Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (SR) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressants. 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 ingredient is presented as a white, crystalline powder that is soluble in water, 0.1N HCl, and alcohol, exhibiting a bitter taste and a local anesthetic effect on the oral mucosa. Bupropion hydrochloride extended-release tablets are formulated for oral administration and are available in three strengths: 100 mg (blue), 150 mg (purple), and 200 mg (pink). Each film-coated tablet contains the specified amount of bupropion hydrochloride along with inactive ingredients, which include ammonium chloride, colloidal silicon dioxide, glyceryl behenate, hydroxy propyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, stearic acid, talc, and titanium dioxide. The 100 mg tablet incorporates FD&C Blue No. 1 Lake, the 150 mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, while the 200 mg tablet includes FD&C Red No. 40 Lake. Bupropion hydrochloride extended-release tablets, USP (SR), 100 mg, 150 mg, and 200 mg, comply with USP Dissolution Test 2.

Uses and Indications

Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder. The efficacy of bupropion in managing a major depressive episode has been established through two 4-week controlled trials involving depressed inpatients and one 6-week controlled trial involving depressed outpatients.

A major depressive episode, as defined by DSM-IV criteria, is characterized by the presence of either a depressed mood or a loss of interest or pleasure, along with at least five of the following symptoms occurring during the same 2-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

Additionally, the efficacy of bupropion hydrochloride extended-release tablets (SR) in maintaining an antidepressant response for up to 44 weeks following an initial 8-week acute treatment phase has been demonstrated in a placebo-controlled trial.

No teratogenic or nonteratogenic effects have been reported in the available data.

Dosage and Administration

Bupropion hydrochloride extended-release tablets (SR) should be administered in a manner that minimizes the risk of seizure. A gradual escalation in dosage is essential to reduce the likelihood of agitation, motor restlessness, and insomnia. If these effects occur, they may be managed by temporarily reducing the dose or by the short-term administration of a sedative hypnotic. The tablets must be swallowed whole and should not be crushed, divided, or chewed.

For initial treatment, the usual adult target dose is 300 mg per day, administered as 150 mg twice daily. Treatment should begin with a single daily dose of 150 mg in the morning. If well tolerated, the dose may be increased to 300 mg per day (150 mg twice daily) as early as day 4, ensuring that there is an interval of at least 8 hours between successive doses.

If no clinical improvement is observed after several weeks at the 300 mg per day dosage, an increase to the maximum dosage of 400 mg per day, given as 200 mg twice daily, may be considered.

For maintenance treatment, extended pharmacological therapy beyond the acute episode is generally required for several months or longer.

In patients with impaired hepatic function, bupropion should be used with extreme caution in cases of severe hepatic cirrhosis, with a maximum dosage not exceeding 100 mg daily or 150 mg every other day. For patients with mild-to-moderate hepatic cirrhosis, a reduced frequency and/or dose should be considered.

In patients with impaired renal function, bupropion should also be used with caution, and a reduced frequency and/or dose may be necessary.

Contraindications

Bupropion hydrochloride extended-release tablets (SR) are contraindicated in the following situations:

• Patients with a seizure disorder, due to the risk of seizure exacerbation.

• Patients currently treated with ZYBAN (bupropion hydrochloride) Extended-Release Tablets, WELLBUTRIN (bupropion hydrochloride) immediate-release formulation, WELLBUTRIN XL (bupropion hydrochloride) extended-release formulation, or any other medications containing bupropion, as the incidence of seizures is dose dependent.

• Patients with a current or prior diagnosis of bulimia or anorexia nervosa, due to a higher incidence of seizures associated with bupropion treatment in these populations.

• Patients undergoing abrupt discontinuation of alcohol or sedatives, including benzodiazepines, as this may increase seizure risk.

• Concurrent administration with a monoamine oxidase (MAO) inhibitor is contraindicated; a minimum of 14 days should elapse between discontinuation of an MAO inhibitor and initiation of bupropion hydrochloride extended-release tablets (SR).

