Bupropion hydrochloride

Description

Bupropion hydrochloride is an antidepressant belonging to the aminoketone class, chemically distinct from tricyclic, tetracyclic, selective serotonin reuptake inhibitors, and other known antidepressant agents. Its structure is similar to 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 of bupropion hydrochloride is 276.21, and its molecular formula is C13H18ClNO•HCl.

The drug appears as a white powder that is soluble in water, has a bitter taste, and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets USP (XL) are available for oral administration in strengths of 150 mg and 300 mg. These tablets are off-white to pale yellow in color and contain the labeled amount of bupropion hydrochloride along with inactive ingredients, which include ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, glyceryl behenate, hydrophobic colloidal silica, hydroxypropyl cellulose, iron oxide black, L-cysteine hydrochloride monohydrate, methacrylic acid copolymer dispersion, polyvinyl alcohol, povidone, propylene glycol, shellac, and triethyl citrate. The tablets are printed with edible black ink.

Uses and Indications

Bupropion hydrochloride extended-release tablet (XL) is indicated for the treatment of major depressive disorder (MDD) in adults. Additionally, it is indicated for the prevention of seasonal affective disorder (SAD).

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

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. The usual target dose is 300 mg once daily, which may be achieved after 4 days of treatment, provided the patient tolerates the initial dose.

In the case of Seasonal Affective Disorder, treatment 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, the dose may be increased to 300 mg once daily, and 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 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.

• 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 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, it is contraindicated 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).

Warnings and Precautions

The use of bupropion hydrochloride extended-release tablets (XL) necessitates careful consideration of several warnings and precautions to ensure patient safety.

Suicidal Thoughts and Behaviors There is a significant warning regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults who are prescribed antidepressants, including bupropion. Healthcare professionals are advised to closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking while using bupropion may experience serious neuropsychiatric adverse events. These can include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, aggression, hostility, agitation, anxiety, panic, and suicidal ideation. It is essential for healthcare providers to observe patients for these symptoms and instruct them to discontinue bupropion and seek immediate medical advice if such adverse events occur.

Seizure Risk The risk of seizures associated with bupropion is dose-dependent. To minimize this risk, it is recommended that the daily dose not exceed 450 mg and that any dose increases be 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. Therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

Activation of Mania/Hypomania Patients with a history of bipolar disorder should be screened prior to treatment, and ongoing monitoring for symptoms of mania or hypomania is recommended.

Psychosis and Other Neuropsychiatric Reactions Patients should be instructed to report any occurrences of psychosis or other neuropsychiatric reactions to their healthcare provider promptly.

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 the initiation of treatment and periodically during the treatment course to ensure patient safety.

In summary, healthcare professionals must provide clear instructions to patients regarding the need to discontinue bupropion hydrochloride extended-release tablets (XL) and seek medical attention if they experience any neuropsychiatric adverse events. This proactive approach is essential for managing the potential risks associated with this medication.

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 least twice the rate of placebo, include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious adverse reactions warrant particular attention. There is a WARNING regarding the increased risk of suicidal thoughts and behaviors 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 reported 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 advised to contact a healthcare professional immediately.

Additional important safety information includes 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, the medication should be discontinued. The use of bupropion hydrochloride extended-release tablets (XL) may also lead to increased blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, necessitating caution in such individuals.

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, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), mental status changes, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with bupropion overdose have been documented, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

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

CYP2B6 Inducers 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 maintain clinical efficacy. However, any dosage adjustments should not exceed the maximum recommended dose.

CYP2D6 Inhibitors Bupropion is known to inhibit CYP2D6, which can lead to increased plasma concentrations of various medications, including 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.

Seizure Threshold Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) in conjunction with other medications that may lower the seizure threshold, as this combination can increase the risk of seizures.

CNS Toxicity 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. Monitoring for signs of CNS effects is recommended.

Hypertensive Reactions The use of bupropion hydrochloride extended-release tablets (XL) in combination with monoamine oxidase inhibitors (MAOIs) can elevate the risk of hypertensive reactions. Close monitoring of blood pressure is advised in patients receiving this combination.

Urine Drug Testing It is important to note that bupropion hydrochloride extended-release tablets (XL) may cause false-positive results in urine tests for amphetamines. This potential for false-positive results should be communicated to patients and healthcare providers.

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 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 years and older participated in trials utilizing the immediate-release formulation of bupropion hydrochloride.

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

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/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, the estimated background risk for major birth defects and miscarriage is unknown for the indicated population, with the U.S. general population having an estimated background risk of 2% to 4% for major birth defects and 15% to 20% for miscarriage in clinically recognized pregnancies.

