Bupropion Hydrochloride Extended Release

Description

Bupropion hydrochloride extended-release tablets (XL) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. The 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 active pharmaceutical ingredient is presented as a white, crystalline powder that is highly soluble in water and possesses a bitter taste, inducing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets (XL) are formulated for oral administration in dosages of 150 mg and 300 mg, appearing as white to off-white tablets.

Each tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, which include alcohol, ethylcellulose, hydrochloric acid, hydroxypropyl cellulose, hypromellose, methacrylic acid and ethyl acrylate copolymer, polyethylene glycol, povidone, purified water, silicon dioxide, stearic acid, and talc. The tablets are imprinted with edible black ink composed of ferrosoferric oxide, hypromellose, propylene glycol, and purified water. The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is excreted in the feces. The formulation meets the USP Dissolution Test 25.

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 Major Depressive Disorder, the recommended starting dose is 150 mg administered once daily. After a period of four 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 150 mg every other day. In patients with mild hepatic impairment, it is advisable to consider a reduction in dose and/or 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 adverse effects.

Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may also increase the risk of seizures.

Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride extended-release tablets (XL) should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride extended-release tablets (XL). Additionally, bupropion hydrochloride extended-release tablets (XL) should not be started in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

Postmarketing surveillance has identified serious neuropsychiatric adverse events associated with the use of bupropion hydrochloride extended-release tablets (XL) during smoking cessation. These events may include significant mood alterations such as depression and mania, as well as psychotic symptoms including hallucinations, paranoia, delusions, and aggressive behaviors. Healthcare professionals are advised to closely monitor patients for the emergence of these symptoms. Should any neuropsychiatric adverse events occur, patients should be instructed to discontinue bupropion hydrochloride XL and seek immediate consultation with a healthcare provider.

The risk of seizures is dose-dependent; therefore, it is crucial to limit the daily dosage to a maximum of 450 mg and to increase the dose gradually. In the event of a seizure, bupropion hydrochloride XL should be discontinued promptly.

Bupropion hydrochloride XL has the potential to elevate blood pressure. It is recommended that blood pressure be assessed prior to the initiation of treatment and monitored periodically throughout the course of therapy to ensure patient safety.

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 essential during treatment.

In addition, patients should be informed about the possibility of psychosis and other neuropsychiatric reactions. They should be encouraged to report any such reactions to their healthcare professional without delay.

There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion hydrochloride XL. Caution is advised in these patients.

It is imperative to note the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Continuous monitoring for the worsening of symptoms and the emergence of suicidal ideation or behaviors is essential throughout the treatment period.

Side Effects

Patients receiving bupropion hydrochloride may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Common adverse reactions, occurring in at least 5% of patients and at a rate greater than twice that 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 have been reported, including an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. Patients should be closely monitored for the emergence or worsening of these symptoms. Additionally, there is a dose-related risk of seizures, which can be minimized by limiting the daily dose to 450 mg and gradually increasing it. If a seizure occurs, discontinuation of the medication is advised.

Hypertension is another serious concern, as bupropion hydrochloride extended-release tablets (XL) can elevate blood pressure. Blood pressure should be monitored before and periodically during treatment. Activation of mania or hypomania has also been observed, necessitating screening for bipolar disorder and careful monitoring for these symptoms.

Adverse reactions leading to discontinuation of treatment were noted in clinical trials, with rash occurring in 2.4% of patients at a dose of 300 mg/day and 0.9% at 400 mg/day. Nausea led to discontinuation in 0.8% of patients at 300 mg/day and 1.8% at 400 mg/day, while agitation was reported in 0.3% and 1.8% of patients, respectively.

Additional adverse reactions occurring at an incidence greater than 1% include headache, infection, asthenia, chest pain, fever, flushing, hot flashes, constipation, diarrhea, vomiting, dysphagia, arthralgia, irritability, memory decrease, paresthesia, central nervous system stimulation, sinusitis, increased cough, pruritus, urticaria, taste perversion, blurred vision or diplopia, urinary urgency, vaginal hemorrhage, and urinary tract infection.

Postmarketing experience has revealed further adverse reactions across various systems. General body reactions include chills, facial edema, and malaise. Cardiovascular events such as postural hypotension, hypertension, stroke, and myocardial infarction have been reported. Digestive system reactions include abnormal liver function, gastric reflux, and pancreatitis. Neuropsychiatric events during smoking cessation have included mood changes, psychosis, and suicidal ideation.

Patients may also experience skin reactions such as maculopapular rash and angioedema, as well as urogenital issues including impotence and urinary retention. Angle-closure glaucoma has been noted in patients with untreated anatomically narrow angles treated with antidepressants.

In summary, while bupropion hydrochloride is effective for its indicated uses, healthcare providers should be vigilant in monitoring for these adverse reactions and managing them appropriately.

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

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

Inhibitors of CYP2D6: Bupropion is a known inhibitor of CYP2D6 and may elevate the 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 lead to central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is recommended.