• Patients with a known allergic response to bupropion or any of the other ingredients in bupropion hydrochloride extended-release tablets (SR).

Warnings and Precautions

Patients diagnosed with major depressive disorder (MDD), including both adults and pediatric populations, may experience a worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), as well as unusual changes in behavior. This risk is present regardless of whether the patient is currently taking antidepressant medications, and it may persist until significant remission is achieved.

Antidepressants are known to increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) who are being treated for MDD and other psychiatric disorders. Therefore, it is imperative that all patients receiving antidepressant therapy for any indication are monitored closely for clinical worsening, suicidality, and any unusual changes in behavior. This monitoring is particularly critical during the initial months of treatment or during any changes in dosage.

Families and caregivers of patients undergoing treatment with antidepressants should be informed about the importance of vigilance in observing for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality. They should be encouraged to report any such symptoms immediately to healthcare providers.

For patients using bupropion for smoking cessation, it is essential to advise both patients and their caregivers to discontinue bupropion and seek immediate medical attention if they observe any signs of agitation, depressed mood, or atypical changes in behavior or thinking. This includes any development of suicidal ideation or behavior.

There are no specific laboratory tests recommended for monitoring patients on this medication. However, healthcare providers should remain alert to the need for ongoing assessment of the patient's mental health status throughout the course of treatment.

Side Effects

Patients receiving bupropion hydrochloride extended-release tablets (SR) may experience a range of adverse reactions. A boxed warning highlights the increased risk of suicidality in children, adolescents, and young adults, necessitating careful monitoring for clinical worsening, suicidality, or unusual behavioral changes in patients of all ages.

In controlled clinical trials, the incidence of adverse events leading to treatment discontinuation included rash (2.4% at 300 mg/day, 0.9% at 400 mg/day), nausea (0.8% at 300 mg/day, 1.8% at 400 mg/day), agitation (0.3% at 300 mg/day, 1.8% at 400 mg/day), and migraine (0.0% at 300 mg/day, 1.8% at 400 mg/day).

Common adverse reactions occurring at an incidence of 1% or more included:

Body (General): Headache (26% at 300 mg/day, 25% at 400 mg/day), infection (8% at 300 mg/day, 9% at 400 mg/day), abdominal pain (3% at 300 mg/day, 9% at 400 mg/day), asthenia (2% at 300 mg/day, 4% at 400 mg/day), chest pain (3% at 300 mg/day, 4% at 400 mg/day), pain (2% at 300 mg/day, 3% at 400 mg/day), and fever (1% at 300 mg/day, 2% at 400 mg/day).

Cardiovascular: Palpitations (2% at 300 mg/day, 6% at 400 mg/day), flushing (1% at 300 mg/day, 4% at 400 mg/day), migraine (1% at 300 mg/day, 4% at 400 mg/day), and hot flashes (1% at 300 mg/day, 3% at 400 mg/day).

Digestive: Dry mouth (17% at 300 mg/day, 24% at 400 mg/day), nausea (13% at 300 mg/day, 18% at 400 mg/day), constipation (10% at 300 mg/day, 5% at 400 mg/day), diarrhea (5% at 300 mg/day, 7% at 400 mg/day), anorexia (5% at 300 mg/day, 3% at 400 mg/day), and vomiting (4% at 300 mg/day, 2% at 400 mg/day).

Musculoskeletal: Myalgia (2% at 300 mg/day, 6% at 400 mg/day), arthralgia (1% at 300 mg/day, 4% at 400 mg/day), and twitching (1% at 300 mg/day, 2% at 400 mg/day).

Nervous System: Insomnia (11% at 300 mg/day, 16% at 400 mg/day), dizziness (7% at 300 mg/day, 11% at 400 mg/day), agitation (3% at 300 mg/day, 9% at 400 mg/day), anxiety (5% at 300 mg/day, 6% at 400 mg/day), tremor (6% at 300 mg/day, 3% at 400 mg/day), and somnolence (2% at 300 mg/day, 3% at 400 mg/day).

