Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (SR), are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressants. The chemical structure is designated as (±)-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 active pharmaceutical ingredient is presented as a white, crystalline powder that is highly soluble in water, exhibiting a bitter taste and a local anesthetic effect on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration and are available in three strengths: 100 mg (yellow), 150 mg (pale yellow), and 200 mg (pale yellow). Each film-coated, sustained-release tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including copovidone, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, titanium dioxide, and triacetin. The 100 mg tablets also contain D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Aluminum Lake, while the 150 mg and 200 mg tablets include iron oxide yellow. The dissolution of the tablets is evaluated using USP Dissolution Test 2.

Uses and Indications

Bupropion hydrochloride extended-release tablets, USP (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 DSM-IV criteria, 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, USP (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.

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 essential to continue pharmacological therapy for several months or longer following the response to acute episodes of depression. Patients should be periodically reassessed to determine the necessity for ongoing maintenance treatment and to establish the appropriate dosage.

In patients with impaired hepatic function, bupropion should be used with extreme caution, particularly in those with severe hepatic cirrhosis. In such cases, the dosage should not exceed 100 mg daily or 150 mg every other day. Caution is also advised for patients with mild-to-moderate hepatic cirrhosis, where a reduced frequency and/or dosage may be warranted.

For patients with impaired renal function, bupropion should be used with caution, and consideration should be given to reducing the frequency and/or dosage as appropriate.

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 ZYBAN (bupropion hydrochloride) Sustained-Release Tablets, WELLBUTRIN (bupropion hydrochloride) immediate-release formulation, WELLBUTRIN XL (bupropion hydrochloride) extended-release formulation, or any other medications containing bupropion, as the incidence of seizures is dose dependent.

Additionally, patients with a current or prior diagnosis of bulimia or anorexia nervosa are contraindicated for use, given the increased incidence of seizures associated with bupropion treatment in bulimia cases. The abrupt discontinuation of alcohol or sedatives, including benzodiazepines, also contraindicates the use of these tablets due to seizure risk.

Concurrent administration with monoamine oxidase (MAO) inhibitors is contraindicated; a minimum of 14 days must elapse between the discontinuation of an MAO inhibitor and the initiation of bupropion hydrochloride extended-release tablets (SR). Lastly, patients with a known allergic response 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 during treatment, should discontinue use and consult a healthcare professional.

Warnings and Precautions

Patients 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, regardless of whether they are receiving antidepressant therapy. 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-dependent risk of seizures, which can be influenced by patient-specific factors, clinical situations, and concomitant medications. Therefore, bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. Additionally, patients should be advised against using bupropion hydrochloride extended-release tablets (SR) in conjunction with ZYBAN or any other medications containing bupropion.

Patients with serious psychiatric illnesses, such as schizophrenia, bipolar disorder, and major depressive disorder, were not included in the pre-marketing studies of ZYBAN. Consequently, caution is warranted when prescribing bupropion to these populations. Furthermore, patients with hepatic impairment should be closely monitored for potential adverse effects that may indicate elevated levels of the drug and its metabolites.

While there are no specific laboratory tests recommended for monitoring, it is crucial for patients and caregivers to seek emergency medical assistance if the patient experiences agitation, a depressed mood, or any atypical changes in behavior or thinking while using bupropion for smoking cessation. Immediate contact with a healthcare provider is advised if suicidal ideation or behavior develops.

Patients should discontinue the use of bupropion hydrochloride extended-release tablets (SR) and consult a healthcare professional 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 receiving bupropion hydrochloride extended-release tablets (SR) may experience a range of adverse reactions. The following sections categorize these reactions based on their seriousness and frequency.

Serious adverse reactions include an increased risk of suicidality, particularly in children, adolescents, and young adults. Patients should be closely monitored for clinical worsening, suicidality, or unusual changes in behavior. Neuropsychiatric symptoms such as mood changes, psychosis, hallucinations, paranoia, delusions, and aggressive behavior have also been reported, particularly in the context of smoking cessation treatment. Additionally, bupropion is associated with a dose-related risk of seizures, which increases with higher doses and in patients with certain predisposing factors. Allergic reactions, including anaphylactoid and anaphylactic reactions, have been documented, with symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been noted.

Common adverse reactions occurring in clinical trials at an incidence of 1% or more include headache (26%), dry mouth (17%), insomnia (11%), constipation (10%), and dizziness (7%). Other notable reactions include nausea (13%), palpitations (2%), and rash (5%). Adverse events leading to treatment discontinuation were reported in 2.4% of patients due to rash, 0.8% due to nausea, and 0.3% due to agitation.

Infrequent adverse reactions include chills, facial edema, musculoskeletal chest pain, and postural hypotension. Rare reactions encompass severe hypertension, myocardial infarction, and gastrointestinal hemorrhage. The nervous system may also be affected, with infrequent occurrences of abnormal coordination, decreased libido, and suicidal ideation, while rare events may include amnesia and hallucinations.