Monoamine Oxidase Inhibitors (MAOIs): The combination of bupropion XL with MAOIs poses an increased risk of hypertensive reactions. Close monitoring is warranted if these agents are used together.

Drug-Laboratory Test Interactions

Bupropion 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 for patients receiving bupropion.

Packaging & NDC

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

Pediatric Use

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

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 years and older participated in 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, it is important to note that while clinical experience has not identified significant differences in responses between these age groups, the potential for greater sensitivity in some older individuals cannot be excluded.

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, there is an increased risk of adverse reactions in this population. Therefore, careful consideration of renal function is advised when selecting doses for geriatric patients. Monitoring of renal function may be beneficial to ensure safe and effective use of bupropion in this demographic.

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 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. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than those who continued treatment. Therefore, healthcare providers should 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.

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, 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 in the indicated population is unknown. 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.

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%, which is 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. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

Healthcare providers should weigh the benefits of treatment against the potential risks when considering the use of bupropion in pregnant patients.

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 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 these patients to ensure safety and efficacy.

Hepatic Impairment

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

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one third of these cases, seizures were reported. Other serious adverse reactions associated with bupropion overdose include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances or arrhythmias. Additionally, severe symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have primarily been observed in cases involving multiple drug overdoses.

While the majority of patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, particularly in individuals who ingested large quantities of the drug. Reports indicate that these patients experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for the most current guidance and recommendations. Healthcare professionals can reach a poison control center by calling 1-800-222-1222 or by visiting www.poison.org.

There are currently no known antidotes for bupropion. Management of an overdose should focus on providing supportive care, which includes close medical supervision and monitoring of the patient. It is also essential to consider the possibility of a multiple drug overdose when assessing the situation.

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, 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, 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 control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was noted in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

During post-approval use of bupropion hydrochloride extended-release tablets (XL), various adverse reactions have been reported voluntarily from a population of uncertain size. Due to the nature of these reports, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General): Reports include chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.

Cardiovascular: Adverse events such as postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism have been documented.

Digestive: Notable reactions include 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: Instances of hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion have been reported.

Hemic and Lymphatic: Reports of ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia have been noted. 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: Glycosuria has been reported.

Musculoskeletal: Adverse events include leg cramps, fever/rhabdomyolysis, and muscle weakness.

Nervous System: Reports 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: Adverse reactions such as bronchospasm and pneumonia have been reported.

Skin: Reports include maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses: Instances of accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis have been documented.

Urogenital: Adverse events reported include impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

Patient Counseling

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 important to counsel patients, their families, and caregivers on the appropriate use of this medication.

Instruct patients, their families, and caregivers to read the Medication Guide thoroughly and assist them in understanding its contents. Encourage patients to discuss the information within the Medication Guide and to ask any questions they may have.

Healthcare providers should inform patients about the potential emergence of 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, particularly during the initial stages of treatment or when adjusting the dose. Families and caregivers should be vigilant in observing for these symptoms on a daily basis, as changes can occur abruptly. Any severe or sudden onset of these symptoms should be reported to the patient’s prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and possible medication adjustments.

Inform patients that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal ideation when attempting to quit smoking while taking bupropion. Patients should be instructed to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience such symptoms.

Educate patients on the signs of hypersensitivity and instruct them to discontinue the medication if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking bupropion hydrochloride extended-release tablets (XL) if they experience a seizure during treatment. Emphasize that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and patients should minimize or avoid alcohol consumption.

Patients should be informed that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals. They may wish to undergo an examination to determine their susceptibility and consider a prophylactic procedure if necessary.

Educate patients that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient as ZYBAN, which is used for smoking cessation, and should not be used in combination with ZYBAN or any other medications containing bupropion hydrochloride.

Advise patients that bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment, motor, and cognitive skills. Until they are certain that the medication does not adversely affect their performance, patients should refrain from driving or operating complex machinery.

Finally, counsel patients to notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion hydrochloride extended-release tablets (XL) may interact with other drugs, affecting their metabolism.

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP guidelines. It is essential to protect the product from light to maintain its integrity and efficacy.

Additional Clinical Information

Postmarketing experience has revealed a range of adverse effects associated with the medication. General body reactions include chills, facial and peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise. Cardiovascular events reported encompass postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.

Gastrointestinal disturbances include abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, and various forms of colitis and gastrointestinal hemorrhage. Endocrine effects such as hyperglycemia and hypoglycemia have also been noted. Hematological issues include ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, and thrombocytopenia, with altered PT and/or INR observed when coadministered with warfarin. Neurological symptoms range from abnormal coordination and emotional lability to severe conditions like coma and suicidal ideation. Respiratory complications include bronchospasm and pneumonia, while dermatological reactions feature maculopapular rash and alopecia. Urogenital effects include impotence, polyuria, and various disorders related to ejaculation and urinary function. Special senses may be affected, leading to dry eye and increased intraocular pressure.

FDA Insert (PDF)

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

View full prescribing information (PDF)