Bupropion Hydrochloride Sr

Description

Bupropion hydrochloride extended-release tablets (SR) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressants. The chemical designation is (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl) amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C₁₃H₁₈ClNO•HCl.

The active pharmaceutical ingredient is a white, crystalline powder that is soluble in water, 0.1N HCl, and alcohol, 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 (blue), 150 mg (purple), and 200 mg (pink). Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including ammonium chloride, colloidal silicon dioxide, glyceryl behenate, hydroxy propyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, stearic acid, talc, and titanium dioxide. The 100 mg tablet includes FD&C Blue No. 1 Lake, the 150 mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200 mg tablet contains FD&C Red No. 40 Lake. Bupropion hydrochloride extended-release tablets, USP (SR), 100 mg, 150 mg, and 200 mg, comply with 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 weeks of acute treatment has been demonstrated in a placebo-controlled trial. There are no teratogenic or nonteratogenic effects mentioned in the available data.

Dosage and Administration

The usual target dose for bupropion hydrochloride extended-release tablets (SR) in adults is 300 mg per day, administered as 150 mg twice daily. Treatment should commence with an initial dose of 150 mg per day, given as a single daily dose in the morning. If the initial 150 mg dose is well tolerated, the dosage may be increased to the target dose of 300 mg per day as early as day 4 of treatment. It is essential to maintain an interval of at least 8 hours between successive doses.

For patients who do not exhibit clinical improvement after several weeks of treatment at the 300 mg per day dosage, an increase to a maximum of 400 mg per day may be considered. This higher dosage should be administered as 200 mg twice daily.

In patients with impaired hepatic function, dosage adjustments are necessary. For those with severe hepatic cirrhosis, the maximum dose should not exceed 100 mg per day or 150 mg every other day. In cases of mild-to-moderate hepatic cirrhosis, a reduced frequency and/or dose should be evaluated.

Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment. In such cases, a reduced frequency and/or dose should also be considered to ensure patient safety.

Contraindications

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

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

• Patients currently treated with ZYBAN (bupropion hydrochloride) Extended-Release Tablets, WELLBUTRIN (bupropion hydrochloride) immediate-release formulation, WELLBUTRIN XL (bupropion hydrochloride) extended-release formulation, 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 there is a higher incidence of seizures associated with bupropion treatment in these populations.

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

• Concurrent administration with a monoamine oxidase (MAO) inhibitor is contraindicated; a minimum of 14 days should elapse between discontinuation of an MAO inhibitor and initiation of bupropion hydrochloride extended-release tablets (SR).

• Patients with a known allergic response to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR).

Warnings and Precautions

Patients diagnosed with major depressive disorder (MDD), including both adults and pediatric populations, are at risk for exacerbation of their depression and/or the emergence of suicidal ideation and behavior (suicidality), as well as unusual changes in behavior. This risk is present regardless of whether patients are currently receiving antidepressant therapy, and it may persist until significant remission is achieved.

Antidepressants, including bupropion, may contribute to the worsening of depression and the emergence of suicidality in certain patients, particularly during the initial phases of treatment. Therefore, it is imperative that all patients undergoing treatment with antidepressants for any indication are monitored closely for clinical deterioration, suicidality, and atypical behavioral changes. This vigilance is especially critical during the first few months of therapy or when there are adjustments to the dosage.

Families and caregivers of patients receiving antidepressants should be informed of the importance of monitoring for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality. Any concerning symptoms should be reported to healthcare providers without delay.

In the context of bupropion use for smoking cessation, patients and their caregivers must be advised to discontinue bupropion and seek immediate medical attention if they observe symptoms such as agitation, depressed mood, or any atypical changes in behavior or thinking. This includes the development of suicidal ideation or behavior.

Bupropion hydrochloride extended-release tablets (SR) should be administered with extreme caution in patients with severe hepatic cirrhosis due to the potential for adverse effects.

Currently, there are no specific laboratory tests recommended for monitoring patients on bupropion. However, healthcare providers should remain vigilant and responsive to any changes in the patient's condition, ensuring that appropriate interventions are made as necessary.