In the digestive system, infrequent adverse reactions such as abnormal liver function and bruxism have been reported, alongside rare occurrences of pancreatitis and liver damage. Urogenital effects may include impotence and polyuria, with rare reports of urinary retention and painful erection.

Overall, while many patients tolerate bupropion hydrochloride extended-release tablets (SR) well, healthcare providers should remain vigilant for these potential adverse reactions and manage them appropriately.

Drug Interactions

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

Pharmacokinetic Interactions

Bupropion is predominantly metabolized by the CYP2B6 isoenzyme to hydroxybupropion. Concomitant use of bupropion with drugs that are substrates, inhibitors, or inducers of CYP2B6 may lead to altered plasma concentrations of either bupropion or the coadministered drug. Notable examples include:

• Inhibitors of CYP2B6: Paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, and efavirenz have been shown to inhibit the hydroxylation of bupropion, potentially increasing bupropion levels.

• Inducers of CYP2B6: Drugs such as carbamazepine, phenobarbital, and phenytoin may induce the metabolism of bupropion, potentially decreasing its efficacy.

Cimetidine does not significantly affect the pharmacokinetics of bupropion but has been associated with increased AUC and C_max of its minor metabolites, threohydrobupropion and erythrohydrobupropion.

Ritonavir, at doses of 100 mg twice daily or 600 mg twice daily, as well as ritonavir combined with lopinavir (KALETRA), has been reported to reduce the exposure of bupropion and its major metabolites by approximately 20% to 80%.

CYP2D6 Interactions

Bupropion and hydroxybupropion are in vitro inhibitors of the CYP2D6 isoenzyme. Coadministration with drugs metabolized by CYP2D6, such as nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline, haloperidol, risperidone, thioridazine, metoprolol, propafenone, and flecainide, should be approached with caution. Bupropion has been shown to increase the C_max, AUC, and half-life of desipramine significantly.

Additionally, bupropion increases the C_max and AUC of citalopram by 30% and 40%, respectively, while citalopram does not affect the pharmacokinetics of bupropion.

Pharmacodynamic Interactions

The acute toxicity of bupropion may be enhanced by the MAO inhibitor phenelzine. Caution is advised when bupropion is used concurrently with levodopa or amantadine, as limited clinical data suggest a higher incidence of adverse experiences.

Furthermore, concurrent administration of bupropion with agents that lower the seizure threshold, including antipsychotics, other antidepressants, theophylline, and systemic steroids, should be undertaken with extreme caution due to the increased risk of seizures.

There have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients consuming alcohol during bupropion treatment. Therefore, it is recommended that alcohol consumption be minimized or avoided during therapy.

In summary, careful monitoring and potential dosage adjustments may be necessary when bupropion is used in conjunction with other medications, particularly those affecting CYP2B6 and CYP2D6 pathways, as well as 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 hydrochloride extended-release tablets (SR). Healthcare professionals considering the use of this medication in children or adolescents must carefully weigh the potential risks against the clinical need for treatment.

Geriatric Use

Clinical trials involving 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. No overall differences in safety or effectiveness were observed between these elderly patients and their younger counterparts. 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 based on available data.

Pharmacokinetic studies indicate that the disposition of bupropion and its metabolites in elderly subjects is comparable 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 is advisable to monitor renal function to mitigate potential risks associated with bupropion therapy 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, which are approximately 11 and 7 times the maximum recommended human dose (MRHD) on a mg/m² basis. 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, approximately equal to the MRHD on a mg/m² basis) and higher doses. Additionally, decreased fetal weights were noted at doses of 50 mg/kg and above.

In a study involving rats, administration of bupropion at oral doses of 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 result in apparent adverse effects on offspring development.

A retrospective managed-care database study assessed the risk of congenital malformations, including cardiovascular malformations, following exposure to bupropion in the first trimester compared to other antidepressants and bupropion outside of 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 same period or to bupropion outside of the first trimester. However, these results have not been corroborated.

Bupropion hydrochloride extended-release tablets (SR) 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 renal impairment should be treated with caution when prescribing bupropion hydrochloride extended-release tablets (SR). In individuals with severe hepatic cirrhosis, a reduced frequency and/or dose is necessary due to significantly increased peak bupropion levels and area under the curve (AUC), which may lead to accumulation. The maximum recommended dose for these patients is 100 mg daily or 150 mg every other day. Regular monitoring of renal function is advised to ensure safety and efficacy in this population.

Hepatic Impairment

Bupropion hydrochloride extended-release tablets (SR) 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 accumulation to a greater extent than usual.

For patients with severe hepatic impairment, the dosage should not exceed 100 mg per day or 150 mg every other day. Close monitoring of these patients is recommended to assess for potential adverse effects and to ensure safe and effective use of the medication.

