Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets, USP (SR), are 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 bupropion hydrochloride powder is a white, soluble substance in 0.1N HCl, 96% alcohol, and water, characterized by a bitter taste and a local anesthetic sensation on the oral mucosa.

These extended-release tablets are formulated for oral administration and are available in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, which include copovidone, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. The 100 mg tablet incorporates FD&C Blue No. 1 Brilliant Blue FCF Aluminium Lake, the 150 mg tablet contains FD&C Blue No. 2 Indigo Carmine Aluminium Lake and FD&C Red No. 40 Allura Red AC Aluminium Lake, while the 200 mg tablet includes FD&C Red No. 40 Allura Red AC Aluminium Lake. Additionally, the flavoring agent consists of dextrose, ethyl alcohol, gum arabic, propylene glycol, and silicon dioxide.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) 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 150 mg per day. 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, administered as 150 mg twice daily, with an interval of at least 8 hours between doses. The usual target dose is 300 mg per day, maintained as 150 mg twice daily.

For patients who do not respond adequately to the 300 mg per day regimen, the maximum dose may be increased to 400 mg per day, given as 200 mg twice daily. It is essential to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Similarly, in patients with renal impairment, a reduction in dose and/or frequency should be considered based on individual patient needs.

Contraindications

Use of bupropion hydrochloride extended-release tablets (SR) 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 (SR) should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (SR). Additionally, it is contraindicated in patients receiving linezolid or intravenous methylene blue.

• Known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR).

Warnings and Precautions

Serious neuropsychiatric adverse events have been reported in patients undergoing smoking cessation with bupropion. These events may include significant mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been instances of suicidal ideation, suicide attempts, and completed suicides. Healthcare professionals are advised to closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and promptly contact a healthcare provider 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 400 mg. In the event of a seizure, bupropion should be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) 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.

The occurrence of psychosis and other neuropsychiatric reactions necessitates that patients be instructed 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, including bupropion.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion, healthcare professionals should implement regular blood pressure monitoring before and during treatment. Patients should be advised to discontinue bupropion and seek immediate medical attention if they experience any neuropsychiatric adverse events or psychotic symptoms.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by seriousness and frequency.

Most common adverse reactions reported include headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitations, myalgia, sweating, rash, and anorexia. These reactions are generally mild to moderate in severity.

Serious adverse reactions warrant careful monitoring. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been observed during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing these symptoms should be instructed to contact a healthcare professional immediately.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride extended-release tablets (SR) may increase blood pressure, necessitating monitoring of blood pressure before and during treatment.

Activation of mania or hypomania has been reported, particularly in patients with a history of bipolar disorder, highlighting the importance of screening and monitoring for these symptoms. Angle-closure glaucoma has also been noted 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 potential for adverse reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

In cases of overdosage, 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), arrhythmias, 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

Coadministration of bupropion with certain drug classes may lead to significant interactions that require careful consideration of dosage adjustments and monitoring.

CYP Enzyme Interactions Bupropion is both a substrate and an inhibitor of cytochrome P450 enzymes. Specifically, CYP2B6 inducers may necessitate an increase in bupropion dosage; however, this should not exceed the maximum recommended dose. Conversely, bupropion inhibits CYP2D6, which may lead to increased plasma concentrations of coadministered medications such as antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics. In such cases, a dose reduction of these medications should be considered.

Cardiovascular Interactions Bupropion may decrease plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy and avoid toxicity. Additionally, there is an increased risk of hypertensive reactions when bupropion is used in conjunction with monoamine oxidase inhibitors (MAOIs). Caution is advised in these scenarios.

Seizure Threshold Considerations When prescribing bupropion hydrochloride extended-release tablets, caution is warranted with drugs that lower the seizure threshold. The potential for seizures may be heightened in such combinations.

CNS Toxicity Risks Concomitant use of bupropion hydrochloride extended-release tablets with dopaminergic drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is advisable.

Urine Drug Testing It is important to note that bupropion hydrochloride extended-release tablets can 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. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for additional information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

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 some older individuals may exhibit greater sensitivity to the medication.

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 an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any 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 https://womensmentalhealth.org/research/pregnancyregistry/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 during pregnancy. 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 treatment. Therefore, healthcare providers should consider the risks 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 11 times the maximum recommended human dose (MRHD) of 400 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 is unknown for the indicated population; however, 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 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, the prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which is similar to the background rate of approximately 1%.

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding a possible association.

In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 4 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 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.

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 extended-release tablets (SR) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment may not have specific dosage adjustments, special monitoring, or safety considerations outlined in the available data. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the lack of detailed information necessitates careful clinical judgment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic efficacy.

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 that may manifest during an overdose include clonus, myoclonus, hyperreflexia, fever, muscle rigidity, hypotension, stupor, coma, and respiratory failure. It is important to note that fatalities have been associated with bupropion overdose, particularly in patients who have ingested large doses, with multiple uncontrolled seizures and cardiac failure being significant contributing factors.

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and close medical supervision. In the event of a bupropion overdose, it is critical to ensure an adequate airway, oxygenation, and ventilation, while also monitoring cardiac rhythm and vital signs closely.

Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance and management strategies in cases of bupropion overdose.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day to rats, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male or female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males received the treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately five times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven and two times the 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, approximately two to seven 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, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide during attempts to quit smoking while taking bupropion. Additionally, new or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been noted in individuals using bupropion for smoking cessation.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been observed in some patients taking bupropion hydrochloride extended-release tablets (SR). Reports of severe allergic reactions have included symptoms such as rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, and difficulty breathing.

The incidence of seizures has been noted to increase with higher doses of bupropion hydrochloride extended-release tablets (SR). Some individuals may experience significant increases in blood pressure while on this medication. Manic episodes have been documented, characterized by heightened energy levels, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and increased talkativeness.

Visual disturbances, including eye pain, changes in vision, and swelling or redness in or around the eye, have been reported by some patients.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important for patients, their families, and caregivers to remain vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial stages of antidepressant treatment and when dosage adjustments are made.

Families and caregivers should be instructed to monitor patients closely for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts or actions 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 should be educated about the signs of hypersensitivity and instructed to stop taking bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue the medication and not restart it.

It is crucial to advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures. Patients should be encouraged to minimize or avoid alcohol consumption. During the initial titration phase, particularly when increasing the dose above 150 mg per day, patients should take bupropion hydrochloride extended-release tablets (SR) in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures.

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals. They should also be informed that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used for smoking cessation, and that these medications should not be used together or with any other bupropion-containing products.

Patients should be cautioned 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. 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 if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (SR) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients should be instructed to store bupropion hydrochloride extended-release tablets (SR) at a temperature of 20° to 25°C (68° to 77°F) and to swallow the tablets whole to ensure the release rate is not altered. They should not chew, divide, or crush the tablets, as they are designed for slow release in the body. 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 seizure.

Patients should be informed that bupropion hydrochloride extended-release tablets (SR) may have an odor and that they can be taken with or without food.

Storage and Handling

The product is supplied in a tight, light-resistant container equipped with a child-resistant closure, as required. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from light and moisture to maintain its integrity.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets 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. Patients should discontinue the medication and seek medical attention if they experience agitation, changes in mood or behavior, or develop suicidal thoughts or behaviors. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Clinicians should be aware of serious neuropsychiatric adverse events reported in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, as well as anaphylactic shock, have also been documented in postmarketing reports.

FDA Insert (PDF)

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

View full prescribing information (PDF)