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 powder, which is soluble in 0.1N hydrochloric acid, 96% alcohol, and water. It possesses a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (XL), are formulated for oral administration in dosages of 150 mg and 300 mg, characterized as white to pale yellow extended-release tablets. Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including colloidal silicon dioxide, copovidone, hydrochloric acid, hypromellose, magnesium stearate, methacrylic acid copolymer dispersion, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl alcohol, silicon dioxide, talc, and triethyl citrate. This product complies with the requirements of USP Dissolution Test 4.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, this medication is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL).

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After a period of 4 days, the dose may be increased to a usual target of 300 mg once daily.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a potential increase to 300 mg once daily after one week. Treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in dose and/or frequency of administration.

In patients with renal impairment, a reduction in dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) is contraindicated in the following situations:

• Patients with a seizure disorder, due to the increased risk of seizures.

• Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of seizures.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (XL).

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Increased Risk of Suicidal Thoughts and Behaviors Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is imperative to monitor these patients closely for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking with bupropion hydrochloride XL may experience serious neuropsychiatric adverse events. These can include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients should be observed for these symptoms, and if they occur, they must discontinue bupropion hydrochloride XL and contact a healthcare provider immediately.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, bupropion hydrochloride XL should be discontinued.

Hypertension Bupropion hydrochloride XL has the potential to increase blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is also advised.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in these patients.

Monitoring Parameters Regular monitoring of blood pressure is recommended before and during treatment with bupropion hydrochloride XL to ensure patient safety.

In summary, healthcare providers must remain vigilant in monitoring patients for the aforementioned risks and adverse events associated with bupropion hydrochloride extended-release tablets (XL). Patients should be educated on the importance of reporting any concerning symptoms and instructed to discontinue the medication and seek medical attention if neuropsychiatric adverse events occur.

Side Effects

Common adverse reactions observed in clinical trials with bupropion hydrochloride extended-release tablets (XL) include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash, with an incidence of 5% or greater and at least twice the rate observed in placebo groups.

Serious adverse reactions warranting attention include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for the emergence or worsening of these symptoms.

Postmarketing reports have identified serious neuropsychiatric adverse events during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking while on bupropion hydrochloride extended-release tablets (XL) should be observed for these symptoms, and they should be instructed to discontinue the medication and contact a healthcare provider if such events occur.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride extended-release tablets (XL) may increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should also be advised to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride extended-release tablets (XL) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either medication.

Overdosage of bupropion has been associated with serious reactions, including seizures in approximately one third of cases, hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in cases of bupropion overdose, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (XL) with certain drug classes may lead to significant interactions that require careful consideration.

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, an increase in bupropion dosage may be necessary to maintain clinical exposure. However, the dosage should not exceed the maximum recommended limit.

CYP2D6 Substrates Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of drugs metabolized by this enzyme. This includes various antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). A dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects.

Drugs That Lower Seizure Threshold Caution is advised when prescribing bupropion XL in conjunction with other medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

Dopaminergic Drugs The concurrent use of bupropion XL with dopaminergic agents such as levodopa and amantadine may lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The combination of bupropion XL with MAOIs poses an increased risk of hypertensive reactions. Close monitoring is warranted if these agents are used together.

Drug-Laboratory Test Interactions Bupropion XL may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to healthcare providers conducting such tests.

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 (XL). When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need for treatment.

Geriatric Use

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

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses between these groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued treatment. Therefore, healthcare providers should consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. In contrast, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown. However, all pregnancies have a background rate of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%).

Study findings regarding bupropion exposure during the first trimester and the risk of left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 mg/kg/day and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while in rabbits, non-dose-related increases in fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m² basis) and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, in a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for bupropion hydrochloride extended-release tablets (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one third of these cases, seizures were reported as a significant adverse effect. Other serious reactions associated with bupropion overdoses include hallucinations, loss of consciousness, alterations in mental status, sinus tachycardia, and various ECG changes such as conduction disturbances or arrhythmias. Additional symptoms may encompass clonus, myoclonus, and hyperreflexia.

In cases where bupropion was involved in multiple drug overdoses, more severe complications have been observed, including fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure.

While the majority of 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.

Healthcare professionals are advised to monitor patients closely for the aforementioned symptoms and to initiate appropriate management strategies, which may include supportive care and symptomatic treatment. Immediate medical attention is crucial in cases of suspected overdose to mitigate potential complications and improve patient outcomes.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice, administering bupropion hydrochloride 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 mg/kg/day to 300 mg/kg/day of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved, as lower doses were not evaluated. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, instances of suicidal ideation and suicide have been noted in individuals attempting to quit smoking while taking bupropion.

Patients are advised to discontinue bupropion hydrochloride extended-release tablets (XL) and to contact a healthcare professional if they experience any of these symptoms.

Patient Counseling

Advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the important information regarding their treatment. Inform patients, their families, and caregivers about the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL) and counsel them on its appropriate use. A Medication Guide is available that covers topics such as “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, 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 (XL)?”

Instruct patients, their families, and caregivers to read the Medication Guide thoroughly and assist them in understanding its contents. Encourage patients to discuss the Medication Guide and to ask any questions they may have. Advise patients to be vigilant for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, particularly during the initial stages of treatment and when doses are adjusted. Families and caregivers should monitor for these symptoms on a daily basis, as changes can occur abruptly.

Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, sudden in onset, or were not part of the patient’s initial presentation. These symptoms may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments. Inform patients that some individuals have reported mood changes, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal thoughts and actions when attempting to quit smoking while on bupropion.

Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience any of these symptoms. Educate patients about the signs of hypersensitivity and advise them to stop taking bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, instruct patients to discontinue the medication and not to restart it if they experience a seizure during treatment.

Advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and recommend minimizing or avoiding alcohol consumption. Patients should be informed that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. Patients may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure if necessary.

Educate patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that they should not be used in combination with ZYBAN or any other medications containing bupropion hydrochloride. Advise patients that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are confident that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Finally, counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (XL) and other drugs may interact and affect each other’s metabolism.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets (XL) should be closely monitored for the emergence of agitation, irritability, and unusual behavioral changes, as well as symptoms of suicidality. Families and caregivers are advised to conduct daily observations and report any concerning symptoms to healthcare providers immediately. If patients exhibit agitation, a depressed mood, or atypical changes in behavior or thinking, they should discontinue the medication and seek medical advice. Additionally, patients should stop taking bupropion and consult a healthcare provider if they experience any allergic or anaphylactoid reactions, such as skin rash, hives, or difficulty breathing.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been documented in association with bupropion use.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bupropion Hydrochloride as submitted by Dr Reddys Laboratories Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)