Bupropion Hydrochloride (sr)

Description

Bupropion hydrochloride USP 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 highly soluble in water, exhibiting a bitter taste and producing a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is formulated as extended-release tablets for oral administration, available in strengths of 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each film-coated, sustained-release tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, including microcrystalline cellulose, colloidal silicon dioxide, hydroxy propyl methyl cellulose, diluted hydrochloric acid, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and polysorbate 80. The 100 mg tablet incorporates FD&C Blue No. 1 Aluminum lake, the 150 mg tablet contains FD&C Blue No. 2 Aluminum lake and FD&C Red No. 40 Aluminum lake, while the 200 mg tablet includes FD&C Red No. 40 Aluminum lake. It is important to note that the FDA-approved dissolution specification for this formulation differs from the USP.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) 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 increased to 300 mg per day, administered as 150 mg twice daily, with an interval of at least 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. Similarly, in patients with renal impairment, a reduction in dose and/or frequency may be warranted.

Contraindications

Use of bupropion hydrochloride extended-release tablets (SR) 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 (SR) should not be used in conjunction with MAOIs or within 14 days of discontinuing either treatment. Additionally, bupropion hydrochloride extended-release tablets (SR) should not be initiated in patients receiving linezolid or intravenous methylene blue.

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

Warnings and Precautions

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

Suicidal Thoughts and Behaviors There is a documented increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including bupropion. Healthcare professionals should closely monitor these patients for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events Postmarketing reports have indicated that patients undergoing smoking cessation with bupropion may experience serious neuropsychiatric adverse events. These can 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. It is imperative to observe patients attempting to quit smoking for these symptoms and instruct them to discontinue bupropion and seek immediate medical advice if such events occur.

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

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

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is also advised.

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 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 Healthcare providers should routinely monitor blood pressure before starting treatment and at regular intervals during therapy to ensure patient safety.

Emergency Instructions Patients must be advised to discontinue bupropion and contact a healthcare provider immediately if they experience any neuropsychiatric adverse events, seizures, or psychotic symptoms.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (SR) may experience a range of adverse reactions. 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.

A boxed warning highlights the 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. Patients should be instructed to contact a healthcare professional if they experience any of these reactions.

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

Activation of mania or hypomania has been reported, particularly in patients with a history of bipolar disorder, underscoring the importance of screening and monitoring for these symptoms. Angle-closure glaucoma has also been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the presence of a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Patients with known hypersensitivity to bupropion or its ingredients should avoid this medication.

In cases of overdosage, seizures have been reported in approximately one-third of instances, along with serious reactions such as hallucinations, loss of consciousness, sinus tachycardia, ECG changes (including QRS prolongation), arrhythmias, 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 (SR) 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, and 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 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 medications should be considered when used concurrently with bupropion.

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

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

Dopaminergic Drugs The concomitant use of bupropion hydrochloride extended-release (SR) 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 use of bupropion hydrochloride extended-release tablets (SR) in combination with MAOIs can heighten the risk of hypertensive reactions. Caution is advised, and monitoring for hypertensive symptoms should be implemented.

Drug-Laboratory Test Interactions Bupropion hydrochloride extended-release tablets (SR) may cause false-positive results in urine tests for amphetamines. 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 (sr) (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

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. The background rate for major malformations in all pregnancies is approximately 2% to 4%, with a pregnancy loss rate of 15% to 20%. Reproductive developmental studies in rats and rabbits did not demonstrate clear teratogenic activity; however, rabbits exhibited slightly increased incidences of fetal malformations and skeletal variations 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 (SR) should be utilized during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

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 reveal an increased risk for malformations overall. Specifically, no increased risk for cardiovascular malformations was observed following bupropion exposure during the first trimester, with a prospectively observed rate of 1.3% (9 cardiovascular malformations out of 675 first-trimester exposures), consistent with the background rate of approximately 1%.

However, findings regarding the association between bupropion exposure during the first trimester and specific cardiovascular defects, such as left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), are inconsistent. The United Healthcare database lacked sufficient power to evaluate the LVOTO association, while the National Birth Defects Prevention Study (NBDPS) identified an increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7). Conversely, the Slone Epidemiology case-control study did not find an increased risk for LVOTO. For VSD, the Slone Epidemiology Study reported an increased risk following first trimester exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0), while the NBDPS and United Healthcare database studies did not find an association. The limitations of these studies, including small sample sizes and inconsistent findings, should be considered when interpreting these results.

