Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets USP (SR) is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride, with a molecular weight of 276.2 and a molecular formula of C13H18ClNO∙HCl. The bupropion hydrochloride, USP powder is white, crystalline, and highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride extended-release tablets USP (SR) are supplied for oral administration in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each tablet is film-coated and designed for sustained release. The tablets contain the labeled amount of bupropion hydrochloride, USP, along with inactive ingredients including cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide. The 100-mg tablet contains FD&C Blue No. 2 Lake, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains Iron Oxide Red and Ferrosoferric Oxide.

Uses and Indications

Bupropion hydrochloride extended-release (SR) tablets are indicated for the treatment of major depressive disorder (MDD).

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

Dosage and Administration

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

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

In patients with moderate to severe hepatic impairment, the recommended dosage is 100 mg daily or 150 mg every other day. For those with mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Additionally, in patients with renal impairment, a reduction in dose and/or frequency may also be warranted.

Contraindications

Use of bupropion hydrochloride extended-release (SR) tablets 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 (SR) tablets should not be used within 14 days of stopping an MAOI or vice versa. Additionally, it should not be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

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

Increased Risk of Suicidal Thoughts and Behaviors Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including bupropion. It is essential to monitor these patients closely for any worsening of symptoms or emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated serious neuropsychiatric adverse events associated with bupropion during smoking cessation. These events may include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Patients attempting to quit smoking should be observed for these symptoms, and they must be instructed to discontinue bupropion and contact a healthcare provider immediately if such adverse events occur.

Seizure Risk Bupropion carries a dose-related risk of seizures. To minimize this risk, it is recommended to gradually increase the dosage and limit the daily dose to a maximum of 400 mg. If a seizure occurs, the medication should be discontinued.

Hypertension Bupropion can elevate blood pressure. Therefore, it is crucial to monitor blood pressure prior to initiating treatment and periodically throughout the treatment course.

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 neuropsychiatric reactions, including psychosis.

Angle-Closure Glaucoma There is a risk of angle-closure glaucoma in patients with untreated anatomically narrow angles who are treated with antidepressants.

Monitoring Parameters Healthcare providers should routinely monitor blood pressure before and periodically during treatment to ensure patient safety.

In summary, it is imperative for healthcare professionals to remain vigilant regarding these warnings and precautions when prescribing bupropion, ensuring that patients are adequately informed and monitored throughout their treatment.

Side Effects

Patients may experience a range of adverse reactions while using bupropion hydrochloride extended-release (SR) tablets. The most common adverse reactions reported include headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitations, myalgia, sweating, rash, and anorexia.

Serious adverse reactions warrant particular attention. There is an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants, necessitating careful monitoring for the emergence or worsening of these symptoms. Neuropsychiatric adverse events have been observed during smoking cessation, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

The risk of seizures is dose-related; therefore, it is recommended to gradually increase the dose and limit the daily dose to 400 mg. If a seizure occurs, discontinuation of the medication is advised. Additionally, bupropion can elevate blood pressure, so monitoring is essential before and during treatment.

Activation of mania or hypomania has been reported, highlighting the importance of screening patients for bipolar disorder and monitoring for these symptoms. Patients should be instructed to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions.

Angle-closure glaucoma has been noted in patients with untreated anatomically narrow angles who are treated with antidepressants. Other important considerations include a history of seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the risks associated with abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs.

Bupropion hydrochloride extended-release (SR) tablets should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI. Known hypersensitivity to bupropion or its ingredients is also a contraindication.

In cases of overdose, seizures have been reported in approximately one-third of instances, along with other serious reactions such as hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including QRS prolongation), arrhythmias, 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 (SR) tablets 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, or phenytoin, an increase in bupropion dosage may be necessary based on clinical response. However, the dosage should not exceed the maximum recommended limit.

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

Pharmacodynamic Interactions

• Seizure Threshold: Caution is advised when prescribing bupropion hydrochloride extended-release (SR) tablets to patients taking other medications that lower the seizure threshold, as this may increase the risk of seizures.

• Digoxin: Bupropion may decrease plasma levels of digoxin. It is recommended to monitor digoxin levels closely in patients receiving this combination.

• Dopaminergic Drugs: The concomitant use of bupropion with dopaminergic medications such as levodopa and amantadine may result in central nervous system (CNS) toxicity. Monitoring for signs of CNS effects is advised.

• Monoamine Oxidase Inhibitors (MAOIs): The use of bupropion in conjunction with MAOIs can heighten the risk of hypertensive reactions. Caution is warranted, and monitoring for hypertensive symptoms is recommended.

Drug-Laboratory Test Interactions

Bupropion hydrochloride extended-release (SR) tablets may cause false-positive results in urine tests for amphetamines. This potential interaction should be communicated to patients and considered when interpreting test results.

