Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion and is related to phenylethylamines. The chemical designation is (±)-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 appears as a white powder that is soluble in 0.1N HCl, 96% alcohol, and water. It has a bitter taste and produces a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets, USP (XL) are supplied for oral administration in strengths of 150 mg and 300 mg, appearing as white to pale yellow extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride along with inactive ingredients, which include colloidal silicon dioxide, copovidone, hydrochloric acid, hypromellose, magnesium stearate, methacrylic acid copolymer dispersion, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl alcohol, silicon dioxide, talc, 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, 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 either the dose or the 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 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. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI or initiated in patients currently receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Serious neuropsychiatric adverse events have been reported in patients using bupropion hydrochloride extended-release tablets (XL) during smoking cessation. These events may include significant mood changes such as 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. Healthcare professionals should closely observe patients attempting to quit smoking with bupropion hydrochloride XL for the emergence of these symptoms. Patients should be instructed to discontinue the medication and contact a healthcare provider immediately if they experience any of these adverse events.

The risk of seizures is dose-related when using bupropion hydrochloride XL. 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.

Bupropion hydrochloride XL has the potential to increase blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

Patients with a history of bipolar disorder should be screened prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is advised.

There is a risk of psychosis and other neuropsychiatric reactions associated with bupropion hydrochloride XL. Patients should be instructed to contact a healthcare professional if they experience any such reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion. Caution should be exercised in these patients.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. It is crucial to monitor these populations for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

To ensure safe use of bupropion hydrochloride XL, healthcare professionals should monitor blood pressure before treatment initiation and periodically during treatment. Patients should be advised to discontinue the medication and seek medical attention if they experience any neuropsychiatric adverse events or if a seizure occurs.

Side Effects

Patients may experience a range of adverse reactions while taking bupropion hydrochloride extended-release tablets (XL). 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 adverse reactions warranting caution include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults. Patients should be closely monitored for the emergence or worsening of these thoughts and behaviors during treatment. Neuropsychiatric events, such as mood changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides, have also been reported, particularly during smoking cessation.

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. Additionally, bupropion can 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. Psychotic symptoms and other neuropsychiatric reactions may occur, and patients are advised to contact a healthcare professional if such symptoms arise. There is also a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles.

Important considerations include the contraindication of bupropion in patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and those who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. The use of monoamine oxidase inhibitors (MAOIs) in conjunction with bupropion is contraindicated, as is the use of bupropion within 14 days of stopping an MAOI.

In cases of overdose, seizures were reported in approximately one third of all instances. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances 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

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 is known to inhibit CYP2D6, which can lead to elevated concentrations of certain medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). In such cases, a dose reduction of these concomitant medications should be considered.

Caution is warranted when prescribing bupropion hydrochloride extended-release tablets (XL) alongside drugs that may lower the seizure threshold, as this combination could increase 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, necessitating careful monitoring of patients.

Additionally, there is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are used in conjunction with monoamine oxidase inhibitors (MAOIs).

It is also important to note that bupropion hydrochloride extended-release tablets (XL) can lead to false-positive results in urine tests for amphetamines, which may have implications for drug screening processes.

Packaging & NDC

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

Pediatric Use

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

Geriatric Use

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

No overall differences in safety or effectiveness were observed between elderly patients and younger 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.

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

Data from epidemiological studies of 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.

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. In contrast, studies in pregnant rabbits during organogenesis revealed non-dose-related increases in the incidence of fetal malformations and skeletal variations at doses approximately equal to the MRHD and greater. Additionally, decreased fetal weights were observed at doses twice the MRHD and higher.

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.

A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare professionals should consider the risks of untreated depression and potential effects on the fetus when contemplating changes to antidepressant therapy 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 with 1,213 first trimester exposures, did not demonstrate an overall increased risk for malformations. Although the Registry was not specifically designed to evaluate individual defects, it suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, comparable to the background rate of approximately 1%.

Inconsistent findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) do not allow for definitive conclusions regarding potential associations.

In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 mg/kg/day and 150 mg/kg/day, respectively. No evidence of fetal malformations was observed in rats, while in rabbits, non-dose-related increases in fetal malformations and skeletal variations were noted at the lowest tested dose of 25 mg/kg/day and higher. 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. Furthermore, a pre- and postnatal development study indicated that bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no adverse effects 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 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 extended-release tablets (XL) and any potential adverse effects on the breastfed child from the medication 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 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 can occur with significant consequences, particularly when doses exceed 30 grams. In such cases, seizures are reported to occur in approximately one third of the instances.

Potential Symptoms Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly pronounced in cases involving multiple drug overdoses, which can complicate the clinical picture.

Management Procedures There have been reports of fatalities linked to bupropion overdose, often preceded by multiple uncontrolled seizures, bradycardia, and cardiac arrest. Given the severity of these potential outcomes, it is critical to implement supportive care and maintain close medical supervision for affected individuals.

As there are no known antidotes for bupropion, healthcare professionals are advised to consult a Certified Poison Control Center for guidance in managing a bupropion overdose. This consultation can provide essential support in determining the appropriate course of action and ensuring patient safety.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice, administering bupropion hydrochloride at doses 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 mg/kg/day 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, 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 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. These symptoms have been observed in some patients upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

The incidence of seizures has been reported to increase with higher doses of bupropion hydrochloride extended-release tablets (XL). Additionally, some individuals may experience significant increases in blood pressure while on this medication.

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, grandiosity, excessive happiness or irritability, and rapid speech.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been reported among patients using bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been documented, with signs including rash, itching, hives, fever, swollen lymph nodes, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

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, 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, particularly when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional immediately.

Patients should be educated about the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be informed that if they experience a seizure while on treatment, they should discontinue and not restart bupropion hydrochloride extended-release tablets (XL). It is crucial to advise 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 also be made aware that bupropion hydrochloride extended-release tablets (XL) can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals. It is important to inform 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.

Healthcare providers should counsel patients that any CNS-active drug, including bupropion hydrochloride extended-release tablets (XL), may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until patients are certain that bupropion does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Patients should be instructed to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy. Communication with the patient and pediatric healthcare provider regarding the infant’s exposure to bupropion through human milk is also essential.

Patients should be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole to avoid altering the release rate. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular time due to the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and may be consumed with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. 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 caregivers should be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and seek immediate medical attention 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 other concerning symptoms, reporting any such changes to healthcare providers promptly. It is recommended that prescriptions for bupropion XL be limited to the smallest quantity necessary to minimize the risk of overdose.

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 with symptoms such as pruritus, urticaria, and dyspnea, necessitating medical intervention. Rare cases of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock have also been documented, 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 Bupropion Hydrochloride as submitted by ScieGen Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)