Bupropion Hydrochloride (xl)

Description

Bupropion hydrochloride extended-release tablets (XL) are chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. The structure of bupropion closely resembles that of diethylpropion and is related to phenylethylamines. 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 bupropion hydrochloride powder is white, crystalline, and highly soluble in water, exhibiting a bitter taste and producing 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, appearing as white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including povidone, tartaric acid, glyceryl distearate, magnesium stearate, hydroxypropyl cellulose, ethylcellulose, methacrylic acid copolymer dispersion, and colloidal silicon dioxide. The tablets are printed with black ink, which consists of shellac glaze (modified) in SD-45, isopropyl alcohol, black iron oxide non-irradiated, n-butyl alcohol, propylene glycol, and ammonium hydroxide.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) and the prevention of seasonal affective disorder (SAD).

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

Dosage and Administration

The dosage and administration of the medication should be approached with caution, particularly in the context of seizure risk. It is recommended that healthcare professionals gradually increase the dose while periodically reassessing the patient's need for maintenance treatment.

For the management of Major Depressive Disorder, the starting dose is 150 mg administered once daily. After a period of 4 days, the dose may be increased to a usual target of 300 mg once daily.

In the case of Seasonal Affective Disorder, treatment should be initiated in the autumn, prior to the onset of seasonal depressive symptoms. The starting dose is also 150 mg once daily, with a potential increase to 300 mg once daily after one week. Treatment should be continued throughout the winter season.

For patients with hepatic impairment, those with moderate to severe conditions should receive a dose of 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in dose and/or frequency of administration.

In patients with renal impairment, a reduction in dose and/or frequency of dosing should also be considered to ensure safety and efficacy.

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 precipitate seizures.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride (XL) should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride (XL). Additionally, bupropion hydrochloride (XL) should not be started in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Patients undergoing treatment with bupropion hydrochloride extended-release tablets (XL) should be closely monitored for a range of potential neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including but not limited to mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Should any of these adverse events occur, patients must be instructed to discontinue the medication immediately and contact their healthcare provider.

The risk of seizures associated with bupropion hydrochloride XL is dose-related. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be made gradually. In the event of a seizure, the medication should be discontinued.

Bupropion hydrochloride XL has been shown to potentially 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. Additionally, patients should be informed to report any occurrences of psychosis or other neuropsychiatric reactions to their healthcare professional.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion.

A critical warning pertains to the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. It is essential to monitor these populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

In summary, healthcare providers should ensure that patients are well-informed about the potential risks associated with bupropion hydrochloride XL, including the necessity to monitor blood pressure and the importance of reporting any neuropsychiatric adverse events.

Side Effects

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

Common adverse reactions observed in clinical trials include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash. Notably, the incidence of these reactions may vary with dosage; for instance, at a dose of 300 mg/day, reactions such as anorexia, dry mouth, rash, sweating, tinnitus, and tremor were commonly reported. At a higher dose of 400 mg/day, additional reactions included abdominal pain, agitation, anxiety, dizziness, insomnia, myalgia, nausea, palpitation, and urinary frequency.

Serious adverse reactions have been reported, including 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. Other serious neuropsychiatric events may include mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal ideation. The risk of seizures is also dose-related, with recommendations to limit the daily dose to 450 mg and to discontinue treatment if a seizure occurs.

Additional adverse reactions leading to treatment discontinuation have included rash, nausea, agitation, migraine, vomiting, sleep disturbances, and seizures. In postmarketing experiences, a variety of adverse reactions have been reported across different systems, including chills, facial edema, postural hypotension, hypertension, abnormal liver function, and gastrointestinal issues such as colitis and pancreatitis.

Patients may also experience neuropsychiatric adverse events during smoking cessation, which can include significant mood changes and suicidal behaviors. Furthermore, the medication may activate mania or hypomania in patients with bipolar disorder, necessitating careful screening and monitoring.

Other notable adverse reactions include angle-closure glaucoma, particularly in patients with untreated anatomically narrow angles, and various skin and subcutaneous tissue disorders such as maculopapular rash and angioedema. Cardiovascular events, including myocardial infarction and stroke, have also been reported.

Patients should be advised to contact a healthcare professional if they experience any serious or concerning symptoms, particularly those related to mood changes or neuropsychiatric reactions. Regular monitoring of blood pressure is recommended, as the medication can increase blood pressure.

Drug Interactions

Coadministration of bupropion hydrochloride (XL) with certain drug classes may lead to significant interactions that require careful consideration.

CYP Enzyme Interactions Bupropion is a substrate and inhibitor of CYP2D6. When administered with drugs that are metabolized by this enzyme, such as certain antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics, an increase in their plasma concentrations may occur. A dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects. Conversely, inducers of CYP2B6 may necessitate an increase in the bupropion dose, although this should not exceed the maximum recommended dose.

Seizure Threshold Caution is warranted when bupropion hydrochloride (XL) is prescribed alongside medications that lower the seizure threshold. Close monitoring of the patient is advised to prevent potential seizure activity.

CNS Toxicity The concomitant use of bupropion hydrochloride (XL) with dopaminergic agents, such as levodopa and amantadine, may lead to increased central nervous system (CNS) toxicity. Healthcare providers should monitor patients for signs of CNS effects and adjust therapy as necessary.

Hypertensive Reactions The risk of hypertensive reactions is elevated when bupropion hydrochloride (XL) is used in conjunction with monoamine oxidase inhibitors (MAOIs). It is recommended to avoid this combination to prevent serious cardiovascular events.

Urine Drug Testing Bupropion hydrochloride (XL) may cause false-positive results in urine tests for amphetamines. Clinicians should be aware of this potential outcome when interpreting drug screening results.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride (xl) (bupropion hydrochloride), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of bupropion hydrochloride extended-release tablets (XL) in the pediatric population have not been established. When considering the use of this medication in children or adolescents, healthcare professionals should carefully balance the potential risks against the clinical need for treatment.