Respiratory: Pharyngitis (3% at 300 mg/day, 11% at 400 mg/day) and sinusitis (3% at 300 mg/day, 1% at 400 mg/day).

Skin: Sweating (6% at 300 mg/day, 5% at 400 mg/day), rash (5% at 300 mg/day, 4% at 400 mg/day), and pruritus (2% at 300 mg/day, 4% at 400 mg/day).

Urogenital: Urinary frequency (2% at 300 mg/day, 5% at 400 mg/day) and urinary urgency (2% at 400 mg/day).

Other adverse events observed during clinical development and postmarketing experience included infrequent reports of chills, facial edema, postural hypotension, abnormal liver function, and neuropsychiatric symptoms such as suicidal ideation. Rare events included seizures, bronchospasm, and maculopapular rash.

Bupropion is associated with a dose-related risk of seizures, which increases with higher doses and in patients with certain predisposing factors. Serious neuropsychiatric symptoms, including mood changes, psychosis, hallucinations, and suicidal ideation, have also been reported in patients taking bupropion for smoking cessation.

Drug Interactions

Concomitant administration of bupropion hydrochloride extended-release tablets (SR) with other medications may lead to significant drug interactions, primarily due to its metabolism and effects on various cytochrome P450 enzymes.

Pharmacokinetic Interactions

Bupropion is extensively metabolized, primarily by the CYP2B6 isoenzyme, which may lead to interactions with drugs that are substrates, inhibitors, or inducers of this enzyme. Notable interactions include:

• CYP2B6 Inhibitors: In vitro studies indicate that paroxetine, sertraline, norfluoxetine, fluvoxamine, nelfinavir, and efavirenz inhibit the hydroxylation of bupropion. However, clinical studies to confirm these findings are lacking.

• CYP2B6 Inducers: Drugs such as ritonavir, KALETRA (lopinavir/ritonavir), and efavirenz have been shown to reduce the exposure of bupropion and its metabolites by 20% to 80%, likely due to induction of bupropion metabolism. Patients receiving these medications may require increased doses of bupropion, but the maximum recommended dose should not be exceeded. Other potential inducers include carbamazepine, phenobarbital, and phenytoin.

• Cimetidine: Co-administration with cimetidine did not significantly affect the pharmacokinetics of bupropion and its active metabolites, although increases in the AUC and Cmax of its minor metabolites were observed.

Pharmacodynamic Interactions

Coadministration of bupropion with drugs that lower the seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids, should be approached with extreme caution. It is recommended to initiate treatment with low doses and to increase gradually.

• Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse effects when bupropion is used with levodopa or amantadine. Caution is advised, with small initial doses and gradual increases.

• CYP2D6 Substrates: Bupropion may affect the metabolism of drugs that are substrates of the CYP2D6 isoenzyme, including certain antidepressants (e.g., nortriptyline, imipramine), antipsychotics (e.g., haloperidol), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). When initiating bupropion in patients already receiving these medications, consideration should be given to reducing the dose of the original medication, especially for those with a narrow therapeutic index.

• Tamoxifen: Drugs requiring metabolic activation by CYP2D6, such as tamoxifen, may have reduced efficacy when administered with bupropion, an inhibitor of CYP2D6.

Other Considerations

Bupropion has been associated with false-positive urine immunoassay screening tests for amphetamines. This lack of specificity may persist even after discontinuation of bupropion therapy. Confirmatory testing, such as gas chromatography/mass spectrometry, is recommended to distinguish bupropion from amphetamines.

In postmarketing experience, there have been rare reports of adverse neuropsychiatric events and reduced alcohol tolerance in patients consuming alcohol during bupropion treatment. Therefore, alcohol consumption should be minimized or avoided during therapy with bupropion hydrochloride extended-release tablets (SR).

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 of bupropion hydrochloride extended-release tablets (SR) in the pediatric population have not been established. Healthcare professionals considering the use of this medication in children or adolescents must carefully weigh the potential risks against the clinical need for treatment.

