Bupropion Hydrochloridexl

Description

Bupropion hydrochloride extended-release tablets (XL) 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 extended-release tablets (XL) are supplied for oral administration as 150 mg, white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: colloidal silicon dioxide, ethylcellulose, hydroxypropyl cellulose, methacrylic acid copolymer, microcrystalline cellulose, stearic acid, talc, titanium dioxide, hydrochloric acid, and triethyl citrate.

Uses and Indications

Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, these tablets are 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

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 dose of 300 mg once daily.

In the treatment of Seasonal Affective Disorder, it is advised to initiate therapy 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 the usual target dose of 300 mg once daily after one week of treatment. Continuation of therapy is recommended 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 cases of mild hepatic impairment, it is advisable to consider a reduction in either the dose or the frequency of administration.

In patients with renal impairment, a reduction in the 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 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, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (XL). Additionally, bupropion hydrochloride extended-release tablets (XL) should not be started in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

The use of this medication necessitates careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors; Neuropsychiatric Reactions There is a significant warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults who are prescribed antidepressants. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors. Additionally, serious neuropsychiatric events have been reported in patients using bupropion for smoking cessation, necessitating vigilance in monitoring.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, it is recommended that the daily dose not exceed 450 mg, with any increases made gradually. Should a seizure occur, the medication must be discontinued immediately.

Hypertension Bupropion hydrochloride extended-release tablets (XL) have the potential to elevate blood pressure. It is essential to monitor blood pressure prior to initiating treatment and to conduct periodic assessments throughout the treatment course.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

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

Angle Closure Glaucoma There is a risk of angle closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants. Caution is advised in these cases.

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

In the event of psychosis or other neuropsychiatric reactions, patients must seek emergency medical help. Furthermore, if a seizure occurs, the patient should discontinue the medication and contact their healthcare provider immediately.

Side Effects

Patients may experience a range of adverse reactions while using this medication. The most common adverse reactions reported include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious warnings associated with this medication include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor patients for the emergence or worsening of suicidal thoughts and behaviors. Additionally, serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation, necessitating careful observation.

The risk of seizures is dose-related; therefore, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, discontinuation of the medication is advised. Patients should also be monitored for hypertension, as bupropion hydrochloride extended-release tablets (XL) can elevate blood pressure. Blood pressure should be assessed before initiating treatment and periodically throughout the treatment course.

Activation of mania or hypomania has been observed, highlighting the importance of screening patients 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 been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, warranting caution in such individuals.

In cases of overdosage, seizures were reported in approximately one-third of all cases. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Severe reactions such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have primarily occurred in the context of multiple drug overdoses. Deaths associated with bupropion overdose have been documented, particularly in patients who ingested large doses, with reports of multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion. However, it is important to ensure that the dosage does not exceed the maximum recommended limit.

Bupropion acts as an inhibitor of CYP2D6, which can lead to elevated 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 these increased drug levels.

Caution is warranted when bupropion is prescribed 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 drugs, such as levodopa and amantadine, may result in central nervous system (CNS) toxicity. Therefore, careful monitoring is recommended.

Additionally, the use of bupropion hydrochloride extended-release tablets (XL) in conjunction with monoamine oxidase inhibitors (MAOIs) can lead to an increased risk of hypertensive reactions. It is advisable to avoid this combination or to monitor blood pressure closely.

Lastly, it should be noted that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines, which could lead to misinterpretation of drug screening results.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloridexl (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 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 studies utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects in these trials. However, while clinical experience has not identified significant differences in responses between these age 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, careful consideration of renal function is advised when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester indicate no overall increased risk of congenital malformations. The background rate for major malformations in all pregnancies is approximately 2% to 4%, with a pregnancy loss rate of 15% to 20%. Reproductive developmental studies in rats and rabbits did not demonstrate clear teratogenic activity; however, rabbits exhibited slightly increased incidences of fetal malformations and skeletal variations at doses around the maximum recommended human dose (MRHD) and higher. Additionally, decreased fetal weights were noted at doses twice the MRHD and above.

Bupropion hydrochloride extended-release tablets (XL) are classified as Pregnancy Category C, indicating that they should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Clinical considerations must include the risk of untreated depression when contemplating the discontinuation or alteration of antidepressant therapy during pregnancy and postpartum.

Human data from the international bupropion Pregnancy Registry, which included 675 first-trimester exposures, and a retrospective cohort study utilizing the United Healthcare database with 1,213 first-trimester exposures, did not reveal an increased risk for malformations overall. Specifically, no increased risk for cardiovascular malformations was observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% (9 cardiovascular malformations out of 675 exposures), consistent with the background rate of approximately 1%.

