Bupropion hydrochloride

Description

Bupropion hydrochloride, USP is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-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, crystalline, and highly soluble in water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa.

Bupropion Hydrochloride Extended-Release Tablets, USP (SR), are supplied for oral administration in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (light pink). Each tablet is film-coated and contains the labeled amount of bupropion hydrochloride along with inactive ingredients, which include cysteine hydrochloride monohydrate, hydroxypropyl methylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The 100 mg tablet contains FD&C Blue #1, the 150 mg tablet contains FD&C Blue #2 and FD&C Red #40, and the 200 mg tablet contains FD&C Red #40.

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 a minimum interval of 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. Additionally, in patients with renal impairment, a reduction in dose and/or frequency should also be considered.

Contraindications

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

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

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

Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated, as it may elevate the risk of seizures.

Bupropion hydrochloride extended-release tablets (SR) should not be used in conjunction with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders, or within 14 days of discontinuing either treatment. Additionally, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any of the components of bupropion hydrochloride extended-release tablets (SR) is a contraindication for use.

Warnings and Precautions

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. It is imperative that healthcare professionals 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 daily dose to a maximum of 400 mg. Should a seizure occur, bupropion must 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 advised.

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 populations for any worsening or emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion, healthcare professionals should implement the following laboratory tests: monitor blood pressure before initiating treatment and periodically during treatment.

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 extended-release tablets (SR). 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 warranting caution include an increased risk of suicidal thoughts and behaviors, particularly 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 should be advised to contact a healthcare professional if they experience any of these reactions.

There is a dose-related risk of seizures associated with bupropion. To minimize this risk, 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 can increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Activation of mania or hypomania has been reported, necessitating screening for bipolar disorder and careful monitoring for these symptoms. Patients with untreated anatomically narrow angles may be at risk for angle-closure glaucoma when treated with antidepressants, including bupropion.

Other important considerations include the potential for adverse reactions in patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who abruptly discontinue alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion 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.

In cases of overdose, seizures were 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 (including conduction disturbances and 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, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate a dose increase of the affected medication based on clinical response. However, it is important that the dosage does not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). In such cases, a dose reduction of these concomitant medications should be considered.

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 medications that lower the seizure threshold, as this combination may increase the risk of seizures.

The concomitant use of dopaminergic drugs, such as levodopa and amantadine, with bupropion hydrochloride extended-release tablets (SR) may result in CNS toxicity, necessitating careful monitoring of patients.

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

Lastly, it should be noted that bupropion hydrochloride extended-release tablets (SR) can cause false-positive results in urine drug tests for amphetamines, which may lead to misinterpretation of 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 extended-release tablets (SR) 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 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 associated with untreated depression during pregnancy, which should be considered when evaluating treatment options.

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. Additionally, decreased fetal weights were noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the general population is approximately 2% to 4% and 15% to 20%, respectively. A prospective longitudinal study indicated that women with a history of major depressive disorder who discontinued antidepressants during pregnancy were more likely to experience a relapse compared to those who continued treatment. Therefore, the risks of untreated depression and potential effects on the fetus should be carefully weighed when considering discontinuation or modification 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 overall increased risk for malformations. However, the Registry suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall was observed. The prospectively observed rate of cardiovascular malformations in pregnancies with first trimester 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 specific cardiovascular defects, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), have been reported. While the Slone Epidemiology Study indicated an increased risk for VSD, other studies, including the NBDPS and United Healthcare database, did not find such associations. The limitations of these studies, including small sample sizes and potential chance findings, should be acknowledged.

In summary, while bupropion exposure during the first trimester does not appear to significantly increase the risk of congenital malformations overall, careful consideration of the risks associated with untreated maternal depression and the potential fetal impacts is essential in clinical decision-making.

Lactation

Bupropion is excreted in breast milk. 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 maximum recommended human dose on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

Lactating mothers should be aware of the potential for bupropion to be present in breast milk and consider the benefits and risks of treatment while breastfeeding. There is limited data on the effects of bupropion on breastfed infants; therefore, healthcare providers should monitor infants for any adverse effects if the mother is taking this medication.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 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 amounts 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.

Currently, there are 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 affected individual. The 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 given to females prior to mating and continued through Day 13 of gestation or lactation, and to males for 60 days prior to and during mating, 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, 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 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.

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 documented in some individuals using bupropion for smoking cessation. These symptoms were more frequently observed in patients with a prior history of mental health disorders compared to those without such a history.

Patients are advised to discontinue bupropion hydrochloride extended-release tablets (SR) and contact their healthcare provider immediately if they experience a seizure, as re-administration is contraindicated following such an event.

There have been reports of severe hypertension occurring in some individuals taking bupropion hydrochloride extended-release tablets (SR), with an increased risk noted in those concurrently using nicotine replacement therapies, such as nicotine patches, for smoking cessation.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported among patients taking bupropion hydrochloride extended-release tablets (SR).

Patients should seek immediate medical attention and discontinue use of bupropion hydrochloride extended-release tablets (SR) if they develop symptoms indicative of a serious allergic reaction, 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, 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, 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 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, 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 inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures. Therefore, patients should be advised to minimize or avoid alcohol consumption. During the initial titration phase, particularly when doses exceed 150 mg/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 also 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. It is important to inform patients that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as 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 counseled 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. They should notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as interactions may affect drug metabolism.

Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant while undergoing treatment with bupropion hydrochloride extended-release tablets (SR). Proper storage of the medication is essential; patients should keep the tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and ensure they remain dry and protected from light.

Patients should be instructed to swallow bupropion hydrochloride extended-release tablets (SR) whole, without chewing, dividing, or crushing them, to maintain the intended release rate of the medication. If a dose is missed, patients should not take an extra tablet to compensate but should take the next dose at the regular scheduled time to avoid the dose-related risk of seizure. Patients may notice that bupropion hydrochloride extended-release tablets (SR) have an odor, and they can be taken with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at room temperature, ideally between 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15°C and 30°C (59°F and 86°F) in accordance with USP Controlled Room Temperature guidelines.

To ensure product integrity, it is essential to protect the product from light and moisture during storage. Proper handling and storage conditions are critical to maintaining the quality and efficacy of the product.

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. Immediate reporting of such symptoms to healthcare providers is essential, and daily observation is recommended. Patients and caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and seek medical attention if they notice any atypical changes in mood or behavior, including suicidal thoughts or actions.

Additionally, patients should be instructed to contact a healthcare professional if they experience neuropsychiatric symptoms such as delusions, hallucinations, or confusion. In the event of an allergic or anaphylactoid reaction, characterized by symptoms like skin rash or shortness of breath, patients must discontinue the medication and consult a healthcare provider. Postmarketing reports indicate that serious neuropsychiatric adverse events, including mood changes and suicidal ideation, have occurred in patients using bupropion for smoking cessation. While many cases resolved after discontinuation, some symptoms persisted, necessitating ongoing monitoring and supportive care.

FDA Insert (PDF)

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

View full prescribing information (PDF)