or atypical changes in thinking or behavior, as well as any development of suicidal ideation or behavior.

In cases where a patient’s depression worsens persistently or where there are emergent symptoms indicative of suicidality or precursors to worsening depression, consideration should be given to modifying the therapeutic regimen, which may include discontinuation of the medication.

There are no specific laboratory tests recommended for monitoring patients on antidepressants. However, the emphasis remains on vigilant clinical observation and communication between patients, caregivers, and healthcare providers to ensure safety and timely intervention.

Side Effects

Patients may experience a range of adverse reactions while using the medication, which can be categorized into common and serious reactions.

Common adverse reactions include agitation (31.9%), dry mouth (27.6%), insomnia (18.6%), headache/migraine (25.7%), nausea/vomiting (22.9%), constipation (26%), and tremor (21.1%). Other frequently reported reactions are anorexia (18.3%), excessive sweating (22.3%), and fatigue (5%).

Serious adverse reactions have been observed in clinical trials and postmarketing experiences. Neuropsychiatric disturbances occurred in 3% of participants, primarily manifesting as agitation and abnormalities in mental status. Gastrointestinal disturbances were reported in 2.1% of subjects, mainly involving nausea and vomiting. Neurological disturbances, including seizures, headaches, and sleep disturbances, were noted in 1.7% of patients. Dermatologic problems, primarily rashes, were reported in 1.4% of participants.

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 were noted in 8%. Gastrointestinal issues included diarrhea (6.8%), dyspepsia (3.1%), and weight changes, with weight gain reported in 13.6% and weight loss in 23.2% of subjects.

In the genitourinary category, impotence was reported in 3.4% of patients, with menstrual complaints noted in 4.7%. Neurological reactions included akathisia (1.5%), akinesia/bradykinesia (8%), and sensory disturbances (4%).

Additional adverse reactions reported infrequently include edema, chest pain, ECG abnormalities, and shortness of breath/dyspnea. Rare events include flushing, pallor, phlebitis, and myocardial infarction.

Patients should be monitored for these adverse reactions, and any serious or concerning symptoms should be reported to a healthcare provider promptly.

Drug Interactions

Concomitant administration of bupropion with other drugs may influence its clinical activity due to its extensive metabolism. Bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme, which suggests potential interactions with drugs that are 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 no clinical studies have confirmed these findings, caution is advised when coadministering these agents with bupropion.

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

• Inducers of Metabolism: Certain drugs, such as carbamazepine, phenobarbital, and phenytoin, may induce the metabolism of bupropion. While not systematically studied, this could lead to clinically significant alterations in the blood levels of bupropion and coadministered drugs.

• 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

• Seizure Threshold: Caution is warranted when bupropion is administered concurrently with agents that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids. It is recommended to initiate treatment with low doses and to increase the dosage gradually.

• Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse experiences when bupropion is used with levodopa or amantadine. Therefore, coadministration should be approached with caution, starting with small initial doses and gradual increases.

• MAO Inhibitors: Animal studies indicate that the acute toxicity of bupropion may be enhanced by the MAO inhibitor phenelzine. Caution is advised when these agents are used together.

• Alcohol: Post-marketing reports have indicated rare adverse neuropsychiatric events and reduced alcohol tolerance in patients consuming alcohol during bupropion treatment. It is recommended that alcohol consumption be minimized or avoided during therapy with bupropion.

In summary, careful consideration and monitoring are advised when bupropion is coadministered with other medications, particularly those affecting CYP2B6 metabolism, seizure threshold, or those that may interact pharmacodynamically.

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 should carefully consider the potential risks associated with its use in children and adolescents against the clinical need before prescribing this medication.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were represented in clinical trials of bupropion hydrochloride sustained-release tablets, with 275 participants aged 65 and over and 47 participants aged 75 and over. No overall differences in safety or effectiveness were observed between these elderly subjects 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 ruled out based on clinical experience.

Pharmacokinetic studies indicate that the disposition of bupropion and its metabolites in elderly subjects is similar to that of younger subjects. Nonetheless, findings from another pharmacokinetic study suggest 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 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 a Pregnancy Category C medication. Animal studies have shown that when bupropion was administered orally to rats and rabbits during the organogenesis period, no clear evidence of teratogenic activity was observed. However, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at doses starting from 25 mg/kg/day, which is approximately equal to the maximum recommended human dose (MRHD) on a mg/m² basis, and at higher doses. Additionally, decreased fetal weights were noted at doses of 50 mg/kg/day and above.

In a study involving rats, administration of bupropion at doses up to 300 mg/kg/day (approximately seven 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 has been conducted in pregnant women to assess the risk of congenital malformations, including cardiovascular malformations, following first trimester exposure to bupropion. 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, when comparing first trimester exposure to bupropion with exposure to other antidepressants in the same period, as well as bupropion exposure outside of the first trimester. However, these results have not been corroborated by further studies.

Given the potential risks, bupropion should be prescribed during pregnancy only if the potential benefits outweigh the risks to the fetus. Healthcare professionals are advised to carefully consider the individual circumstances of pregnant patients when recommending this medication.

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.

Renal Impairment

Bupropion 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 substantially increased peak bupropion levels and area under the curve (AUC), which may lead to significant accumulation. The maximum recommended dose for these patients is 75 mg once daily. Monitoring for potential adverse effects is advised in patients with reduced kidney function 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 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 than typically observed. The maximum recommended dose for patients with severe hepatic impairment should not exceed 75 mg once daily. Close monitoring of these patients is advised 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.

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-related risk of seizures associated with bupropion, 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 also important 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 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 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 evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. In contrast, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either species.

A fertility study in rats indicated no evidence of impairment of fertility at oral doses up to 300 mg/kg/day. Bupropion demonstrated a borderline positive response in some strains during the Ames bacterial mutagenicity test, with mutation rates 2 to 3 times higher than 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 implications of these findings for assessing the risk of human exposure to therapeutic doses remain uncertain.

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 preexisting psychiatric conditions and completed suicides, have been documented in individuals attempting to quit smoking while using ZYBAN. Most reported symptoms occurred during treatment; however, some cases were noted following the discontinuation of ZYBAN.

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, resolution of symptoms was noted after discontinuation of ZYBAN, although 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, and they should receive counseling on its appropriate use. A patient Medication Guide is available, which includes important information regarding “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 alert their prescriber if they experience any of the following while taking bupropion: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, or other unusual changes in behavior, as well as worsening of depression and suicidal ideation, particularly early during antidepressant treatment and when the dose is adjusted.

It is important to inform patients that quitting smoking, whether with or without ZYBAN, may be associated with nicotine withdrawal symptoms, including depression or agitation, or may exacerbate preexisting psychiatric conditions. Patients should be advised to stop taking bupropion and contact a healthcare provider immediately if they develop agitation, hostility, depressed mood, or any atypical changes in thinking or behavior, or if they experience suicidal ideation or behavior.

Patients should be instructed to take bupropion in equally divided doses 3 or 4 times a day to minimize the risk of seizure. They should also be informed that bupropion should be discontinued and not restarted if they experience a seizure while on treatment.

Additionally, patients should be made aware that any CNS-active drug, including bupropion, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Therefore, they should refrain from driving or operating complex, hazardous machinery until they are reasonably certain that bupropion does not adversely affect their performance.

Patients should be advised that excessive use or abrupt discontinuation of alcohol or sedatives, including benzodiazepines, may alter the seizure threshold. Furthermore, they should inform their physicians if they are taking or plan to take any prescription or over-the-counter medications, as bupropion and other drugs 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 that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, the product must be protected 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 H. J. Harkins Company, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)