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. Decreased fetal weights were noted at doses twice the MRHD and greater.

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 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.

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. However, the registry suggested a possible increase in cardiac malformations, with a prospectively observed rate of 1.3% for cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester, which is similar to the background rate of approximately 1%. Study findings regarding bupropion exposure and risks 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 studies conducted in pregnant rats and rabbits, bupropion was administered orally 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 rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest tested dose. No maternal toxicity was evident at doses of 50 mg/kg/day or less, and in a pre-and postnatal development study, bupropion administered 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.

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.

Currently, 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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside 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

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 doses of 30 grams or more. In approximately one third of these cases, seizures have been reported.

Serious adverse reactions associated with bupropion overdose may include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes. Additional symptoms that may manifest include alterations in mental status, clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure.

Fatalities linked to bupropion overdose have occurred, particularly in patients who have ingested large quantities. These cases often involve multiple uncontrolled seizures and significant cardiac complications prior to death.

Currently, there are no known antidotes for bupropion overdose. Therefore, supportive care and close medical supervision are essential for managing affected patients. In the event of a bupropion overdose, it is crucial to consult a Certified Poison Control Center for expert guidance on appropriate management strategies.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice using bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day of bupropion hydrochloride, which is approximately 2 to 7 times the MRHD on a mg/m² basis. Lower doses were not evaluated in this study. 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.

In terms of mutagenicity, 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 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. No information is available regarding teratogenic effects or animal pharmacology and toxicology.

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.

Patients experiencing a seizure while on bupropion hydrochloride extended-release tablets (XL) are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride extended-release tablets (XL) is contraindicated following a seizure.

Instances of severe hypertension have been reported in some individuals taking bupropion hydrochloride extended-release tablets (XL), with an increased risk noted in those concurrently using nicotine replacement therapy, such as nicotine patches, for smoking cessation.

Some individuals may experience episodes of mania while on bupropion hydrochloride extended-release tablets (XL), characterized by symptoms such as significantly 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 been reported by some patients taking bupropion hydrochloride extended-release tablets (XL).

Severe allergic reactions to bupropion hydrochloride extended-release tablets (XL) have been observed. Patients should discontinue use and seek immediate medical attention if they experience symptoms such as 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 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.

Providers should instruct patients and their support systems to read the Medication Guide thoroughly and assist them in comprehending its contents. Patients should be encouraged to discuss the information within the Medication Guide and to ask any questions they may have.

Healthcare providers must inform patients about the potential emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual behavioral changes, as well as worsening depression and suicidal ideation, particularly during the initial stages of treatment or when dosage adjustments occur. Families and caregivers should be advised to monitor 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 prescriber, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and possible medication adjustments.

Patients should be educated on the signs of hypersensitivity and instructed to discontinue bupropion hydrochloride extended-release tablets (XL) if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue and not restart the medication.

Providers should caution patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can elevate the risk of seizures, and patients should be advised to minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride extended-release tablets (XL) may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

Patients should be made aware 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 conjunction with ZYBAN or any other medications containing bupropion hydrochloride. Furthermore, patients should be counseled 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.

Healthcare providers should encourage patients to notify them of any prescription or over-the-counter medications they are taking or plan to take, as interactions may affect the metabolism of bupropion hydrochloride extended-release tablets (XL). Patients should also inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Patients must be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole, without crushing, dividing, or chewing, to ensure the proper release rate of the medication. If a patient misses a dose, they should not take an extra tablet to compensate but should instead take the next tablet at the regular scheduled time due to the dose-related risk of seizure.

Lastly, patients should be informed that they may notice an inert matrix in their stool, which is normal, as the active medication has already been absorbed by the time they see the inert matrix tablet.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP guidelines for controlled room temperature.

Care should be taken to ensure that the product is kept in its original container to maintain stability and integrity. Special handling requirements should be observed to prevent exposure to extreme temperatures or conditions that may compromise the product's quality.

Additional Clinical Information

Patients receiving bupropion hydrochloride extended-release tablets (XL) for major depressive disorder or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion XL and seek medical attention if they experience agitation, mood changes, or suicidal thoughts that are atypical for the patient. Additionally, any signs of allergic reactions, such as skin rash, pruritus, or respiratory difficulties, warrant immediate cessation of the medication and consultation with a healthcare provider.

Postmarketing experience has revealed serious neuropsychiatric adverse events in patients using bupropion for smoking cessation, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, characterized by symptoms such as pruritus and dyspnea, necessitating medical intervention. Rare cases of severe skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been associated with bupropion use.

FDA Insert (PDF)

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

View full prescribing information (PDF)