Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its structure is closely related to diethylpropion and phenylethylamines, designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1 propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.21, and its molecular formula is C13H18ClNO•HCl.

The drug appears as a white powder that is soluble in water, has a bitter taste, and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets USP (XL) are available for oral administration in strengths of 150 mg and 300 mg. These tablets are off-white to pale yellow and contain the labeled amount of bupropion hydrochloride along with inactive ingredients, which include ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, glyceryl behenate, hydrophobic colloidal silica, hydroxypropyl cellulose, iron oxide black, L-cysteine hydrochloride monohydrate, methacrylic acid copolymer dispersion, polyvinyl alcohol, povidone, propylene glycol, shellac, and triethyl citrate. The tablets are printed with edible black ink.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

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

Dosage and Administration

Healthcare professionals are advised to initiate treatment with a gradual increase in dosage to minimize the risk of seizures. It is essential to periodically reassess the patient's dose and the necessity for maintenance treatment.

For the management of Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. The usual target dose is 300 mg once daily, with the option to increase the dose to 300 mg after 4 days if clinically indicated.

In the case of Seasonal Affective Disorder, treatment should commence in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a target dose of 300 mg once daily. After one week of treatment, the dose may be increased to 300 mg once daily, and it is recommended to continue treatment throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive 150 mg every other day. In patients with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration.

In patients with renal impairment, it is advisable to consider a reduction in the dose and/or frequency of dosing based on the severity of the impairment.

Contraindications

Use of bupropion hydrochloride extended-release tablets (XL) 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 extended-release tablets (XL) 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 (XL) should not use this medication.

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors There is a significant warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults who are prescribed antidepressants, including bupropion. Healthcare professionals are advised to closely monitor these patients for any worsening of symptoms or the emergence of suicidal ideation and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking while using bupropion hydrochloride XL may experience serious neuropsychiatric adverse events. These can include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal ideation. It is essential for healthcare providers to observe patients for these symptoms and instruct them to discontinue the medication and seek immediate medical advice if such events occur.

Seizure Risk The risk of seizures is dose-dependent. To minimize this risk, it is recommended that the daily dose of bupropion hydrochloride XL not exceed 450 mg, and that the dosage be increased gradually. Should a seizure occur, the medication must be discontinued immediately.

Hypertension Bupropion hydrochloride XL has the potential to elevate blood pressure. Therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

Activation of Mania/Hypomania Patients with a history of bipolar disorder should be screened prior to treatment, and ongoing monitoring for symptoms of mania or hypomania is recommended.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact their healthcare provider if they experience any signs of psychosis or other neuropsychiatric reactions.

Angle-Closure Glaucoma There have been reports of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in these patients.

Laboratory Tests Blood pressure should be monitored before the initiation of treatment and periodically during the course of therapy to ensure patient safety.

In the event of neuropsychiatric adverse events, patients must be instructed to discontinue bupropion hydrochloride XL and seek immediate medical assistance. This proactive approach is essential for managing potential risks associated with the medication.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of participants and at least twice the rate of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

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.

Neuropsychiatric adverse events have been reported 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 instructed to contact a healthcare professional if they experience any of these reactions.

Additional important safety information includes a dose-related risk of seizures, which can be minimized by limiting the daily dose to 450 mg and gradually increasing it. Discontinuation of treatment is advised if a seizure occurs. Bupropion hydrochloride extended-release tablets (XL) may also increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment. Patients should be screened for bipolar disorder due to the potential activation of mania or hypomania.

Psychosis and other neuropsychiatric reactions have been reported, necessitating prompt communication with healthcare professionals if such symptoms arise. Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles who were treated with antidepressants.

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, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), mental status changes, 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 an increase in the dosage of bupropion; however, the total dosage should not exceed the maximum recommended limit.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated plasma 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. Clinicians should monitor patients for potential adverse effects associated with increased drug levels.

Caution is warranted when bupropion is administered alongside medications that may lower the seizure threshold, as this combination can heighten the risk of seizures.

