Wellbutrin

Description

WELLBUTRIN SR (bupropion hydrochloride) is an antidepressant belonging to the aminoketone class and is chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. Its chemical designation is (±)-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 characterized as white, crystalline, and highly soluble in water, possessing a bitter taste and inducing a sensation of local anesthesia on the oral mucosa.

WELLBUTRIN SR is formulated for oral administration in film-coated, sustained-release tablets available in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (light pink). Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, which include carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide, and is printed with edible black ink. The 100 mg tablet incorporates FD&C Blue No. 1 Lake, the 150 mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, while the 200 mg tablet includes FD&C Red No. 40 Lake.

Uses and Indications

WELLBUTRIN SR is an aminoketone antidepressant indicated for the treatment of major depressive disorder (MDD).

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

Dosage and Administration

The recommended starting dose is 150 mg per day. To minimize the risk of seizures, the dose should be increased gradually. After an initial period of 3 days, the dose may be escalated to 300 mg per day, administered as 150 mg twice daily, with an interval of at least 8 hours between doses. The usual target dose is 300 mg per day, maintained as 150 mg twice daily.

For patients who do not respond adequately to the 300 mg per day regimen, the maximum allowable dose is 400 mg per day, which should be given as 200 mg twice daily. It is essential to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, in patients with renal impairment, it is advisable to evaluate the need for dose and/or frequency adjustments.

Contraindications

Use of WELLBUTRIN SR is contraindicated in the following situations:

Patients with a seizure disorder are at increased risk of seizures when using this medication.

WELLBUTRIN SR should not be administered to individuals with a current or prior diagnosis of bulimia or anorexia nervosa due to the heightened risk of seizures associated with these conditions.

The abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs is contraindicated, as it may increase the risk of seizures.

Concurrent use of Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. WELLBUTRIN SR should not be used in conjunction with MAOIs or within 14 days of discontinuing either treatment. Additionally, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

Known hypersensitivity to bupropion or any other components of WELLBUTRIN SR is a contraindication for its use.

Warnings and Precautions

The use of antidepressants, including bupropion, is associated with an increased risk of suicidal thinking and behavior, particularly in children, adolescents, and young adults. Healthcare professionals should closely monitor these populations for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During smoking cessation, patients may experience serious neuropsychiatric adverse events. Postmarketing reports have documented changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Additionally, there have been reports of suicidal ideation, suicide attempts, and completed suicides. It is imperative that healthcare providers observe patients attempting to quit smoking with bupropion for these symptoms. Patients should be instructed to discontinue bupropion and contact a healthcare provider immediately if they experience any of these adverse events.

Seizure Risk The risk of seizures is dose-related. To minimize this risk, healthcare professionals should gradually increase the dose and limit the daily dose to a maximum of 400 mg. If a seizure occurs, bupropion should be discontinued.

Hypertension Bupropion can lead to increased blood pressure. It is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Bipolar Disorder Screening Patients should be screened for bipolar disorder prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is recommended.

Psychosis and Neuropsychiatric Reactions Patients should be advised to contact a healthcare professional if they experience any psychotic symptoms 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.

Laboratory Tests Blood pressure should be monitored before initiating treatment with bupropion and periodically during the treatment to ensure patient safety.

Patients should be instructed to seek emergency medical help if they experience psychosis or other neuropsychiatric reactions. Additionally, they should discontinue bupropion and contact a healthcare provider if they experience any neuropsychiatric adverse events or if a seizure occurs.

Side Effects

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

Serious adverse reactions warrant particular attention. A WARNING: SUICIDAL THOUGHTS AND BEHAVIORS is indicated, as there is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been observed during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides. Patients experiencing any of these symptoms should be instructed to contact a healthcare professional immediately.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, the medication may increase blood pressure, necessitating monitoring before and periodically during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Angle-closure glaucoma has also occurred in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. The use of Monoamine Oxidase Inhibitors (MAOIs) is contraindicated with this medication; it should not be used in conjunction with MAOIs intended for psychiatric disorders or within 14 days of stopping treatment with either agent.

In cases of overdosage, seizures have been reported in approximately one-third of cases. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation) or arrhythmias, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of WELLBUTRIN SR with certain drug classes may lead to significant interactions that require careful management.

CYP2B6 Inducers When WELLBUTRIN SR is administered alongside CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, an increase in the WELLBUTRIN SR dose may be necessary based on clinical response. However, the dosage should not exceed the maximum recommended limit.

CYP2D6 Substrates Bupropion is known to inhibit CYP2D6, which can lead to elevated plasma concentrations of drugs metabolized by this enzyme, including certain antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics. A dose reduction of these medications should be considered when used concurrently with WELLBUTRIN SR.

Digoxin WELLBUTRIN SR may reduce plasma levels of digoxin. It is advisable to monitor digoxin levels closely in patients receiving this combination.

Drugs Lowering Seizure Threshold Caution is warranted when dosing WELLBUTRIN SR in conjunction with medications that lower the seizure threshold, as this may increase the risk of seizures.

Dopaminergic Drugs Concomitant use of WELLBUTRIN SR with dopaminergic agents such as levodopa and amantadine may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs) The use of WELLBUTRIN SR with MAOIs can elevate the risk of hypertensive reactions. This combination should be avoided unless under strict medical supervision.

