Bupropion hydrochloride

Description

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

The bupropion hydrochloride powder is characterized as white, crystalline, and highly soluble in water, exhibiting a bitter taste and a local anesthetic sensation on the oral mucosa. The extended-release tablets are available for oral administration in strengths of 100 mg, 150 mg, and 200 mg, presented as white to off-white, film-coated, sustained-release tablets. Each tablet contains the specified amount of bupropion hydrochloride, USP, along with inactive ingredients including hydroxypropyl cellulose, saccharin, anhydrous lactose, colloidal silicon dioxide, talc, stearic acid, polyvinyl alcohol, titanium dioxide, and polyethylene glycol 3350. The 100 mg strength complies with USP dissolution test 7, while the 150 mg and 200 mg strengths meet USP dissolution test 2.

Uses and Indications

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

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

Additionally, the efficacy of bupropion hydrochloride extended-release tablets (SR) in maintaining an antidepressant response for up to 44 weeks following an initial 8-week acute treatment phase has been demonstrated in a placebo-controlled trial.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

Bupropion hydrochloride extended-release tablets (SR) should be administered in a manner that minimizes the risk of seizure. A gradual escalation in dosage is recommended to reduce the likelihood of agitation, motor restlessness, and insomnia. These tablets must be swallowed whole and should not be crushed, divided, or chewed.

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

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

For maintenance treatment, it is important to note that acute episodes of depression may necessitate several months or longer of sustained pharmacological therapy.

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

In patients with impaired renal function, bupropion should be used with caution, and a reduced frequency and/or dose may be necessary.

Contraindications

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

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

Patients with a diagnosis of bulimia or anorexia nervosa are contraindicated for treatment with bupropion hydrochloride extended-release tablets (SR) due to an increased risk of seizures associated with the use of bupropion in these populations.

The abrupt discontinuation of alcohol or sedatives, including benzodiazepines, is another contraindication, as it may increase the risk of seizures.

Concurrent use of bupropion hydrochloride extended-release tablets (SR) with monoamine oxidase (MAO) inhibitors is contraindicated. A minimum of 14 days should elapse between the discontinuation of an MAO inhibitor and the initiation of bupropion hydrochloride extended-release tablets (SR).

Lastly, patients with a known allergy to bupropion or any of the excipients in bupropion hydrochloride extended-release tablets (SR) should not use this medication.

Patients experiencing allergic or anaphylactoid reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath, should discontinue use and consult a healthcare professional.

Warnings and Precautions

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

All patients undergoing treatment with antidepressants for any indication should be monitored closely for clinical worsening, suicidality, and unusual behavioral changes, particularly during the initial months of therapy or following any dose adjustments. 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 to report any such symptoms to healthcare providers without delay.

Bupropion is associated with a dose-related risk of seizures, which can be influenced by patient-specific factors, clinical situations, and concomitant medications. Therefore, bupropion should be used with extreme caution in patients with severe hepatic cirrhosis.

Prior to initiating treatment with an antidepressant, patients exhibiting depressive symptoms should be adequately screened to assess the risk of bipolar disorder. Additionally, patients must be advised that bupropion hydrochloride extended-release tablets (SR) should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

While there are no specific laboratory tests recommended for monitoring, it is crucial for patients and caregivers to be vigilant. Patients using bupropion for smoking cessation should be instructed to discontinue the medication and seek immediate medical attention 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 also be advised to stop taking bupropion and consult a healthcare provider if they experience any allergic or anaphylactoid/anaphylactic reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath during treatment.

Side Effects

Patients treated with bupropion hydrochloride extended-release tablets (SR) may experience a range of adverse reactions, which can be categorized by incidence and seriousness.

In clinical trials, the most common adverse events reported at an incidence of 1% or more included headache (26% at 300 mg/day, 25% at 400 mg/day), infection (8% at 300 mg/day, 9% at 400 mg/day), and dry mouth (17% at 300 mg/day, 24% at 400 mg/day). Other notable reactions included nausea (13% at 300 mg/day, 18% at 400 mg/day), insomnia (11% at 300 mg/day, 16% at 400 mg/day), and dizziness (7% at 300 mg/day, 11% at 400 mg/day).

Serious adverse reactions leading to treatment discontinuation were observed, including rash (2.4% at 300 mg/day, 0.9% at 400 mg/day), nausea (0.8% at 300 mg/day, 1.8% at 400 mg/day), and agitation (0.3% at 300 mg/day, 1.8% at 400 mg/day).

Additional adverse reactions reported during clinical development and postmarketing experience included infrequent occurrences of chills, facial edema, and musculoskeletal chest pain. Rare events included malaise and syncope. Cardiovascular events such as postural hypotension and tachycardia were also noted, alongside infrequent reports of abnormal liver function and bruxism in the digestive system.

Patients should be monitored for neuropsychiatric symptoms, including depression and suicidal ideation, particularly during the initial months of treatment or following dose adjustments. A boxed warning highlights the increased risk of suicidality in children, adolescents, and young adults, necessitating close observation for clinical worsening or unusual behavioral changes.

Bupropion is associated with a dose-related risk of seizures, which increases with higher doses and in patients with specific risk factors. It is advised that bupropion be discontinued in any patient who experiences a seizure during treatment.

Overall, while many patients tolerate bupropion well, awareness of these potential adverse reactions is essential for effective monitoring and management.

