Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, distinguished by its chemical structure, which is unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or 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 compound appears as a white, crystalline powder that is soluble in water, 0.1N HCl, and alcohol. It possesses a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets, USP (XL), for oral administration, each containing 150 mg of bupropion hydrochloride. The tablets are white to off-white in color and include inactive ingredients such as ammonium chloride, colloidal silicon dioxide, ethyl cellulose, eudragit L30D55, glyceryl behenate, iron oxide black, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, propylene glycol, silicon dioxide, shellac glaze, talc, titanium dioxide, and triethyl citrate. The tablets are printed with edible black ink.

The extended-release tablet's insoluble shell may remain intact during gastrointestinal transit and is excreted in the feces. The USP dissolution test for this formulation is currently pending.

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) in individuals at risk.

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

Dosage and Administration

Dosing should be initiated at a low level and 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. The usual target dose is 300 mg once daily. After an initial period of 4 days, the dose may be increased to 300 mg once daily if clinically indicated.

In the treatment of Seasonal Affective Disorder, therapy should commence 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. 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 cases of mild hepatic impairment, it is advisable to consider a reduction in the dose and/or 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 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. Bupropion should not be used within 14 days of stopping an MAOI, nor should it be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

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

Suicidal Thoughts and Behaviors; Neuropsychiatric Reactions There is an increased risk of suicidal thinking and behavior 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 taking bupropion for smoking cessation, necessitating vigilant observation.

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 periodically throughout the course of therapy to detect any significant changes.

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 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 and periodically during therapy to ensure patient safety.

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

Side Effects

Patients may experience a range of adverse reactions while using this medication. Common adverse reactions, occurring in 5% or more of patients and at a rate at least 2% higher than 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. A WARNING is issued regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for the emergence or worsening of suicidal thoughts and behaviors. Additionally, serious neuropsychiatric events have been reported in patients taking bupropion for 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. Bupropion hydrochloride extended-release tablets (XL) may also increase blood pressure, necessitating monitoring of blood pressure before and during treatment.

Patients with a history of bipolar disorder should be screened, as there is a risk of activation of mania or hypomania. Neuropsychiatric reactions, including psychosis, have been reported, and patients are advised to contact a healthcare professional if such symptoms occur. Furthermore, angle closure glaucoma has been observed in patients with untreated anatomically narrow angles who are treated with antidepressants.

In cases of overdosage, serious reactions have been documented. Reports indicate that overdoses of 30 grams or more of bupropion can lead to seizures in approximately one third of cases. Other serious reactions associated with bupropion overdoses include hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Additional severe outcomes, primarily in the context of multiple drug overdoses, include fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion alone, with multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest occurring prior to death.

Drug Interactions

Coadministration of bupropion hydrochloride extended-release tablets (XL) with certain drug classes may lead to significant interactions that require careful consideration.

Pharmacokinetic Interactions

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

• CYP2D6 Substrates: Bupropion is a known inhibitor of 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.

Pharmacodynamic Interactions

• Drugs that Lower Seizure Threshold: Caution is advised when prescribing bupropion XL with other medications that may lower the seizure threshold, as this combination could increase the risk of seizures.

• Dopaminergic Drugs: The concurrent use of bupropion XL 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 combination of bupropion XL with MAOIs can elevate the risk of hypertensive reactions. Close monitoring is warranted when these agents are used together.

Laboratory Test Interactions

Bupropion XL may interfere with laboratory tests, specifically causing false-positive results for amphetamines in urine drug screenings. This potential interaction should be communicated to healthcare providers conducting such tests.

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 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 6000 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 in these studies. 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, 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 in this demographic.

Pregnancy

Pregnancy Category C. Data from epidemiological studies involving pregnant women exposed to bupropion during the first trimester indicate no overall increased risk of congenital malformations. It is important to note that all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. Reproductive developmental studies in rats and rabbits did not demonstrate clear evidence of teratogenic activity; however, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations observed at doses approximately equal to the maximum recommended human dose (MRHD) and higher. Additionally, decreased fetal weights were noted at doses twice the MRHD and greater.

Bupropion hydrochloride extended-release tablets (XL) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical considerations must include the risk of untreated depression when discontinuing or altering treatment with antidepressant medications during pregnancy and postpartum.

Human 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 show an increased risk for malformations overall. Specifically, the observed rate of cardiovascular malformations in pregnancies with first trimester exposure to bupropion was 1.3%, which aligns with the background rate of approximately 1%. While some studies have reported inconsistent findings regarding the association of bupropion exposure during the first trimester with left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), the overall evidence does not support a definitive conclusion regarding these risks. The NBDPS found an increased risk for LVOTO, while the Slone Epidemiology case-control study did not. Similarly, the findings regarding VSD were inconsistent, with some studies indicating an increased risk and others not supporting this association.

