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) in adults. Additionally, this medication is indicated for the prevention of seasonal affective disorder (SAD).

There are no teratogenic or nonteratogenic effects associated with the use of bupropion hydrochloride extended-release tablets (XL).

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. 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 commence in the autumn, prior to the onset of seasonal depressive symptoms. The initial 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 lead to an increased risk of 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 discontinuing 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 components of bupropion hydrochloride extended-release tablets (XL) is also a contraindication.

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 mood changes such as depression and mania, as well as psychosis, hallucinations, paranoia, delusions, and aggressive behaviors. Notably, there have been instances of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients for these symptoms and instruct them to discontinue bupropion hydrochloride XL and seek immediate medical advice if such adverse events occur.

The risk of seizures is dose-related; therefore, it is crucial to limit the daily dose to a maximum of 450 mg and to increase the dosage gradually. Should a seizure occur, the medication must be discontinued immediately.

Bupropion hydrochloride XL has the potential to elevate blood pressure. Healthcare professionals should monitor blood pressure prior to initiating treatment and continue to do so 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 recommended.

Additionally, patients should be informed about the risk of angle-closure glaucoma, particularly those with untreated anatomically narrow angles who are being treated with antidepressants.

A significant warning is the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the emergence or worsening of suicidal thoughts and behaviors is essential.

In the event of neuropsychiatric reactions, including psychosis, patients should be instructed to contact a healthcare professional promptly. If a seizure occurs, the patient must discontinue the medication and seek medical attention.

To ensure safe use of bupropion hydrochloride XL, regular monitoring of blood pressure is recommended before treatment initiation and periodically thereafter.

Side Effects

Patients receiving bupropion hydrochloride extended-release (XL) may experience a range of adverse reactions. The most common adverse reactions reported include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions have been observed, including an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for the emergence or worsening of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported during smoking cessation treatment, 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 hydrochloride (XL). To minimize this risk, it is recommended to limit the daily dose to 450 mg and to gradually increase the dose. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion hydrochloride (XL) may 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 monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles who were treated with antidepressants.

Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the potential for serious reactions following abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride (XL) should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with an MAOI. Furthermore, bupropion hydrochloride (XL) should not be initiated in patients receiving linezolid or intravenous methylene blue.

In cases of overdose, seizures were reported in approximately one third of all instances. Other serious reactions associated with bupropion overdose included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), clonus, myoclonus, and hyperreflexia. Severe reactions such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been noted, particularly in the context of multiple drug overdoses. Fatalities associated with bupropion overdose have been documented, often involving large doses of the drug, with reports of multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Drug Interactions

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

CYP2B6 Inducers When bupropion is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, an increase in bupropion dosage may be necessary to maintain clinical efficacy. However, the total dosage should not exceed the maximum recommended limit.

CYP2D6 Inhibitors Bupropion is a known inhibitor of CYP2D6 and may elevate the plasma concentrations of various medications metabolized by this enzyme. This includes antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). A dose reduction of these concomitant medications should be considered to mitigate the risk of adverse effects.

Seizure Threshold Bupropion hydrochloride (XL) should be used with caution in patients who are concurrently taking medications that lower the seizure threshold, as this may increase the risk of seizures.

CNS Toxicity Concomitant use of bupropion hydrochloride (XL) with dopaminergic agents such as levodopa and amantadine may lead to central nervous system toxicity. Monitoring for signs of CNS effects is advised.

Hypertensive Reactions The use of bupropion hydrochloride (XL) in conjunction with monoamine oxidase inhibitors (MAOIs) can heighten the risk of hypertensive reactions. Close monitoring of blood pressure is recommended in such cases.

Urine Drug Testing It is important to note that bupropion hydrochloride (XL) may cause false-positive results in urine tests for amphetamines. This should be taken into account 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 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. For further details, refer to the Boxed Warning and Warnings and Precautions (5.1).

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 trials using the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses between these groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Elderly patients are more likely to have decreased renal function, which may increase the risk of adverse reactions. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients. Monitoring of renal function may be beneficial to ensure safety and efficacy in this population.

Pregnancy

There is no specific information available regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or special precautions that should be taken. Healthcare professionals are advised to consider the lack of data when prescribing this medication to pregnant patients and to weigh the potential benefits against any unknown risks to fetal outcomes. Women of childbearing potential should be counseled on the importance of effective contraception during treatment and the need to inform their healthcare provider if they become pregnant or plan to become pregnant while on this medication.

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

Patients with renal impairment may not have specific dosage adjustments, special monitoring, or safety considerations outlined in the available data. Therefore, healthcare professionals should exercise caution when prescribing to this population, as the lack of information necessitates careful clinical judgment regarding the use of the medication in individuals with reduced kidney function. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic efficacy.

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.

Symptoms of Overdosage

Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and electrocardiogram (ECG) changes such as arrhythmias. Additional symptoms can manifest as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

Tragically, fatalities linked to bupropion overdose have occurred, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Management of Overdosage

Currently, there are no known antidotes for bupropion. Therefore, supportive care and close medical supervision are essential in managing an overdose situation. Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in cases of overdose. The Poison Control Center can be reached at 1-800-222-1222 or through their website at 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. The potential for these lesions to serve as precursors to liver neoplasms remains 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.

In terms of mutagenicity, 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 a negative result 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

Some patients have reported experiencing 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 using bupropion. New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have also been documented. These symptoms have been observed in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been reported. Patients are advised to discontinue use and contact their healthcare provider immediately if they experience symptoms 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, as these may indicate a serious allergic reaction.

The risk of seizures is noted to increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some individuals may experience significant increases in blood pressure while taking bupropion, with a heightened risk observed in those concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Periods of mania have been reported in some patients taking bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as markedly 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 documented in patients during treatment with 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 ensure they are informed about their treatment. It is important to instruct 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. These symptoms may occur, particularly during the initial stages of antidepressant treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can be significant. Any severe or sudden onset of such symptoms should be reported to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. Patients must be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience any of these symptoms.

Education on hypersensitivity is crucial; patients should be made aware of the symptoms of severe allergic reactions and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if such reactions occur. Additionally, patients should be advised to stop taking the medication and not to restart it if they experience a seizure during treatment.

Healthcare providers should counsel patients regarding the risks associated with excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase the risk of seizures. Patients should be advised to minimize or avoid alcohol consumption.

Patients should also be informed that bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. It is important to educate 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 in combination with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be cautioned 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. 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 the metabolism of bupropion hydrochloride extended-release tablets (XL).

Patients who become pregnant or intend to become pregnant during therapy with bupropion hydrochloride extended-release tablets (XL) should inform their healthcare provider. It is essential to instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to maintain the proper release rate. If a dose is missed, patients should be advised not to take an extra tablet to compensate but to take the next tablet at the regular scheduled time due to the dose-related risk of seizure.

Finally, bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food, ensuring that patients are aware of these guidelines for optimal use.

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

Patients and their caregivers should be advised to discontinue bupropion hydrochloride (XL) and seek immediate medical attention if they experience agitation, depressed mood, or any atypical changes in behavior or thinking, including suicidal ideation or behavior. Families and caregivers of patients receiving antidepressants for major depressive disorder or other indications should closely monitor for signs of agitation, irritability, and unusual behavioral changes, reporting any concerning symptoms to healthcare providers promptly. Daily observation is recommended to ensure patient safety.

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 reported, presenting as pruritus, urticaria, angioedema, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been documented in association with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)