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 occurring at an incidence of 1% or more included headache (26%), infection (8%), and dry mouth (17%). Other notable reactions were nausea (13%), insomnia (11%), constipation (10%), and dizziness (7%). Less frequent reactions included abdominal pain (3%), chest pain (3%), and palpitations (2%). Serious adverse events leading to treatment discontinuation were reported, with rash occurring in 2.4% of patients, nausea in 0.8%, and agitation in 0.3%.

Additional adverse reactions observed during clinical development and postmarketing experience included a variety of body system effects. Infrequent events reported in the general category included chills, facial edema, and musculoskeletal chest pain. Cardiovascular effects such as postural hypotension, tachycardia, and severe hypertension were also noted, alongside rare occurrences of syncope and myocardial infarction.

Gastrointestinal disturbances were common, with infrequent reports of abnormal liver function and gastrointestinal hemorrhage. The endocrine system may also be affected, with observations of hyperglycemia and hypoglycemia. Neurological effects included infrequent reports of abnormal coordination and suicidal ideation, with rare instances of amnesia and completed suicide.

Patients should be aware of the boxed warning regarding suicidality and antidepressant drugs, which indicates an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults. Additionally, there is a warning about the potential for clinical worsening and the emergence of suicidal ideation in patients with major depressive disorder.

Bupropion is associated with a dose-related risk of seizures, which may be influenced by patient-specific factors and concomitant medications. Therefore, careful monitoring is advised, particularly in patients with a history of seizures or other risk factors.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (SR) with other medications may lead to significant drug interactions, primarily due to its metabolism by the CYP2B6 isoenzyme and potential effects on the pharmacokinetics of concomitant drugs.

Pharmacokinetic Interactions

CYP2B6 Substrates and Inhibitors Bupropion is extensively metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, drugs that are substrates, inhibitors, or inducers of CYP2B6 may alter bupropion's clinical activity. In vitro studies indicate that paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, and efavirenz inhibit bupropion hydroxylation. While no clinical studies have confirmed these findings, caution is advised when bupropion is used concurrently with these agents.

Cimetidine In a study involving healthy volunteers, cimetidine did not significantly affect the pharmacokinetics of bupropion and its active metabolites. However, increases in the AUC and Cmax of the combined moieties of threohydrobupropion and erythrohydrobupropion were observed, suggesting that monitoring may be warranted when these drugs are coadministered.

Ritonavir and Efavirenz Ritonavir (100 mg or 600 mg twice daily) and efavirenz (600 mg once daily) have been shown to reduce bupropion exposure by 20% to 80% and approximately 55%, respectively. This reduction is attributed to the induction of bupropion metabolism. Patients receiving these medications may require increased doses of bupropion, but the maximum recommended dose should not be exceeded.

Other Inducers Certain drugs, such as carbamazepine, phenobarbital, and phenytoin, may also induce bupropion metabolism, potentially necessitating dosage adjustments.

Pharmacodynamic Interactions

CYP2D6 Substrates Coadministration of bupropion with drugs metabolized by the CYP2D6 isoenzyme, including certain antidepressants (e.g., nortriptyline, imipramine), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone), should be approached with caution. Initiating treatment at the lower end of the dose range for these medications is recommended. If bupropion is added to a regimen that includes a CYP2D6 substrate, consideration should be given to reducing the dose of the original medication, especially for those with a narrow therapeutic index.

Tamoxifen Drugs requiring metabolic activation by CYP2D6, such as tamoxifen, may exhibit reduced efficacy when administered with bupropion, an inhibitor of CYP2D6.

Citalopram While citalopram is not primarily metabolized by CYP2D6, bupropion has been shown to increase the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram does not affect the pharmacokinetics of bupropion.

Seizure Threshold Coadministration of bupropion with agents that lower seizure threshold, such as antipsychotics and systemic steroids, should be undertaken with extreme caution. Low initial doses and gradual increases are recommended.