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 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. In a prospective, longitudinal study, women with a history of major depressive disorder who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 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 in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. However, the Registry suggested a possible increase in cardiac malformations, with a prospectively observed rate of 1.3% for cardiovascular malformations in pregnancies with first trimester exposure to bupropion, which is similar to the background rate of approximately 1%.

Findings regarding specific cardiovascular malformations, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), are inconsistent and do not allow for definitive conclusions regarding associations with bupropion exposure during the first trimester. The NBDPS found an increased risk for LVOTO, while the Slone Epidemiology case-control study did not find an increased risk for LVOTO or any other cardiovascular malformations. Similarly, while the Slone Epidemiology Study indicated an increased risk for VSD, the NBDPS and United Healthcare database studies did not find an association between first trimester maternal bupropion exposure and VSD.

In summary, while bupropion exposure during the first trimester has not been conclusively linked to an increased risk of major malformations, careful consideration of the risks associated with untreated maternal depression is essential.

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.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for bupropion hydrochloride (XL) and any potential adverse effects on the breastfed child from bupropion hydrochloride (XL) or from the underlying maternal condition.

Renal Impairment

In patients with renal impairment, specifically those with a glomerular filtration rate (GFR) of less than 90 mL/min, consideration should be given to a reduced dose and/or dosing frequency of bupropion hydrochloride (XL). Bupropion and its metabolites are primarily cleared renally, and in individuals with reduced kidney function, there is a potential for accumulation of the drug and its metabolites. Therefore, it is essential to monitor these patients closely for any adverse reactions that may suggest elevated levels of bupropion or its metabolites.

Hepatic Impairment

In patients with moderate to severe hepatic impairment, as defined by a Child-Pugh score of 7 to 15, the maximum recommended dose of bupropion hydrochloride extended-release tablets (XL) is 150 mg every other day. For patients with mild hepatic impairment, indicated by a Child-Pugh score of 5 to 6, it is advisable to consider a reduction in the dose and/or frequency of dosing.

Close monitoring of liver function is recommended in patients with hepatic impairment to ensure safety and efficacy of treatment. Adjustments to the dosing regimen should be made based on the patient's clinical response and any changes in liver function status.

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, highlighting the potential neurological risks associated with excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly concerning in scenarios involving multiple drug overdoses, where the risk of severe complications is heightened.

Fatalities linked to bupropion overdose have been observed, often occurring after multiple uncontrolled seizures. Other critical cardiovascular events such as bradycardia, cardiac failure, and cardiac arrest may precede these tragic outcomes, underscoring the importance of prompt medical intervention.

Currently, there are no known antidotes for bupropion overdose. Therefore, the primary approach to management involves supportive care and vigilant medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for expert guidance in managing cases of bupropion overdose, ensuring that appropriate measures are taken to mitigate risks and provide optimal patient care.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with 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. The implications of these lesions as potential precursors to liver neoplasms remain unresolved. Conversely, the mouse study did not reveal similar liver lesions, nor was there an increase in malignant tumors in the liver or other organs in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, indicating 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 one of three 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.

Postmarketing Experience

During post-approval use of bupropion hydrochloride extended-release tablets (XL), a range of adverse reactions have been reported voluntarily from a population of uncertain size. Due to the nature of these reports, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified:

Chills, facial edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise have been reported. Cardiovascular events such as postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, pulmonary embolism, and Brugada pattern/syndrome have also been noted.

Gastrointestinal reactions include abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, tongue edema, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer. Endocrine-related events such as hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion have been observed.

Hematological reactions include ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered prothrombin time (PT) and/or international normalized ratio (INR), associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Glycosuria has also been reported.

Musculoskeletal and neurological events include leg cramps, fever/rhabdomyolysis, muscle weakness, abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, unmasking tardive dyskinesia, and aseptic meningitis.

Respiratory events such as bronchospasm and pneumonia have been reported. Dermatological reactions include maculopapular rash, alopecia, angioedema, exfoliative dermatitis, hirsutism, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Ocular events include accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis. Genitourinary events reported include impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

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 symptoms can manifest suddenly. Any severe, abrupt, 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 hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

Education on hypersensitivity symptoms is essential, and patients should discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking bupropion hydrochloride extended-release tablets (XL) and not to restart if they experience a seizure during treatment.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can heighten the risk of seizures, and they should minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient (bupropion) as ZYBAN, which is used for smoking cessation, and that these medications should not be used concurrently. Furthermore, patients should be advised that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks that require judgment or motor and cognitive skills.

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

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole to ensure the release rate is not altered. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular scheduled time due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed 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 controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Postmarketing experience has revealed a range of adverse reactions associated with the use of bupropion hydrochloride extended-release tablets (XL). These reactions, reported voluntarily from a population of uncertain size, may not have reliable frequency estimates or established causal relationships to drug exposure.

Adverse reactions include general symptoms such as chills, facial edema, and malaise, as well as cardiovascular issues like postural hypotension and myocardial infarction. Digestive system effects encompass abnormal liver function and gastrointestinal hemorrhage, while endocrine reactions include hyperglycemia and hypoglycemia. Hematological concerns involve ecchymosis and altered PT/INR when coadministered with warfarin. Neurological effects range from abnormal coordination to severe conditions like coma and suicidal ideation. Respiratory issues such as bronchospasm and pneumonia, skin reactions including maculopapular rash and angioedema, and urogenital effects like impotence and urinary retention have also been reported. Special senses may be affected, leading to dry eye and increased intraocular pressure.

FDA Insert (PDF)

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

View full prescribing information (PDF)