Bupropion hydrochloride

Description

Bupropion hydrochloride tablets USP are an antidepressant belonging to the aminoketone class, chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. 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 substance appears as a white powder, soluble in water in 0.1 N hydrochloric acid and in alcohol. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride tablets USP are available for oral administration in two strengths: 75 mg (yellow) and 100 mg (red) film-coated tablets.

Each 75 mg tablet contains bupropion hydrochloride along with inactive ingredients including cysteine hydrochloride, low-substituted hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, stearic acid, D&C yellow No. 10 aluminum lake, triacetin, titanium dioxide, FD&C yellow No. 6, and hydroxypropyl cellulose. Each 100 mg tablet contains bupropion hydrochloride and the inactive ingredients: cysteine hydrochloride, low-substituted hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, stearic acid, triacetin, FD&C Red No. 40, FD&C yellow No. 6, titanium dioxide, and hydroxypropyl cellulose.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD).

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The recommended starting dose is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, the dose should be increased gradually. After an initial period of 3 days, the dose may be escalated to 300 mg per day, given as 100 mg three times daily, ensuring that there is an interval of at least 6 hours between doses. The usual target dose is 300 mg per day, administered in the same manner of 100 mg three times daily.

The maximum allowable dose is 450 mg per day, which can be given as 150 mg three times daily. It is essential for healthcare professionals to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

For patients with moderate to severe hepatic impairment, the recommended dose is 75 mg once daily. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Similarly, for patients with renal impairment, a reduction in dose and/or frequency may be warranted.

Contraindications

Use of bupropion hydrochloride tablets is contraindicated in the following situations:

Patients with a seizure disorder are at increased risk of seizures when using this medication.

Bupropion is contraindicated in individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the potential for increased seizure risk.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is also a contraindication, as it may elevate the risk of seizures.

The use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated in conjunction with bupropion hydrochloride tablets or within 14 days of discontinuing either treatment. Additionally, bupropion hydrochloride tablets should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of its components is a contraindication for use.

Warnings and Precautions

Patients undergoing smoking cessation with bupropion should be closely monitored for neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Healthcare providers are advised to observe these patients for the emergence of such symptoms and to instruct them to discontinue bupropion and seek immediate medical attention if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended to gradually increase the dosage and limit the maximum daily dose to 450 mg. Should a seizure occur, bupropion should be discontinued immediately.

Bupropion hydrochloride tablets have the potential to elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

Patients with a history of bipolar disorder should be screened prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is also recommended.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional if they experience any such reactions.

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

There is a WARNING: SUICIDAL THOUGHTS AND BEHAVIORS associated with the use of antidepressants, particularly in children, adolescents, and young adults. Increased risk of suicidal thinking and behavior necessitates careful monitoring for any worsening or emergence of suicidal thoughts and behaviors in these populations.

To ensure patient safety, it is crucial to monitor blood pressure before starting treatment and at regular intervals thereafter. Patients should be advised to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events or if psychosis and other neuropsychiatric reactions occur.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride tablets. The most common adverse reactions reported include agitation, dry mouth, constipation, headache or migraine, nausea or vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbances.

Serious adverse reactions warrant particular attention. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, including bupropion. Patients should be closely monitored for the emergence or worsening of suicidal thoughts and behaviors. Additionally, neuropsychiatric adverse events may occur during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. If a seizure occurs, discontinuation of the medication is advised. Bupropion hydrochloride tablets may also increase blood pressure, necessitating monitoring before and during treatment.

Activation of mania or hypomania has been observed, particularly in patients with a history of bipolar disorder, and these patients should be screened and monitored for symptoms. Psychosis and other neuropsychiatric reactions may occur, and patients are advised to contact a healthcare professional if such reactions arise.

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 abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Bupropion hydrochloride tablets should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders, or within 14 days of stopping treatment with either bupropion or an MAOI. Furthermore, bupropion should not be initiated in patients receiving linezolid or intravenous methylene blue.

In cases of overdose, seizures have been reported in approximately one-third of cases, along with other serious reactions such as hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with overdoses of bupropion alone have been documented, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Co-administration of bupropion hydrochloride tablets with other medications may lead to significant drug interactions that require careful consideration and monitoring.

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

CYP2D6 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including 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 medications should be considered when used concurrently with bupropion.

Digoxin Bupropion may decrease plasma levels of digoxin. It is advisable to monitor digoxin levels closely in patients receiving both medications.

Seizure Threshold Caution is warranted when prescribing bupropion in conjunction with drugs that lower the seizure threshold, as this combination may increase the risk of seizures.

CNS Toxicity The concomitant use of bupropion with dopaminergic drugs such as levodopa and amantadine may result in central nervous system toxicity. Monitoring for adverse effects is recommended.

MAO Inhibitors (MAOIs) The use of bupropion with MAOIs can elevate the risk of hypertensive reactions. Close monitoring of blood pressure is advised in patients receiving this combination.

Urine Drug Testing Bupropion hydrochloride tablets may cause false-positive results in urine tests for amphetamines. This should be taken into account when interpreting drug screening results.