Inconsistent findings regarding the association between bupropion exposure during the first trimester and left ventricular outflow tract obstruction (LVOTO) have been reported. The United Healthcare database lacked sufficient power to evaluate this association, while the National Birth Defects Prevention Study (NBDPS) identified an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. Similarly, findings related to ventricular septal defect (VSD) are inconsistent; the Slone Epidemiology Study reported an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0), while the NBDPS and United Healthcare database studies did not establish an association. Limitations in these studies include small sample sizes, inconsistent results, and the potential for chance findings due to multiple comparisons.

Animal studies involving oral administration of bupropion in rats and rabbits during organogenesis did not show clear teratogenic effects. However, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at doses starting from 25 mg/kg/day (approximately equal to the MRHD on a mg/m² basis) and higher, with decreased fetal weights observed at doses of 50 mg/kg and above. In rats, administration of bupropion at doses up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

Lactation

Bupropion and its metabolites are present 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.

Exercise caution when administering bupropion hydrochloride extended-release tablets (XL) to lactating mothers.

Renal Impairment

Patients with renal impairment may require dosage adjustments. Regular monitoring of renal function is essential. For patients with severe renal impairment, defined as a creatinine clearance of less than 30 mL/min, the use of this medication is contraindicated. In patients with moderate renal impairment, characterized by a creatinine clearance between 30 and 60 mL/min, a reduced dose is recommended. Additionally, renal function tests should be conducted prior to the initiation of treatment and periodically throughout the course of therapy.

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 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, sinus tachycardia, and notable changes on the electrocardiogram (ECG). These symptoms indicate a significant impact on both the central nervous system and cardiovascular function, necessitating immediate medical attention.

Tragically, there have been reports of fatalities linked to bupropion overdose, often characterized by multiple uncontrolled seizures and subsequent cardiac failure prior to death. This underscores the critical nature of prompt intervention in overdose situations.

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose primarily involves supportive care and close medical supervision. Healthcare professionals are advised to monitor the patient closely for any developing symptoms and to provide appropriate interventions as necessary.

In the event of a bupropion overdose, it is essential to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach out to the Poison Control Center at 1-800-222-1222 for assistance in managing the situation effectively.

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 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.

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 mutagenicity 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.

Postmarketing Experience

Serious neuropsychiatric reactions have been reported in patients taking bupropion for smoking cessation. The majority of these reactions occurred during treatment; however, some were noted during the discontinuation of therapy. A causal relationship to bupropion treatment remains uncertain in many instances, as depressed mood may be a symptom of nicotine withdrawal. Notably, some cases were reported in patients who continued to smoke while on bupropion.

Although bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation, it is recommended that all patients be monitored for neuropsychiatric reactions. Patients should be instructed to contact a healthcare provider if such reactions occur.

Anaphylactoid and anaphylactic reactions have also been documented during clinical trials with bupropion, characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea, which required medical intervention. Additionally, rare spontaneous postmarketing reports have indicated occurrences of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.

Patients should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek medical attention if they experience any allergic or anaphylactoid/anaphylactic reactions, including skin rash, pruritus, hives, chest pain, edema, or shortness of breath during treatment. Reports of arthralgia, myalgia, fever with rash, and other symptoms suggestive of serum sickness indicative of delayed hypersensitivity have also been noted.

Patient Counseling

Healthcare providers should inform patients that the use of antidepressants has been associated with an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults during short-term trials. It is essential to monitor patients of all ages who are initiated on antidepressant therapy closely for any worsening of their condition and for the emergence of suicidal thoughts and behaviors. Providers should advise families and caregivers about the importance of maintaining close observation and open communication with the prescriber regarding the patient's mental health status.

Additionally, healthcare providers should be aware that serious neuropsychiatric reactions have been reported in patients taking bupropion for smoking cessation. It is crucial to observe all patients for any signs of neuropsychiatric reactions and instruct them to contact their healthcare provider immediately if such reactions occur.

Families and caregivers of patients receiving antidepressants for major depressive disorder or other indications should be alerted to monitor for signs of agitation, irritability, unusual changes in behavior, and any emergence of suicidality. They should be encouraged to report any concerning symptoms to healthcare providers without delay.

When prescribing bupropion hydrochloride extended-release tablets (XL), providers should write prescriptions for the smallest quantity of tablets that is consistent with effective patient management. This practice is intended to minimize the risk of overdose.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Bupropion hydrochloride extended-release tablets (XL) should be administered whole, without crushing, dividing, or chewing, preferably in the morning, and can be taken with or without food. Clinicians are advised to prescribe the smallest quantity of tablets necessary for effective patient management to minimize the risk of overdose.

Patient counseling should emphasize the importance of close observation by families and caregivers for any emergence of suicidal thoughts or behaviors. Patients should be instructed to report any neuropsychiatric reactions to their healthcare provider. Additionally, caregivers should monitor for signs of agitation, irritability, or unusual behavioral changes in patients receiving antidepressants.

FDA Insert (PDF)

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

View full prescribing information (PDF)