Drug Interactions

Bupropion exhibits potential drug interactions primarily through its metabolism and effects on various cytochrome P450 isoenzymes.

Pharmacokinetic Interactions

Bupropion is predominantly metabolized by the CYP2B6 isoenzyme to its active metabolite, hydroxybupropion. Concomitant administration of bupropion with drugs that are either substrates or inhibitors of CYP2B6, such as orphenadrine, thiotepa, and cyclophosphamide, may lead to altered drug levels and effects.

Inhibitors of bupropion hydroxylation include paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, ritonavir, and efavirenz. The coadministration of these agents may increase bupropion levels, necessitating careful monitoring and potential dosage adjustments.

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

Conversely, drugs that induce CYP2B6 metabolism, such as carbamazepine, phenobarbital, and phenytoin, may decrease bupropion levels, which could necessitate dosage adjustments of bupropion.

Bupropion and hydroxybupropion are also known in vitro inhibitors of the CYP2D6 isoenzyme. Caution is advised when bupropion is used concurrently with drugs metabolized by CYP2D6, including nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, thioridazine, metoprolol, propafenone, and flecainide, as this may lead to increased plasma concentrations of these medications.

Pharmacodynamic Interactions

Coadministration of bupropion with drugs that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids, should be approached with extreme caution due to the increased risk of seizures.

Limited clinical data indicate a higher incidence of adverse experiences when bupropion is used concurrently with levodopa or amantadine. If these combinations are necessary, it is recommended to initiate treatment with small doses and to increase gradually.

In postmarketing reports, there have been rare instances of adverse 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 with bupropion.

Overall, careful monitoring and consideration of dosage adjustments are recommended when bupropion is used in conjunction with other medications, particularly those affecting CYP2B6 and CYP2D6 pathways or those that may lower seizure thresholds.

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 with the clinical need for treatment.

Geriatric Use

Clinical trials involving bupropion hydrochloride extended-release tablets (SR) included approximately 6,000 patients, of which 275 were aged 65 and older, and 47 were aged 75 and older. Additionally, several hundred patients aged 65 and over participated in clinical trials utilizing the immediate-release formulation of bupropion for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects in these studies. 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 available data.

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 regimens.

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 ensure safe and effective use of bupropion in geriatric patients.

Pregnancy

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. 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) and higher. Additionally, decreased fetal weights were noted at doses of 50 mg/kg/day and above. In a separate study involving rats, administration of bupropion at oral doses up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

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

Bupropion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

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

Renal Impairment

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

Hepatic Impairment

Bupropion should be used with extreme caution in patients with severe hepatic cirrhosis. In this population, a reduced frequency and/or dose is required due to significantly increased peak bupropion levels and area under the curve (AUC) levels, which may lead to greater accumulation than usual. The maximum recommended dose for patients with severe hepatic impairment should not exceed 100 mg per day or 150 mg every other day. 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.

Overdosage Management

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

Activated charcoal should be administered to the patient. There is currently no established experience with the use of 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, hospitalization should be considered following any suspected overdose. Based on animal studies, it is recommended that seizures be managed with intravenous benzodiazepines and other supportive measures as deemed appropriate.

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

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice at doses up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, which is approximately 2 to 7 times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. 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 administered doses up to 300 mg/kg/day demonstrated no evidence of impaired fertility.

Bupropion exhibited a positive response in the Ames bacterial mutagenicity test, showing a mutation rate that was 2 to 3 times higher than the control in 2 of 5 strains tested. Additionally, an increase in chromosomal aberrations was observed in 1 of 3 in vivo rat bone marrow cytogenetic studies.

No information is available regarding teratogenic effects or animal pharmacology and toxicology.

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. Patients undergoing treatment with bupropion for smoking cessation should be closely monitored for neuropsychiatric symptoms, which may manifest as changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempts.

In the postmarketing experience, symptoms such as worsening of pre-existing psychiatric conditions and completed suicides have been documented in some individuals attempting to quit smoking while using ZYBAN. Most reported symptoms occurred during treatment; however, some cases were noted following the discontinuation of ZYBAN. While many cases indicated a resolution of symptoms after stopping the medication, there were instances where 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, emphasizing the importance of appropriate use. A Medication Guide is available that covers critical topics such as “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)?”

Patients should be advised to alert their prescriber if they experience any symptoms such as 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. Families and caregivers should be encouraged to monitor for the emergence of these symptoms on a day-to-day basis and report any concerns to the healthcare provider.

For patients using bupropion for smoking cessation, it is crucial 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 also be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN, which is used as an aid to smoking cessation treatment. Therefore, bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride.

Patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures. If a patient experiences a seizure while on treatment, bupropion should be discontinued and not restarted. Additionally, patients should be advised that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) 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 certain that bupropion does not adversely affect their performance.

Patients should also be advised to minimize or avoid alcohol consumption while taking bupropion, as excessive use or abrupt discontinuation of alcohol may alter the seizure threshold. It is important for patients to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs, as bupropion and other drugs may affect each other’s metabolism. Furthermore, patients should notify their physicians if they become pregnant or intend to become pregnant during therapy. Lastly, patients should be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole and not chew, divide, or crush the tablets.

Storage and Handling

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

Additional Clinical Information

There are no specific laboratory tests recommended for patients. Additionally, there is no further information available regarding abuse 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)