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 as tablets for oral administration, available in strengths 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 essential to reduce the likelihood of agitation, motor restlessness, and insomnia. No single dose should exceed 150 mg. The recommended administration schedule is 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. This initial 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. When using the 100 mg tablet, it must be administered 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 a reduced frequency and/or dose should be considered.

In patients with impaired renal function, caution is also recommended, and a reduced frequency and/or dose should be evaluated.

Contraindications

Bupropion is contraindicated in the following situations:

Patients with a seizure disorder should not use bupropion due to the risk of seizures. Additionally, bupropion hydrochloride tablets are contraindicated in individuals currently treated with ZYBAN (bupropion hydrochloride) Sustained-Release Tablets, WELLBUTRIN SR (bupropion hydrochloride), WELLBUTRIN XL (bupropion hydrochloride), 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 also contraindicated for bupropion use, given the increased risk of seizures in this population. Furthermore, bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives, including benzodiazepines, due to the potential for seizure activity.

The concurrent administration of bupropion 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 bupropion treatment. Lastly, bupropion is contraindicated in patients with a known allergic response to bupropion or any of the other ingredients in bupropion hydrochloride tablets.

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 signs of clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be informed of the importance of maintaining close observation and open communication with the prescribing healthcare provider.

Patients diagnosed 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 must be monitored diligently for clinical deterioration, suicidality, and atypical behavioral changes, particularly during the initial months of therapy or following any adjustments in dosage. Families and caregivers play a crucial role in this monitoring process and should be vigilant for signs of agitation, irritability, or any unusual behavioral changes, reporting these symptoms to healthcare providers without delay.

In cases where patients using bupropion for smoking cessation exhibit agitation, hostility, depressed mood, or any atypical changes in thinking or behavior, it is essential that they discontinue the medication and seek immediate medical assistance. Additionally, if suicidal ideation or behavior develops, prompt communication with a healthcare provider is critical.

Consideration should be given to modifying the therapeutic regimen, which may include discontinuation of the medication, for patients whose depression remains persistently worse or who display emergent suicidality or symptoms indicative of potential worsening depression or suicidality.

Currently, there are no specific laboratory tests recommended for monitoring patients on antidepressants.

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 fatigue (5%), upper respiratory complaints (5%), and blurred vision (14.6%).

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, primarily 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 anorexia (18.3%), weight gain (13.6%), and weight loss (23.2%), with diarrhea occurring in 6.8% of subjects.

In the genitourinary category, impotence was reported in 3.4% of patients, and menstrual complaints were noted in 4.7%. Neurological reactions included akathisia (1.5%), akinesia/bradykinesia (8%), and excessive sweating (22.3%).

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 medications may lead to significant drug interactions, primarily due to its metabolism and effects on the central nervous system.

Pharmacokinetic Interactions

Bupropion is extensively metabolized, primarily by the CYP2B6 isoenzyme, which suggests potential interactions with drugs that are substrates or inhibitors of this enzyme. Notable examples include orphenadrine, thiotepa, and cyclophosphamide. In vitro studies indicate that paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, ritonavir, and efavirenz may inhibit the hydroxylation of bupropion, although clinical studies to confirm these findings are lacking.

Cimetidine has been studied in healthy volunteers and was found to have no significant effect on the pharmacokinetics of bupropion and its active metabolites. However, it did result in a 16% increase in the AUC and a 32% increase in Cmax for the combined moieties of threohydrobupropion and erythrohydrobupropion.

Certain drugs, such as carbamazepine, phenobarbital, and phenytoin, may induce the metabolism of bupropion, potentially leading to decreased efficacy. While multiple doses of bupropion did not significantly affect the pharmacokinetics of lamotrigine, caution is advised due to the potential for clinically important alterations in the blood levels of coadministered drugs.

Pharmacodynamic Interactions

The acute toxicity of bupropion may be enhanced by the MAO inhibitor phenelzine. Additionally, there is limited clinical evidence suggesting a higher incidence of adverse effects when bupropion is used concurrently with levodopa or amantadine. Therefore, when bupropion is prescribed alongside these medications, it is recommended to initiate treatment with small doses and to increase the dosage gradually.

Caution is also warranted when bupropion is administered with agents that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids. In these cases, it is advisable to start with low initial doses and to make gradual increases.

In post-marketing experience, rare reports have indicated adverse neuropsychiatric events or reduced alcohol tolerance in patients consuming alcohol during bupropion treatment. Consequently, it is recommended that alcohol consumption be minimized or avoided during the course of treatment with bupropion.

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

Elderly patients, defined as those aged 65 years 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. Additionally, several hundred patients aged 65 and older were included in studies utilizing the immediate-release formulation of bupropion for depression.

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects in these trials. 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, other studies have suggested that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites, particularly in the context of single and multiple dosing.

Given that bupropion is extensively metabolized in the liver and excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function. Since elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection in this population. Monitoring of renal function may be beneficial 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 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 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 first trimester and to bupropion outside of the first trimester. It is important to note that 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 against the potential risks to the nursing infant.

Renal Impairment

Bupropion 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. Monitoring for potential adverse effects is advised in this population due to the increased risk associated with elevated drug levels.

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. Specifically, the dose should not exceed 75 mg once daily in patients with severe hepatic impairment. Regular monitoring of liver function is recommended to assess the safety and efficacy of bupropion in these patients.

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 fatalities linked to bupropion overdoses, particularly in those who ingested large quantities. Reports indicate that these patients 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 to manage the overdose. There is currently no established experience with forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the treatment of bupropion overdoses, and no specific antidotes for bupropion are known.

Given the dose-related risk of seizures associated with bupropion, hospitalization should be considered following a suspected overdose. Based on animal studies, seizures should be treated with intravenous benzodiazepines and other supportive measures as appropriate.

It is important to consider the potential for multiple drug involvement in cases of overdose. 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 performed in rats indicated no evidence of impairment of fertility at oral doses up to 300 mg/kg/day.

Bupropion exhibited a borderline positive response in some strains during the Ames bacterial mutagenicity test, with mutation rates observed to be 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. 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, 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 and should be counseled 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, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted.

It is important to inform patients that quitting smoking, with or without ZYBAN, may be associated with nicotine withdrawal symptoms, including depression or agitation, or exacerbation of preexisting psychiatric illness. Patients should be advised to stop taking bupropion and contact a healthcare provider immediately if they develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if they develop 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 advised that excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold.

Patients should be encouraged to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Furthermore, patients should be advised to 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 should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. 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)