Animal studies have shown that bupropion was administered orally at doses up to 450 mg/kg/day in rats and 150 mg/kg/day in rabbits during the period of organogenesis, with no clear evidence of teratogenic effects. However, increased fetal malformations and decreased fetal weights were observed at certain doses in rabbits. In rats, no adverse effects on offspring development were noted when bupropion was administered at doses up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation.

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.

Caution is advised when administering bupropion hydrochloride extended-release tablets (XL) to lactating mothers.

Renal Impairment

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when prescribing to patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

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 these cases, seizures occurred in approximately one third of the patients, highlighting the significant risk associated with excessive intake of this medication.

Serious adverse reactions have been observed in cases of bupropion overdose. These include hallucinations, loss of consciousness, sinus tachycardia, and various electrocardiogram (ECG) changes, such as conduction disturbances and arrhythmias. Additionally, when bupropion was involved in multiple drug overdoses, symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure were reported.

While the majority of patients experiencing bupropion overdose have recovered without lasting effects, there have been fatalities linked to high doses of the drug. In these severe cases, multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest were noted prior to death.

Healthcare professionals are advised to monitor patients closely for these symptoms and to initiate appropriate management strategies in the event of an overdose. Immediate medical intervention is crucial to mitigate the risks associated with bupropion overdose and to ensure patient safety.

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 implications of these lesions as potential precursors to liver neoplasms remain 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 assay. Additionally, an increase in chromosomal aberrations was noted in one of three 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

During post-approval use of bupropion hydrochloride extended-release tablets (XL), various adverse reactions have been reported voluntarily from a population of uncertain size. The frequency of these events and their causal relationship to drug exposure cannot be reliably estimated.

General adverse reactions include chills, facial edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise. Cardiovascular events reported include postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive system reactions encompass abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of the tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer. Endocrine-related events include hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and lymphatic reactions consist of ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered prothrombin time (PT) and/or international normalized ratio (INR), associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Metabolic and nutritional events include glycosuria.

Musculoskeletal reactions reported are leg cramps, fever/rhabdomyolysis, and muscle weakness. Nervous system events include abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory reactions include bronchospasm and pneumonia. Skin-related events consist of maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism. Special senses reactions involve accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.

Urogenital adverse reactions reported are impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Medication Guide, to understand the benefits and risks associated with bupropion hydrochloride extended-release tablets (XL). It is essential to counsel patients, their families, and caregivers on the appropriate use of this medication.

Patients should be instructed to review the Medication Guide, which includes critical information about antidepressant medicines, the potential for suicidal thoughts or actions, and the implications of quitting smoking. Providers should encourage patients to discuss the contents of the Medication Guide and address any questions they may have.

Healthcare providers must instruct patients, 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 behavioral changes. These symptoms may worsen depression or lead to suicidal ideation, particularly during the initial treatment phase or when adjusting the dosage. It is crucial for families and caregivers to monitor these changes closely and report any severe or abrupt symptoms to the prescriber.

Patients should be informed that quitting smoking, whether or not using ZYBAN, may trigger nicotine withdrawal symptoms or exacerbate pre-existing psychiatric conditions. They should be made aware of the potential for mood changes, psychosis, and suicidal thoughts during this process. If any concerning symptoms arise, patients should be encouraged to contact their healthcare provider immediately.

Education on hypersensitivity reactions is important; patients should discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, patients must be instructed to stop taking the medication if they experience a seizure and to avoid excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics, as these can increase seizure risk.

Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which can lead to angle closure glaucoma in susceptible individuals. They may wish to undergo an examination to assess their risk and consider prophylactic procedures if necessary.

It is important to inform patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN and should not be used in conjunction with ZYBAN or any other bupropion-containing medications.

Healthcare providers should counsel patients that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor skills. Until they are certain of how the medication affects them, patients should refrain from driving or operating complex machinery.

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

For breastfeeding patients, communication with the pediatric healthcare provider regarding the infant's exposure to bupropion through human milk is essential. Patients should be instructed to contact the infant's healthcare provider if they observe any concerning or persistent side effects in the infant.

Finally, patients should be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to maintain the proper release rate. If a dose is missed, patients should not take an extra tablet but should resume their regular dosing schedule, as this medication carries a dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (XL) should be taken in the morning and can be consumed with or without food.

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), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)