Geriatric Use

Elderly patients, defined as those aged 65 and older, were represented in clinical trials of bupropion extended-release tablets, with 275 participants aged 65 and over and 47 participants aged 75 and over. No overall differences in safety or effectiveness were observed between these elderly subjects and younger patients. However, it is important to note that while clinical experience has not identified significant differences in responses between elderly and younger patients, greater sensitivity in some older individuals cannot be ruled out.

Pharmacokinetic studies indicate that the disposition of bupropion and its metabolites in elderly subjects is similar to that of younger subjects. Nonetheless, another study has suggested that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites. Given that bupropion is extensively metabolized in the liver and excreted by the kidneys, the risk of toxic reactions may be heightened in patients with impaired renal function.

Elderly patients are more likely to have decreased renal function; therefore, careful consideration should be given to dose selection in this population. It may be beneficial to monitor renal function to mitigate potential risks associated with bupropion therapy in geriatric patients.

Pregnancy

Pregnancy Category C. In animal studies, bupropion was administered orally to rats and rabbits during the period of organogenesis at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively, which are approximately 11 and 7 times the maximum recommended human dose (MRHD) on a mg/m² basis. No clear evidence of teratogenic activity was observed in either species; however, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and higher doses. Additionally, decreased fetal weights were noted at doses of 50 mg/kg/day and above.

In a study where rats were administered 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, no apparent adverse effects on offspring development were observed.

A retrospective managed-care database study involving pregnant women assessed the risk of congenital malformations, including cardiovascular malformations, following exposure to bupropion in the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, of which 1,213 were exposed to bupropion in the first trimester. The findings indicated no greater risk for congenital malformations overall or specifically for cardiovascular malformations following first trimester exposure to bupropion compared to exposure to other antidepressants in the first trimester or to bupropion outside of the first trimester. However, these results have not been corroborated.

Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Bupropion and its metabolites are secreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, a decision should be made regarding whether to discontinue nursing or to discontinue bupropion hydrochloride extended-release tablets (SR). This decision should consider the importance of the medication to the lactating mother.

Renal Impairment

Patients with severe hepatic cirrhosis should use bupropion hydrochloride extended-release tablets (SR) with extreme caution. In this population, a reduced frequency and/or dose is necessary due to significantly increased peak bupropion levels and area under the curve (AUC), which may lead to greater accumulation than typically observed. The maximum recommended dose for these patients is 100 mg daily or 150 mg every other day. Monitoring for potential adverse effects is advised in this patient group.

Hepatic Impairment

Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In this population, a reduced frequency and/or dose is required due to significantly increased peak bupropion levels and area under the curve (AUC) levels, which may lead to greater accumulation than usual. Specifically, the dose should not exceed 100 mg per day or 150 mg every other day for patients with compromised liver function. Close monitoring of these patients is recommended to mitigate the risk of adverse effects associated with elevated drug levels.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 g or more. In approximately one-third of these cases, seizures were reported. Other serious adverse reactions associated with bupropion overdoses include hallucinations, loss of consciousness, sinus tachycardia, and various ECG changes, such as conduction disturbances (including QRS prolongation) and 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 most patients have recovered without lasting effects, fatalities have been associated with bupropion overdoses, particularly in those who ingested large quantities. Reports indicate that patients who succumbed to overdose experienced multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death.

In the event of an overdose, it is crucial to ensure an adequate airway, oxygenation, and ventilation. Continuous monitoring of cardiac rhythm and vital signs is essential, and EEG monitoring is recommended for the first 48 hours following ingestion. General supportive and symptomatic measures should be implemented, while the induction of emesis is not advised.

Activated charcoal should be administered as part of the management protocol. There is currently no established experience with forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the context of bupropion overdoses, and no specific antidotes for bupropion are available.

Given the dose-related risk of seizures associated with bupropion hydrochloride extended-release tablets (SR), hospitalization should be considered following any suspected overdose. Based on animal studies, seizures should be treated with intravenous benzodiazepines and other supportive measures as deemed appropriate.

