Wellbutrin

Description

Wellbutrin XL (bupropion hydrochloride) is an antidepressant of the aminoketone class, chemically unrelated to other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight of bupropion hydrochloride is 276.2 g/mol, and its molecular formula is 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.

Wellbutrin XL tablets are supplied for oral administration in strengths of 150 mg and 300 mg. These tablets are creamy-white to pale yellow extended-release formulations. Each tablet contains the labeled amount of bupropion hydrochloride along with inactive ingredients, which include ethylcellulose, glyceryl dibehenate, methacrylic acid copolymer dispersion, polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, and triethyl citrate.

Uses and Indications

This drug 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 effects associated with this drug. Furthermore, no nonteratogenic effects have been reported.

Dosage and Administration

The dosage of the medication should be increased gradually to minimize the risk of seizures. Healthcare professionals are advised 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 an initial 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 usual 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 a dose of 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 Wellbutrin XL is contraindicated in the following situations:

• Patients with a seizure disorder, due to the increased risk of seizures associated with bupropion.

• Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may heighten the risk of seizures.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase seizure risk.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Wellbutrin XL should not be used within 14 days of stopping an MAOI or vice versa. Additionally, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any other components of Wellbutrin XL.

Warnings and Precautions

The use of Wellbutrin XL necessitates careful consideration of several warnings and precautions to ensure patient safety and effective treatment outcomes.

Increased Risk of Suicidal Thoughts and Behaviors Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including Wellbutrin XL. It is essential to monitor these patients closely for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking while using Wellbutrin 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, as well as suicidal ideation, suicide attempts, and completed suicides. Patients should be observed for these symptoms, and if they occur, they must discontinue Wellbutrin XL and contact a healthcare provider immediately.

Seizure Risk The risk of seizures associated with Wellbutrin XL is dose-related. To minimize this risk, it is recommended to limit the daily dose to 450 mg and to increase the dose gradually. If a seizure occurs, the medication should be discontinued.

Hypertension Wellbutrin XL has the potential to increase 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 should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is also advised during treatment.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to contact a healthcare professional if they experience any neuropsychiatric reactions, including psychosis.

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.

Monitoring Parameters Blood pressure should be monitored before starting treatment with Wellbutrin XL and periodically during treatment to ensure patient safety.

In summary, healthcare professionals must remain vigilant in monitoring patients for the aforementioned risks and adverse events associated with Wellbutrin XL. Patients should be educated on the importance of reporting any concerning symptoms promptly.

Side Effects

Patients receiving Wellbutrin XL may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of patients 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. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, necessitating careful monitoring for the emergence or worsening of these symptoms. Additionally, postmarketing reports have identified serious neuropsychiatric adverse events during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking while on Wellbutrin XL should be observed for these symptoms and instructed to discontinue the medication and contact a healthcare provider if they occur.

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, the medication should be discontinued. Wellbutrin XL may also elevate blood pressure, necessitating monitoring before and during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is essential. Furthermore, angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Additional considerations include the presence of a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Wellbutrin 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. Similarly, Wellbutrin XL should not be initiated within 14 days of discontinuing an MAOI. Known hypersensitivity to bupropion or other ingredients in Wellbutrin XL is also a contraindication.

Drug Interactions

Coadministration of Wellbutrin XL with certain drug classes may necessitate careful monitoring and potential dosage adjustments due to significant interactions.

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

CYP2D6 Substrates Bupropion, a component of Wellbutrin XL, is known to inhibit CYP2D6, which can lead to elevated plasma concentrations of drugs metabolized by this enzyme. This includes various 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.

Drugs Lowering Seizure Threshold Caution is advised when prescribing Wellbutrin XL with other medications that may lower the seizure threshold. Close monitoring of the patient is recommended to prevent potential seizure activity.

Dopaminergic Drugs The concurrent use of Wellbutrin XL with dopaminergic agents such as levodopa and amantadine may increase the risk of central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is warranted.

Monoamine Oxidase Inhibitors (MAOIs) The combination of Wellbutrin XL with MAOIs can elevate the risk of hypertensive reactions. It is essential to avoid this combination or to monitor blood pressure closely if coadministration is unavoidable.

