Bupropion hydrochloride

Description

Bupropion hydrochloride, USP is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1­-propanone hydrochloride. The molecular weight is 276.2, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride tablets, USP are supplied for oral administration as 75 mg (yellow) and 100 mg (maroon) film-coated tablets. Each 75 mg tablet contains colloidal silicone dioxide, crospovidone, D&C yellow No.10, FD&C yellow No.6, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. Each 100 mg tablet contains colloidal silicone dioxide, crospovidone, D&C yellow No.10, FD&C red No.40, FD&C yellow No.6, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

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 for the medication is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, healthcare professionals should increase the dose gradually. After an initial period of 3 days, the dose may be increased 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, maintained as 100 mg three times daily.

The maximum allowable dose is 450 mg per day, which can be administered as 150 mg three times daily. It is essential for healthcare providers 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. Additionally, for patients with renal impairment, a reduction in dose and/or frequency may also be warranted.

Contraindications

Use of bupropion hydrochloride tablets 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 adverse effects.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase the risk of seizures.

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride tablets should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride tablets. Additionally, bupropion should not be started 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

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 is a risk of suicidal ideation, suicide attempts, and completed suicide. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion for the emergence of these symptoms. Patients should be instructed to discontinue bupropion and contact a healthcare provider immediately 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. If a seizure occurs, bupropion should be discontinued.

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

Patients should be screened for bipolar disorder prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is advised. In the event of psychosis or other neuropsychiatric reactions, patients should be instructed to contact a healthcare professional promptly.

There is a risk of angle-closure glaucoma 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, healthcare professionals should monitor blood pressure before starting treatment and periodically during the course of therapy. Patients should be advised to discontinue bupropion and seek medical attention 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.

A significant warning associated with the use of antidepressants, including bupropion, is the increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for any worsening of mood or emergence of suicidal ideation during treatment.

Neuropsychiatric adverse events have been observed during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

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 450 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride tablets may increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is essential.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Bupropion hydrochloride 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. Known hypersensitivity to bupropion or any of its ingredients is also a contraindication.

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, changes in mental status, sinus tachycardia, ECG changes (such as 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, the dosage should not exceed the maximum recommended limit.

Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications. This includes antidepressants like venlafaxine and nortriptyline, antipsychotics such as haloperidol, beta-blockers including metoprolol, and Type 1C antiarrhythmics like propafenone.

It is important to monitor digoxin levels in patients taking bupropion, as it may decrease plasma concentrations of digoxin. Additionally, caution is advised when prescribing bupropion hydrochloride tablets to patients who are on medications that lower the seizure threshold, due to the potential for increased seizure risk.

Concomitant use of bupropion hydrochloride tablets with dopaminergic drugs, such as levodopa and amantadine, may result in CNS toxicity. Furthermore, there is an increased risk of hypertensive reactions when bupropion is used alongside monoamine oxidase inhibitors (MAOIs).

Lastly, it should be noted that bupropion hydrochloride tablets can cause false-positive results in urine tests for amphetamines.

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, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

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 utilizing the immediate-release formulation of bupropion.

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 in some older individuals cannot be ruled out.

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. Monitoring of renal function may also be beneficial to ensure safe and effective use of bupropion in this demographic.

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. Animal studies indicate 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, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater, 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. 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.

Clinical considerations suggest that women with a history of major depressive disorder who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue treatment. Therefore, it is essential to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications 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, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. However, the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, 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. The United Healthcare database lacked sufficient power to evaluate these associations; while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, the Slone Epidemiology case-control study did not.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats. However, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater, with decreased fetal weights noted at doses of 50 mg/kg/day and higher. No maternal toxicity was evident at doses of 50 mg/kg/day or less. Additionally, in a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

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 3 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 of breastfeeding alongside the potential risks to the breastfed infant.

Renal Impairment

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

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 can occur with significant consequences, particularly when doses of 30 grams or more are ingested. In such cases, seizures have been reported in approximately one-third of affected individuals.

Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and various cardiac complications. It is important to note that fatalities have been documented, especially in patients who have experienced multiple drug overdoses.

Management of bupropion overdose necessitates supportive care, which includes close medical supervision and vigilant monitoring of vital signs and cardiac rhythm. Given the absence of known antidotes for bupropion, the induction of emesis is not recommended in overdose situations.

Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in managing bupropion overdose. The contact number for the Poison Control Center is 1-800-222-1222.

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 (approximately 6 times the maximum recommended human dose MRHD on a mg/m² basis) to female rats prior to mating, and either through Day 13 of gestation or through lactation, as well as to male rats for 60 days prior to and during mating, did not result in any effects on male or female fertility. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) or higher caused transient ataxia or behavioral changes in adult female rats. Additionally, 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 of up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately 6 and 2 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 2 to 6 times the MRHD on a mg/m² basis), while 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 2 to 3 times higher than the control in 2 of 5 strains tested. Furthermore, an increase in chromosomal aberrations was reported in 1 of 3 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.

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.

Severe allergic reactions to bupropion hydrochloride tablets have been reported, with signs including 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.

The potential for seizures (convulsions) exists with bupropion hydrochloride tablets, particularly in individuals with specific medical conditions or those taking certain medications. The risk of seizures increases with higher doses of the medication.

Instances of high blood pressure, which can be severe, have been reported in some patients taking bupropion hydrochloride tablets. The likelihood of developing high blood pressure may be elevated in individuals concurrently using nicotine replacement therapy for smoking cessation.

Some patients have experienced episodes of mania while on bupropion hydrochloride tablets, characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech.

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

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. Healthcare providers should instruct patients, their families, and/or 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. These symptoms are particularly important to monitor during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior, as these may occur suddenly. 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 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.

It is essential to educate patients about the signs of hypersensitivity and to instruct them to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Patients should also be advised to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Healthcare providers should inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should be encouraged to minimize or avoid alcohol consumption.

Patients should be made aware that bupropion hydrochloride tablets can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals. Additionally, it should be noted that bupropion hydrochloride tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used for smoking cessation. Therefore, bupropion hydrochloride tablets should not be used in combination with ZYBAN or any other medications containing bupropion.

Patients should be advised 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 bupropion hydrochloride tablets do not adversely affect their performance, patients should refrain from driving or operating complex, hazardous 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 tablets may interact with other drugs. Furthermore, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy 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 3 or 4 times a day, ensuring that doses are separated by at least 6 hours to minimize the risk of seizure. 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.

Finally, patients should be instructed to swallow bupropion hydrochloride tablets whole, without crushing, dividing, or chewing them. These tablets 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 a temperature range of 20º to 25ºC (68º to 77ºF), with permissible excursions between 15º to 30ºC (59º to 86ºF) 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 and handling.

Additional Clinical Information

The maximum recommended dose of bupropion hydrochloride tablets is 450 mg per day, administered as 150 mg three times daily, with a gradual titration to minimize the risk of seizure. Clinicians should counsel patients and caregivers to discontinue the medication and seek immediate medical attention if they observe any atypical changes in behavior, mood, or thinking, including suicidal ideation or behavior. Patients should also be advised to report any neuropsychiatric symptoms such as delusions, hallucinations, or confusion, as well as any signs of allergic reactions, including skin rash or difficulty breathing.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal thoughts or actions. Additionally, anaphylactoid and anaphylactic reactions have been documented, presenting with symptoms such as pruritus and dyspnea. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been reported, along with instances of delayed hypersensitivity characterized by arthralgia and fever with rash.

FDA Insert (PDF)

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

View full prescribing information (PDF)