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. Therefore, caution is advised when considering the use of this medication in children, infants, and adolescents. Further studies are necessary to determine appropriate dosing and potential outcomes in these age groups.

Geriatric Use

Clinical trials involving bupropion sustained-release tablets included approximately 6,000 subjects, of which 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred subjects aged 65 years and older participated in trials using the immediate-release formulation of bupropion 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, it is important to note that greater sensitivity 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 doses for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an increased risk of congenital malformations overall. However, there are inherent risks to the mother associated with untreated depression during pregnancy. 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. Conversely, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater, with decreased fetal weights noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown, although all pregnancies carry a background risk 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 approximately 2% to 4% and 15% to 20%, respectively.

A prospective longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication. Therefore, healthcare professionals should consider the risks associated with untreated depression and the potential effects on the fetus when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, along with a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures), did not demonstrate an overall increased risk for malformations. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% for cardiovascular malformations, which aligns with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and risks for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during organogenesis at doses of up to 450 mg and 150 mg/kg/day, respectively, with no evidence of fetal malformations in rats. However, in rabbits, fetal malformations and skeletal variations were noted at the lowest tested dose of 25 mg/kg/day and higher, with decreased fetal weights observed at doses of 50 mg/kg/day and above. Importantly, no maternal toxicity was evident at doses of 50 mg/kg/day or less. Additionally, a pre-and postnatal development study indicated that bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no adverse effects 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 10 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.

Currently, 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside the mother’s clinical need for bupropion hydrochloride tablets and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Dosage adjustments may be necessary for patients with renal impairment. It is recommended to monitor renal function tests periodically in these patients. For those with severe renal impairment, defined as a creatinine clearance of less than 30 mL/min, a reduced dose should be administered.

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 have been reported. Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as QRS prolongation.

Additional symptoms observed in cases of bupropion overdose encompass sinus tachycardia, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. There have been reports of fatalities linked to bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac failure noted prior to death.

Currently, there are no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are critical in managing these cases. In the event of an overdose, it is imperative to ensure an adequate airway, oxygenation, and ventilation, while continuously monitoring cardiac rhythm and vital signs.

Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in managing a bupropion overdose. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered at doses up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 6 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 6 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. 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 the Ames bacterial mutagenicity assay, with a mutation rate 2 to 3 times higher than the control in 2 of 5 strains tested. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

Regarding reproductive toxicity, no adverse effects on male or female fertility were observed when rats received oral doses of bupropion up to 300 mg/kg/day (approximately 6 times the MRHD on a mg/m² basis) prior to mating and during gestation or lactation. Males were treated for 60 days prior to and through mating without any fertility issues. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) or higher resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects on fertility, reproduction, or the growth and development of male or female offspring.

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. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. These symptoms have been observed in some patients upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

The incidence of seizures has been reported to increase with higher doses of bupropion hydrochloride tablets. Additionally, some individuals have experienced significant elevations in blood pressure while on this medication.

Periods of mania have been reported in some patients, characterized by symptoms such as markedly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, and confusion, have also been observed in some patients taking bupropion hydrochloride tablets.

Severe allergic reactions to bupropion hydrochloride tablets have been reported, with symptoms including rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, and difficulty breathing.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they are well-informed about their treatment. It is important to instruct patients, their families, and caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly concerning during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can occur suddenly. Any severe or unexpected symptoms should be reported to the patient’s prescriber or healthcare professional promptly. Patients should be informed that some individuals may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and suicidal thoughts, particularly when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion and contact a healthcare professional immediately.

Patients must be educated about the signs of hypersensitivity and instructed to stop taking bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, if a patient has a seizure while on treatment, they should discontinue the medication and not restart it. It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should be advised to minimize or avoid alcohol consumption.

Patients should be made aware that bupropion hydrochloride tablets can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. They should also be informed that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in conjunction with ZYBAN or any other medications containing bupropion.

It is important to counsel patients that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks that require judgment or motor and cognitive skills. Until they are certain that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride and other drugs may interact with each other. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment with bupropion hydrochloride tablets.

Patients should be instructed to store bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), keeping them dry and protected from light. They should take bupropion hydrochloride tablets in equally divided doses three or four times a day, ensuring that doses are separated by at least six hours to minimize the risk of seizures. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular time due to the dose-related risk of seizures. Furthermore, patients should be instructed to swallow bupropion hydrochloride tablets whole, without crushing, dividing, or chewing them, and they can take the tablets with or without food.

Storage and Handling

The product is supplied in a tight container to ensure its integrity. It should be stored at room temperature, specifically between 20° to 25°C (68° to 77°F). Temporary excursions are permissible within the range of 15° to 30°C (59° to 86°F). It is essential to protect the product from light and moisture to maintain its quality and efficacy.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants for major depressive disorder (MDD) or other indications should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. It is crucial that any concerning symptoms are reported to healthcare providers immediately, with daily observation recommended. Patients and caregivers should be advised to discontinue bupropion hydrochloride tablets and seek medical attention if there are any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. Reports include mood changes, psychosis, hallucinations, and suicidal ideation, among others. Additionally, anaphylactoid and anaphylactic reactions have been documented, presenting with symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)