Drug-Laboratory Test Interactions WELLBUTRIN SR may cause false-positive results in urine tests for amphetamines. Clinicians should be aware of this potential interaction 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 in the pediatric population have not been established. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for further information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

Geriatric Use

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

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, it is important to note that some older individuals may exhibit greater sensitivity to the medication.

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 geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any 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 https://womensmentalhealth.org/research/pregnancyregistry/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 during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 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 greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. 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.

Clinical considerations suggest that women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression compared to those who continue treatment. Therefore, it is essential to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

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 was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, similar to the background rate of approximately 1%.

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding possible associations. The United Healthcare database lacked sufficient power to evaluate these associations, while the National Birth Defects Prevention Study (NBDPS) found an increased risk for LVOTO, and the Slone Epidemiology case-control study did not find an increased risk for VSD.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while pregnant rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, in a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day had no effect on pup growth or development.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving 10 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, 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 considered alongside the mother’s clinical need for WELLBUTRIN SR and any potential adverse effects on the breastfed child from WELLBUTRIN SR or from the underlying maternal condition.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 various cardiac complications. It is important to note that fatalities have been associated with bupropion overdose, frequently linked to multiple uncontrolled seizures and subsequent cardiac failure.

Currently, there are no known antidotes for bupropion overdose. Therefore, the management of such cases relies heavily on supportive care and vigilant medical supervision. Healthcare professionals are advised to ensure the patient's airway is secure, and that adequate oxygenation and ventilation are maintained.

In the event of a suspected overdose, it is crucial to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center by calling 1-800-222-1222 or visiting www.poison.org. It is important to note that the induction of emesis is not recommended in cases of bupropion overdose, further emphasizing the need for professional medical intervention.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day to rats, which is approximately seven times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male and female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males received the treatment for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately five times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven and two times the 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, approximately two to seven 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 the Ames bacterial mutagenicity assay, yielding a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

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 taking 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 in some individuals using bupropion for smoking cessation. These symptoms were more frequently observed in patients with a prior history of mental health disorders compared to those without such a history.

Severe allergic reactions to WELLBUTRIN SR have been reported, including 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, and difficulty breathing.

The incidence of seizures has been found to increase with higher doses of WELLBUTRIN SR. Additionally, some patients have experienced significant increases in blood pressure while taking WELLBUTRIN SR, particularly those also using nicotine replacement therapy to aid in smoking cessation.

Episodes of mania, characterized by greatly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, and rapid speech, have been reported in some individuals. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, and confusion, have also been observed in patients taking WELLBUTRIN SR.

Visual disturbances, such as eye pain, changes in vision, and swelling or redness in or around the eye, have been documented in postmarketing reports.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Medication Guide) thoroughly. 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, particularly during the initial stages of antidepressant treatment and when adjusting the dose.

Families and caregivers should be encouraged to monitor patients on a day-to-day basis for any abrupt changes in behavior, which should be reported to the patient’s prescriber or healthcare professional, especially if these changes are severe or were not part of the patient’s initial symptoms. 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. Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience any of these symptoms.

Patients should be educated about the signs of hypersensitivity and advised to discontinue WELLBUTRIN SR if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking WELLBUTRIN SR and not to restart it if they experience a seizure during treatment. It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

Patients should take WELLBUTRIN SR in two divided doses, preferably with at least 8 hours between doses, to reduce the risk of seizures when increasing the dose above 150 mg/day. They should also be made aware that taking WELLBUTRIN SR can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals. Furthermore, patients should be informed that WELLBUTRIN SR contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used for smoking cessation, and that it should not be used in combination with ZYBAN or any other medications containing bupropion.

Patients should be advised that any CNS-active drug, including WELLBUTRIN SR, may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are certain that WELLBUTRIN SR does not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery. They should also notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as WELLBUTRIN SR and other drugs may affect each other's metabolism.

Patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with WELLBUTRIN SR. It is important to instruct patients to store WELLBUTRIN SR at room temperature, between 68°F and 77°F (20°C to 25°C), keeping the tablets dry and protected from light. Patients should swallow WELLBUTRIN SR tablets whole to ensure the release rate is not altered; they should not chew, divide, or crush the tablets, as they are designed for slow release in the body.

If a patient misses a dose, they should be instructed not to take an extra tablet to compensate for the missed dose but to take the next tablet at the regular time due to the dose-related risk of seizure. Patients should also be informed that WELLBUTRIN SR tablets may have an odor and that the medication 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 room temperature, ideally between 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15°C and 30°C (59°F and 86°F) in accordance with USP Controlled Room Temperature guidelines.

To ensure product integrity, it is essential to protect the product from light and moisture during storage and handling.

Additional Clinical Information

Patients receiving treatment with WELLBUTRIN should be closely monitored for the emergence of agitation, irritability, and unusual behavioral changes, as well as symptoms of suicidality. Families and caregivers are advised to conduct daily observations and report any concerning symptoms to healthcare providers immediately. Patients should discontinue WELLBUTRIN and seek medical advice if they experience agitation, changes in mood or behavior, or develop suicidal thoughts or behaviors. Additionally, patients are instructed to contact a healthcare professional if any neuropsychiatric reactions occur.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, particularly in patients using it for smoking cessation. These events include mood changes, psychosis, and suicidal ideation, among others. Anaphylactoid and anaphylactic reactions have also been reported, with symptoms such as pruritus, urticaria, and dyspnea. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have been documented in association with bupropion.

FDA Insert (PDF)

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

View full prescribing information (PDF)