Levodopa and Amantadine Limited clinical data suggest a higher incidence of adverse experiences when bupropion is used concurrently with levodopa or amantadine. Caution is advised, with small initial doses and gradual dose increases.

Alcohol Interaction

Postmarketing reports indicate a higher incidence of 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.

Urine Screening Tests

Patients taking bupropion may produce false-positive results in urine immunoassay screening tests for amphetamines. Confirmatory tests, such as gas chromatography/mass spectrometry, are recommended to distinguish bupropion from amphetamines, even after discontinuation of therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride Sr (bupropion hydrochloride), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of bupropion hydrochloride extended-release tablets (SR) in the pediatric population have not been established. 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

In clinical trials involving approximately 6,000 patients treated with bupropion extended-release tablets for depression and smoking cessation, 275 participants were aged 65 and older, with 47 participants aged 75 and older. Overall, no significant 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.

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, which included both single and multiple doses, suggest that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites.

Additionally, the risk of toxic reactions to bupropion may be heightened in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection in this population. It may also be beneficial 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/day and above.

In a separate study involving rats, administration of bupropion at doses up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation did not result in 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 exposure to bupropion in the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, of which 1,213 were exposed to bupropion in the first trimester. The findings indicated no greater risk for congenital malformations overall or specifically for cardiovascular malformations following first trimester exposure to bupropion compared to exposure to other antidepressants in the first trimester or to bupropion outside of the first trimester. 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

Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required, as peak bupropion levels, as well as AUC, are substantially increased, leading to a greater likelihood of accumulation. The maximum recommended dose for these patients should not exceed 100 mg daily or 150 mg every other day. Monitoring for potential adverse effects is advised due to the increased risk associated with altered pharmacokinetics 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 greater accumulation than typically observed.

For patients with severe hepatic impairment, the daily dose should not exceed 100 mg, and the maximum dose should not exceed 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

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.

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, 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 treatment 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 hydrochloride extended-release tablets (SR), hospitalization should be considered following any suspected overdose. Based on animal studies, seizures should be treated with intravenous benzodiazepines and other supportive measures as necessary.

In cases of 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

Pregnancy Category C. In nonclinical studies involving rats and rabbits, bupropion was administered orally at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively, during the organogenesis period. No definitive 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 tested dose of 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 separate study, rats received bupropion at oral doses of up to 300 mg/kg/day, approximately seven times the MRHD on a mg/m² basis, prior to mating and throughout pregnancy and lactation. This administration did not result in any apparent adverse effects on the development of the offspring.

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 increased risk for congenital malformations overall or specifically for cardiovascular malformations following first trimester exposure to bupropion when compared to exposure to other antidepressants in the same period or to bupropion outside of the first trimester. It is important to note that the results of this study have not been corroborated. Bupropion hydrochloride extended-release tablets (SR) should be utilized during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Postmarketing Experience

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

Notably, some patients taking bupropion who continued to smoke have also experienced these symptoms. It is recommended that all patients undergoing treatment with bupropion for smoking cessation be closely monitored for neuropsychiatric symptoms, including 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. Most reported symptoms occurred during treatment, although some were noted following 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 signs of 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 advised to alert their prescriber if they experience any of the following symptoms while taking bupropion hydrochloride extended-release tablets (SR): anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, or suicidal ideation. Families and caregivers should monitor patients for the emergence of these symptoms on a day-to-day basis and report any severe, abrupt changes to the healthcare provider.

It is important to inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used to help patients quit smoking. 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, especially when increasing the dose above 150 mg/day, to minimize the risk of seizures. They should also be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and not restart if they experience a seizure while on treatment.

Patients should be warned that excessive use or abrupt discontinuation of alcohol or sedatives may alter the seizure threshold, and therefore, alcohol consumption should be minimized or avoided. Additionally, patients should inform their healthcare provider of any other prescription or over-the-counter medications they are taking.

Patients should notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. Finally, patients should be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole and not to chew, divide, or crush the tablets to avoid altering the release rate and increasing the risk of adverse effects, including seizures.

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°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature 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 Sr as submitted by Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)