Overdosage

In cases of bupropion overdosage, significant clinical manifestations have been observed, particularly with doses exceeding 30 g. Approximately one-third of reported overdose cases have resulted in seizures. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances and arrhythmias. Additionally, severe symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have predominantly occurred in instances of multiple drug overdoses. While most patients have recovered without lasting effects, fatalities have been documented, particularly in cases involving large doses of bupropion. These fatalities were often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Management of bupropion overdosage requires immediate and comprehensive medical intervention. It is essential to ensure an adequate airway, oxygenation, and ventilation, while closely monitoring cardiac rhythm and vital signs. Continuous EEG monitoring is recommended for the first 48 hours following ingestion to detect any seizure activity. General supportive and symptomatic measures should be implemented, and 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 are available. Given the dose-dependent risk of seizures associated with bupropion hydrochloride extended-release tablets, hospitalization should be considered following any suspected overdose. In cases of seizure activity, intravenous benzodiazepines are recommended for treatment, along with other supportive measures as necessary.

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

Nonclinical Toxicology

Pregnancy Category C. In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively, during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were noted at doses of 50 mg/kg and higher. When rats were administered bupropion at oral doses of up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. A retrospective managed-care database study in pregnant women assessed the risk of congenital malformations following exposure to bupropion in the first trimester compared to other antidepressants. This study included 7,005 infants, with 1,213 exposed to bupropion in the first trimester, and showed no greater risk for congenital malformations overall or cardiovascular malformations specifically. The results of this study have not been corroborated, and bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study, there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower doses were not tested. The question of whether such lesions may be precursors of neoplasms of the liver remains unresolved. Similar liver lesions were not observed in the mouse study, and no increase in malignant tumors of the liver or other organs was seen in either study. Bupropion produced a positive response in 2 of 5 strains in the Ames bacterial mutagenicity test, indicating a 2 to 3 times control mutation rate, and an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies. A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.

Postmarketing Experience

Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation, including depression, suicidal ideation, suicide attempts, and completed suicides. Some cases may have been complicated by symptoms of nicotine withdrawal in patients who stopped smoking, as depressed mood can also be a symptom of nicotine withdrawal. Additionally, depression, including rare instances of suicidal ideation, has been observed in smokers attempting to quit without medication.

Notably, some patients taking bupropion who continued to smoke have experienced these symptoms. It is recommended that all patients undergoing treatment with bupropion for smoking cessation be closely monitored for neuropsychiatric symptoms, which may include changes in behavior, hostility, agitation, depressed mood, and suicide-related events, such as ideation, behavior, and attempts.

Reports indicate that these symptoms, along with the worsening of pre-existing psychiatric conditions and completed suicides, have occurred in some patients attempting to quit smoking while on ZYBAN. While most reported symptoms occurred during treatment, some were noted following the discontinuation of ZYBAN. These events have been documented in patients both with and without pre-existing psychiatric disorders, with some experiencing exacerbation of their psychiatric illnesses.

It is important to note that patients with serious psychiatric conditions, such as schizophrenia, bipolar disorder, and major depressive disorder, were not included in the premarketing studies of ZYBAN. Patients and caregivers are advised that if any agitation, hostility, depressed mood, or atypical changes in thinking or behavior are observed, or if suicidal ideation or behavior develops, the patient should discontinue bupropion and contact a healthcare provider immediately.

In many postmarketing cases, resolution of symptoms was reported after discontinuation of ZYBAN; however, in some instances, 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 benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (SR). It is essential for patients to read the Medication Guide and discuss its contents with their healthcare provider to ensure a comprehensive understanding of the treatment.

Patients should be encouraged to remain vigilant for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as any worsening of depression and suicidal ideation, particularly during the initial stages of treatment and when the dosage is adjusted. Families and caregivers are advised to monitor patients closely for these symptoms on a day-to-day basis and to report any severe, abrupt, or unusual changes to the prescriber promptly.

Patients should be informed that quitting smoking, whether or not using bupropion, may lead to nicotine withdrawal symptoms, which can include depressed mood, trouble sleeping, irritability, frustration, anger, anxiety, and suicidal thoughts. They should be advised to discontinue bupropion and contact their 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.

It is important for patients to understand that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN, a medication used to assist with smoking cessation. Therefore, these tablets should not be used in combination with ZYBAN or any other medications that contain bupropion.

Patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, preferably with at least 8 hours between doses, to minimize the risk of seizures. If a patient experiences a seizure while on treatment, they should discontinue the medication and not restart it.

Patients should also be made aware that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks that require judgment or motor and cognitive skills. They should refrain from driving or operating complex machinery until they are certain of how the medication affects them. Additionally, patients are advised to minimize or avoid alcohol consumption, as excessive use or abrupt discontinuation of alcohol or sedatives may alter the seizure threshold.

Patients should inform their physicians of any prescription or over-the-counter drugs they are taking or plan to take, as bupropion hydrochloride extended-release tablets (SR) and other medications may interact and affect each other’s metabolism. Furthermore, patients should notify their physicians if they become pregnant or intend to become pregnant during therapy.

Finally, patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole and not to chew, divide, or crush the tablets, as doing so may increase the risk of adverse effects, including seizures.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 Liberty Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)