Drug-Laboratory Test Interactions Wellbutrin XL may interfere with urine drug screening tests, potentially resulting in false-positive results for amphetamines. Clinicians should be aware of this possibility when interpreting test results.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness of Wellbutrin XL in the pediatric population have not been established. When considering the use of Wellbutrin XL 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 trials using the immediate-release formulation of bupropion hydrochloride.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients. However, while clinical experience has not identified significant differences in responses, 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. Notably, no maternal toxicity was evident at doses of 50 mg/kg/day or less in these studies.

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.

While data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an overall increased risk for malformations, the registry suggested a possible increase in cardiac malformations. 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%.

Inconsistent findings regarding the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) following first trimester maternal bupropion exposure limit the ability to draw definitive conclusions. The studies were constrained by small sample sizes and the potential for chance findings due to multiple comparisons.

Healthcare providers should carefully consider the risks to the mother of untreated depression and the potential effects on the fetus when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum.

Lactation

Bupropion is excreted in breast milk. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the maximum recommended human dose on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

The effects of bupropion on breastfed infants have not been established. Therefore, healthcare professionals should weigh the potential benefits of bupropion therapy against the risks to the nursing infant when considering its use in lactating mothers.

Renal Impairment

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

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving amounts 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, supportive care and close medical supervision are essential for managing affected patients. Healthcare professionals are advised to consult a Certified Poison Control Center for guidance in overdose situations. For assistance, they can contact 1-800-222-1222.

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, 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, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in 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 reported 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

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while on bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. 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.

The occurrence of these symptoms appears to be more frequent in individuals with a prior history of mental health disorders compared to those without such a history.

Severe allergic reactions to Wellbutrin 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.

There is a risk of seizures associated with Wellbutrin XL, particularly in individuals with certain medical conditions or those taking specific medications. The likelihood of seizures increases with higher doses of the medication.

Some patients may experience episodes of mania while taking Wellbutrin XL, characterized by significantly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported in patients taking Wellbutrin XL.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to ensure they are well-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 (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms may occur particularly early in the course 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, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals have reported experiencing 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. Patients must be instructed to discontinue Wellbutrin XL and contact a healthcare professional if they experience any of these symptoms.

Education regarding hypersensitivity is essential; patients should be made aware of the symptoms of severe allergic reactions and instructed to discontinue Wellbutrin XL if such reactions occur. Additionally, patients should be advised to stop taking Wellbutrin XL and not to restart it if they experience a seizure during treatment.

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

Patients should be made aware that Wellbutrin XL can cause mild pupillary dilation, which may lead to angle-closure glaucoma in susceptible individuals. It is also important to inform patients that Wellbutrin XL contains bupropion, the same active ingredient found in ZYBAN, which is used for smoking cessation. Therefore, Wellbutrin XL should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

Patients should be cautioned that Wellbutrin XL, being a CNS-active drug, may impair their ability to perform tasks that require judgment, motor skills, or cognitive function. Until they are certain that Wellbutrin XL does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Patients must notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of Wellbutrin XL. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Instructions should be given to patients to swallow Wellbutrin XL tablets whole, as altering the tablet may affect the release rate of the medication. 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 time due to the dose-related risk of seizure. Wellbutrin XL should be administered in the morning and can be taken with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15° to 30°C (59° 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 and caregivers should be advised to discontinue Wellbutrin XL and contact a healthcare provider immediately if they observe any signs of agitation, depressed mood, or 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 be vigilant in monitoring for the emergence of agitation, irritability, and unusual behavioral changes, as well as suicidality, and report any concerning symptoms to healthcare providers. Daily observation by families and caregivers is recommended. Prescriptions for Wellbutrin XL should be limited to the smallest quantity necessary to minimize the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients taking bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Additionally, anaphylactoid and anaphylactic reactions have been reported, characterized by symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been associated with bupropion, along with reports of delayed hypersensitivity symptoms like arthralgia and fever with rash.

FDA Insert (PDF)

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

View full prescribing information (PDF)