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. Therefore, caution is advised when considering the use of this medication in children, infants, and adolescents. Further studies are necessary to determine appropriate dosing and potential outcomes in these age groups.

Geriatric Use

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

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses, it is important to note that some older individuals may exhibit greater sensitivity to the medication.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-4056185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. Conversely, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater, with decreased fetal weights noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first trimester exposures, did not show an increased risk for malformations overall. However, the registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, no increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester, with a prospectively observed rate of 1.3%, similar to the background rate of approximately 1%.

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

In animal studies, bupropion was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while pregnant rabbits exhibited non-dose-related increases in fetal malformations and skeletal variations at the lowest dose tested and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day and greater, with no maternal toxicity evident at doses of 50 mg/kg/day or less. Additionally, in a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day 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 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for bupropion hydrochloride extended-release (SR) tablets, as well as 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 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 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. Healthcare professionals should be vigilant for serious reactions associated with bupropion overdose, which may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

Fatalities linked to bupropion overdose have occurred, often following a series of uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest. Given the potential severity of these outcomes, immediate medical intervention is critical.

Currently, there are no known antidotes for bupropion. Therefore, the management of overdose cases relies heavily on supportive care and close medical supervision. It is imperative to ensure adequate airway management, oxygenation, and ventilation for the patient. The induction of emesis is not recommended in cases of bupropion overdose.

For further guidance in managing an overdose, healthcare professionals are advised to consult a Certified Poison Control Center. They can be reached at 1-800-222-1222 or through their website at www.poison.org.

Nonclinical Toxicology

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

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately seven and two times the MRHD on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, approximately two to seven times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. 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 (SR) tablets. Additionally, some individuals have experienced significant increases in blood pressure while on this medication.

Periods of mania have been reported in some patients taking bupropion hydrochloride extended-release (SR) tablets, 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 (SR) tablets.

Severe allergic reactions to bupropion hydrochloride extended-release (SR) tablets 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 understand the medication's use and potential risks. 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 behavioral changes, as well as worsening depression and suicidal ideation, particularly during the initial treatment phase and when adjusting the dose.

Families and caregivers should be encouraged to monitor patients daily for any abrupt changes in behavior, as these may require immediate reporting to the prescriber or healthcare professional, especially if the symptoms are severe or were not part of the patient's initial presentation. Patients should be informed that some individuals may experience mood changes, psychosis, hallucinations, paranoia, delusions, aggression, and suicidal thoughts when attempting to quit smoking while on bupropion. If such symptoms occur, patients should discontinue bupropion and contact their healthcare provider.

Patients should be educated about the signs of hypersensitivity and instructed to stop taking bupropion hydrochloride extended-release (SR) tablets if they experience a severe allergic reaction. Additionally, if a patient experiences a seizure while on treatment, they should discontinue the medication and not restart it. It is crucial to inform patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

During the initial titration phase, particularly when increasing the dose above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release (SR) tablets in two divided doses, with at least 8 hours between doses, to reduce the risk of seizures. Patients should also be made aware that the medication may cause mild pupillary dilation, which could lead to angle-closure glaucoma in susceptible individuals.

It is important to inform patients that bupropion hydrochloride extended-release (SR) tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that they should not be used in combination with ZYBAN or any other bupropion-containing medications. Patients should be cautioned that any CNS-active drug, including bupropion, may impair their ability to perform tasks requiring judgment or 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.

Patients should notify their healthcare provider of any prescription or over-the-counter medications they are taking or plan to take, as bupropion may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during treatment.

Storage instructions should be provided, advising patients to keep bupropion hydrochloride extended-release (SR) tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and to keep them dry and protected from light. Patients should be instructed to swallow the tablets whole, without chewing, dividing, or crushing them, to maintain the intended release rate of the medication.

If patients miss a dose, they should be advised not to take an extra tablet to compensate for the missed dose but to take the next tablet at the regular time, due to the dose-related risk of seizure. Patients should also be informed that bupropion hydrochloride extended-release (SR) tablets may have an odor and that they can be taken with or without food.

Storage and Handling

The product is supplied in configurations that include specific NDC numbers. It should be stored at room temperature, ideally between 20°C and 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines.

To ensure product integrity, it is essential to protect the product from light and moisture during storage. Proper handling and storage conditions are critical to maintaining the quality and efficacy of the product.

Additional Clinical Information

Patients receiving bupropion hydrochloride, particularly for major depressive disorder (MDD) or other indications, should be closely monitored by families and caregivers for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of 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 and seek medical attention if they experience agitation, mood changes, or suicidal thoughts. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion, including mood changes, psychosis, and suicidal ideation. Anaphylactoid and anaphylactic reactions have also been reported, presenting as skin rash, hives, and respiratory distress, necessitating immediate medical intervention. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, have been documented in association with bupropion use.

FDA Insert (PDF)

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

View full prescribing information (PDF)