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 powder form of bupropion hydrochloride is white and soluble in 0.1N HCl, 96% alcohol, and water. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa.

These extended-release tablets are available for oral administration in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each tablet is film-coated and contains the labeled 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 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 may be warranted.

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 associated with bupropion.

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 or initiated in patients currently receiving linezolid or intravenous methylene blue.

Patients with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR) should not use this medication.

Warnings and Precautions

Patients undergoing treatment with bupropion should be closely monitored for a range of potential neuropsychiatric adverse events associated with smoking cessation. 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, and panic. Additionally, there have been reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients for these symptoms and instruct them to discontinue bupropion and seek immediate medical attention if such adverse events occur.

The risk of seizures is dose-related; therefore, it is essential to minimize this risk by gradually increasing the dosage and limiting the maximum daily dose to 400 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride extended-release tablets (SR) have been associated with increased blood pressure. Healthcare professionals should monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy to ensure patient safety.

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 recommended.

There is also a risk of psychosis and other neuropsychiatric reactions. Patients should be advised to contact their healthcare provider 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. Caution is advised in these patients.

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 of symptoms or emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion, healthcare providers should conduct regular blood pressure assessments before and during treatment. Patients should be instructed to discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms.

Side Effects

Patients may experience a range of adverse reactions while using the medication. The 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.

Serious adverse reactions warrant particular attention. A boxed warning highlights the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors. Additionally, neuropsychiatric adverse events may occur 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.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. If a seizure occurs, discontinuation of the medication is advised. Patients should also be monitored for hypertension, as bupropion hydrochloride extended-release tablets (SR) can elevate blood pressure. Blood pressure should be assessed before initiating treatment and periodically during therapy.

Activation of mania or hypomania has been observed, necessitating screening for bipolar disorder and ongoing monitoring for these symptoms. Patients are 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. Additional 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 all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances including QRS prolongation or arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest noted prior to death.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion based on clinical response, without exceeding the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications. This includes antidepressants like venlafaxine and nortriptyline, antipsychotics such as haloperidol, beta-blockers including metoprolol, and Type 1C antiarrhythmics like propafenone. A dose reduction of these medications should be considered to mitigate potential adverse effects.

Additionally, bupropion may reduce plasma levels of digoxin; therefore, monitoring of digoxin levels is recommended to ensure therapeutic efficacy.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (SR) alongside drugs that may lower the seizure threshold. The concomitant use of dopaminergic medications, such as levodopa and amantadine, with bupropion hydrochloride extended-release tablets (SR) may result in CNS toxicity, necessitating careful patient monitoring.

There is also an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are used in conjunction with monoamine oxidase inhibitors (MAOIs).

Lastly, it is important to note that bupropion hydrochloride extended-release tablets (SR) can lead to false-positive results in urine tests for amphetamines, which should be taken into consideration during drug screening processes.

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 needed 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 clinical trials utilizing 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 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

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an overall increased risk of congenital malformations. However, there are inherent risks to the mother associated with untreated depression during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, no fetal malformations were observed 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 noted at doses approximately equal to the MRHD and higher, with decreased fetal weights observed at doses twice the MRHD and greater.

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 treatment. 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 therapy during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first-trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first-trimester exposures did not demonstrate an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, although no overall increased risk for cardiovascular malformations has been observed following first-trimester exposure to bupropion. The prospectively observed rate of cardiovascular malformations in pregnancies with bupropion exposure was 1.3%, 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) have been reported. While the National Birth Defects Prevention Study (NBDPS) indicated an increased risk for LVOTO, the Slone Epidemiology case-control study did not find a similar association. For VSD, the Slone Epidemiology Study reported an increased risk following first-trimester exposure, but no increased risk for other cardiovascular malformations was observed. Limitations in these studies, including small sample sizes and inconsistent findings, hinder definitive conclusions regarding these associations.

In animal studies, bupropion was administered orally during organogenesis at doses of up to 450 mg/kg/day in rats and 150 mg/kg/day in rabbits, corresponding to approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis. No fetal malformations were observed in rats, while rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose. Decreased fetal weights were noted at doses of 50 mg/kg/day and higher, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, a pre-and postnatal development study in rats indicated that bupropion administered at doses 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.

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

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when prescribing to patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

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. Healthcare professionals should be vigilant for serious reactions associated with bupropion overdose, which may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly concerning in the context of multiple drug overdoses.

Fatalities linked to bupropion overdose have occurred, often following a series of uncontrolled seizures, bradycardia, cardiac failure, and ultimately cardiac arrest. Given the potential severity of these outcomes, immediate medical intervention is critical.

There are currently no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and close medical supervision. It is imperative to ensure adequate airway management, oxygenation, and ventilation for the patient. Induction of emesis is not recommended in cases of bupropion overdose due to the risk of further complications.

In the event of a suspected overdose, healthcare professionals are advised to consult a Certified Poison Control Center for expert guidance. The National Capital Poison Center can be reached at 1-800-222-1222 or through their website at www.poison.org for additional resources and support.

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 both male and female rats did not adversely affect fertility. This dosing regimen, which was maintained prior to mating and continued through Day 13 of gestation or through lactation for females, and for 60 days prior to and during mating for males, is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis. 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, indicating a potential concern, although the relationship of these lesions to 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 species.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, yielding 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 and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, suicidal ideation and suicide attempts have been noted in individuals attempting to quit smoking while taking bupropion.

Reports indicate that new or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have occurred in some individuals using bupropion for smoking cessation. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been documented in patients taking bupropion hydrochloride extended-release tablets (SR).

There is a potential risk of seizures (convulsions) associated with bupropion hydrochloride extended-release tablets (SR), particularly in individuals with certain medical conditions or those taking specific medications. The likelihood of seizures may increase with higher doses of the medication.

Some patients have experienced severe hypertension while on bupropion hydrochloride extended-release tablets (SR). Furthermore, episodes of mania have been reported, characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and rapid speech.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (SR) have been observed, 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, or difficulty breathing.

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 be 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 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 mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, and suicidal thoughts 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 discontinue 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 stop taking bupropion hydrochloride extended-release tablets (SR) and not restart the medication.

It is crucial to advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures. Patients should be encouraged to minimize or avoid alcohol consumption. During the initial titration phase, particularly when doses exceed 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 taking 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 as ZYBAN, which is used for smoking cessation, and should not be used in conjunction with ZYBAN or any other medications containing bupropion.

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 store bupropion hydrochloride extended-release tablets (SR) at a temperature of 20° to 25°C (68° to 77°F) and should 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 patient misses a dose, they 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. It is also important to note that bupropion hydrochloride extended-release tablets (SR) may have an odor and 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 and efficacy.

Additional Clinical Information

Families and caregivers of patients treated with antidepressants, including bupropion hydrochloride extended-release tablets, should be vigilant in monitoring for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion and seek medical attention if any atypical changes in mood or behavior occur, or if suicidal thoughts or behaviors develop.

Clinicians should be aware that serious neuropsychiatric adverse events have been reported in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. While some patients may experience symptoms of nicotine withdrawal, which can include depression, it is important to note that adverse events have also occurred in patients who continued to smoke while on bupropion. In many cases, symptoms resolved after discontinuation of the medication, but persistent symptoms have been noted, necessitating ongoing monitoring and supportive care until resolution.

FDA Insert (PDF)

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

View full prescribing information (PDF)