Animal studies involving oral administration of bupropion during organogenesis in rats and rabbits at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively, did not show clear teratogenic effects. However, in rabbits, increased incidences of fetal malformations and skeletal variations were noted at doses starting from 25 mg/kg/day (approximately equal to the MRHD on a mg/m² basis) and higher, with decreased fetal weights observed at doses of 50 mg/kg/day and above. In rats, administration of bupropion at doses up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation did not result in apparent adverse effects on offspring development.

Healthcare professionals should consider the risks of untreated depression when contemplating the discontinuation or alteration of antidepressant treatment during pregnancy and postpartum.

Lactation

Bupropion and its metabolites are present 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 per kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

Exercise caution when administering bupropion hydrochloride extended-release tablets (SR) to lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions 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 (including QRS prolongation) and arrhythmias. Additionally, symptoms such as fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been observed, particularly in cases involving multiple drug overdoses.

While most patients have recovered without lasting effects, there have been fatalities linked to bupropion overdoses, particularly in those 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 bupropion overdose, it is imperative to consult a Certified Poison Control Center for current guidance and recommendations. Contact information for certified poison control centers can be found in the Physician’s Desk Reference (PDR), or by calling 1-800-222-1222 or visiting www.poison.org.

There are no known antidotes for bupropion. Management of an overdose should focus on supportive care, which includes close medical supervision and monitoring. It is essential to consider the possibility of a multiple drug overdose. Healthcare professionals should ensure the maintenance of an adequate airway, oxygenation, and ventilation, while also monitoring cardiac rhythm and vital signs. Induction of emesis is not recommended in cases of bupropion overdose.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion administered at doses of up to 300 mg per kg per day and 150 mg per kg per day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg per 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 per kg per day, which is approximately 2 to 7 times the MRHD on a mg per 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 the Ames bacterial mutagenicity assay, with a mutation rate that was 2 to 3 times higher than the control in 2 of 5 strains tested. 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 per kg per day indicated no evidence of impaired fertility.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, during treatment with bupropion. Additional psychiatric events noted include psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. There have also been reports of suicidal ideation and suicide attempts in individuals attempting to quit smoking while on bupropion therapy. These events were reported voluntarily or identified through surveillance programs.

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 (SR). It is important to counsel patients, their families, and caregivers on the appropriate use of this medication. A Medication Guide is available that covers critical topics such as “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About bupropion hydrochloride extended-release tablets (SR)?”

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.

Advise patients to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation, particularly during the initial treatment phase and when adjusting the dose. Families and caregivers should monitor for these symptoms on a daily basis, as changes can occur abruptly. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional, as they may indicate an increased risk for suicidal thoughts and behaviors, necessitating close monitoring and potential medication adjustments.

Inform patients that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while on bupropion. Patients should be instructed to discontinue bupropion and contact a healthcare professional if they experience such symptoms.

Educate patients on the signs of hypersensitivity and instruct them to discontinue bupropion hydrochloride extended-release tablets (SR) if they experience a severe allergic reaction. Additionally, patients should stop taking the medication and not restart it if they experience a seizure during treatment. Advise patients that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption.

During the initial titration phase, as the dose increases above 150 mg per day, instruct patients to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, preferably with at least 8 hours between doses, to reduce the risk of seizures. Patients should also be informed that bupropion can cause mild pupillary dilation, which may 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 (SR) 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. Advise patients that bupropion hydrochloride extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Until they are confident that the medication does not adversely affect their performance, patients should refrain from driving or operating complex, hazardous machinery.

Finally, counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride extended-release tablets (SR) and other drugs may interact and affect each other's metabolism.

Storage and Handling

Bupropion hydrochloride extended-release tablets, USP (SR) are supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It is essential to store the tablets at a controlled room temperature of 20° to 25°C (68°F to 77°F) to maintain their efficacy and stability.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)