The concomitant use of bupropion hydrochloride extended-release tablets (XL) with dopaminergic agents, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity.

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

It is important to note that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines, which should be considered in the context of drug screening.

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 for bupropion hydrochloride extended-release tablets (XL). When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 years and older participated in clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients in these studies. 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 elderly patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to 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 National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression, which should be considered when evaluating treatment options. A prospective, longitudinal study indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, in pregnant rabbits, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater, with decreased fetal weights noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage in the indicated population remains unknown. 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. The international bupropion Pregnancy Registry, which included 675 first trimester exposures, did not show an overall increased risk for malformations. However, it suggested a possible increase in cardiac malformations, although no increased risk for cardiovascular malformations overall has been observed. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which aligns with 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 possible associations. In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively, with no evidence of fetal malformations in rats. However, in rabbits, fetal malformations and skeletal variations were noted at the lowest tested dose of 25 mg/kg/day and greater, with decreased fetal weights observed at doses of 50 mg/kg/day and higher. Additionally, a pre-and postnatal development study indicated that bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

Healthcare providers should carefully 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.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten 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 (XL) and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 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, sinus tachycardia, and various ECG changes. Additionally, patients may exhibit alterations in mental status, clonus, myoclonus, and hyperreflexia. In cases of multiple drug overdoses involving bupropion, further complications such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been observed.

Fatalities linked to bupropion overdose have occurred, particularly in patients who have ingested large doses. These cases often involve multiple uncontrolled seizures and significant cardiac events prior to death.

Currently, there are no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are essential for managing affected patients. In the event of a bupropion overdose, it is crucial to consult a Certified Poison Control Center for expert guidance. Healthcare professionals can reach the Poison Control Center by calling 1-800-222-1222 or by visiting www.poison.org.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. The potential for these lesions to serve as precursors to neoplasms of the liver remains unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors of the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility. No information is available regarding teratogenic effects or animal pharmacology and toxicology.

Postmarketing Experience

Postmarketing experience has revealed a range of adverse events reported voluntarily or through surveillance programs. Some patients have experienced 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 reported in individuals using bupropion for smoking cessation. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been noted in some patients taking bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions have been documented, presenting 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. The incidence of seizures has been observed to increase with higher doses of bupropion hydrochloride extended-release tablets (XL).

Furthermore, some individuals may experience episodes of mania while on bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as significantly increased energy, severe insomnia, racing thoughts, reckless behavior, grandiose ideas, excessive happiness or irritability, and rapid speech. There have also been reports of severe hypertension in some patients taking bupropion hydrochloride extended-release tablets (XL).

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL). It is essential to counsel patients, their families, and caregivers on the appropriate use of this medication.

Providers should instruct patients and their support systems to read the Medication Guide thoroughly and assist them in comprehending its contents. Patients should be encouraged to discuss the information within the Medication Guide and to ask any questions they may have.

Healthcare providers must inform patients about the potential emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual behavioral changes, as well as worsening depression and suicidal ideation. These symptoms may occur, particularly during the initial stages of treatment or when the dosage is adjusted. Families and caregivers should be vigilant in observing for these symptoms on a daily basis, as changes can be abrupt. Any severe or sudden onset of these symptoms should be reported to the prescriber, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and possible medication adjustments.

Patients should be educated on the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue and not restart the medication.

Providers should advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and therefore, minimizing or avoiding alcohol is recommended. Patients should also be informed that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

It is important to inform patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these should not be used concurrently with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be cautioned that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring 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.

Healthcare providers should encourage patients to notify them of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL). Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to ensure the proper release rate. 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. It is also important to inform patients that they may notice an inert matrix in their stool, which is normal, as the active medication has already been absorbed.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets (XL) for major depressive disorder or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion XL and seek medical attention if they observe any atypical changes in mood or behavior, or if suicidal thoughts or behaviors arise. Additionally, patients should stop taking the medication and consult a healthcare provider if they experience any allergic reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, hallucinations, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been documented in association with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)