When managing an overdose, it is important to consider the potential for multiple drug involvement. Physicians are encouraged to contact a poison control center for further guidance on the treatment of any overdose. Contact information for certified poison control centers can be found in the Physicians’ Desk Reference (PDR).

Nonclinical Toxicology

Pregnancy Category C. In nonclinical studies involving rats and rabbits, bupropion was administered orally at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively, during the organogenesis period. No definitive evidence of teratogenic activity was observed in either species. However, in rabbits, there were slightly increased incidences of fetal malformations and skeletal variations at the lowest tested dose of 25 mg/kg/day, which is approximately equal to the maximum recommended human dose (MRHD) on a mg/m² basis, and at higher doses. Additionally, decreased fetal weights were noted at doses of 50 mg/kg/day and above.

In a separate study, rats received bupropion at oral doses of up to 300 mg/kg/day, approximately seven times the MRHD on a mg/m² basis, prior to mating and throughout pregnancy and lactation. This administration did not result in any apparent adverse effects on the development of the offspring.

A retrospective managed-care database study involving pregnant women assessed the risk of congenital malformations, including cardiovascular malformations, following first trimester exposure to bupropion compared to other antidepressants. This study included 7,005 infants with antidepressant exposure during pregnancy, of which 1,213 were exposed to bupropion in the first trimester. The findings indicated no increased risk for congenital malformations overall or specifically for cardiovascular malformations following first trimester exposure to bupropion when compared to exposure to other antidepressants in the same period or to bupropion outside of the first trimester. It is important to note that these results have not been corroborated. Bupropion hydrochloride extended-release tablets (SR) should be utilized during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Postmarketing Experience

Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation, including depression, suicidal ideation, suicide attempts, and completed suicides. Patients undergoing treatment with bupropion for smoking cessation should be closely monitored for neuropsychiatric symptoms, which may include changes in behavior, hostility, agitation, depressed mood, and suicide-related events.

In the postmarketing experience, these symptoms, along with the worsening of pre-existing psychiatric conditions and completed suicides, have been documented in individuals attempting to quit smoking while using ZYBAN. While most reported symptoms occurred during treatment with ZYBAN, some cases were noted following the discontinuation of the medication.

These events have been observed in both patients with and without a history of psychiatric disorders, with some individuals experiencing exacerbation of their psychiatric conditions. In numerous postmarketing cases, resolution of symptoms was reported after discontinuation of ZYBAN; however, in certain instances, symptoms persisted. Therefore, ongoing monitoring and supportive care are recommended until symptoms fully resolve.

Patient Counseling

Patients, their families, and caregivers should be informed about the benefits and risks associated with treatment using bupropion hydrochloride extended-release tablets (SR). It is essential for patients to read the Medication Guide and discuss its contents with their healthcare provider to ensure a comprehensive understanding of the treatment.

Patients should be advised to alert their prescriber if they experience any of the following symptoms while taking bupropion hydrochloride extended-release tablets (SR): anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, or suicidal ideation. Families and caregivers should monitor patients for the emergence of these symptoms on a day-to-day basis and report any severe, abrupt changes to the prescriber.

Patients should be informed that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient as ZYBAN, which is used to assist patients in quitting smoking. Therefore, it should not be used in combination with ZYBAN or any other medications that contain bupropion.

Patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in two divided doses, preferably with at least 8 hours between doses, especially when increasing the dose above 150 mg/day, to minimize the risk of seizures. They should also be advised to discontinue bupropion hydrochloride extended-release tablets (SR) and contact their healthcare provider immediately if they experience a seizure.

It is important to inform patients that any CNS-active drug, including bupropion hydrochloride extended-release tablets (SR), may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Patients should refrain from driving or operating complex machinery until they are certain of the drug's effects.

Patients should minimize or avoid alcohol consumption while taking bupropion hydrochloride extended-release tablets (SR) due to the potential for reduced alcohol tolerance and increased seizure risk. Additionally, patients should notify their physician if they become pregnant or intend to become pregnant during therapy.

Finally, patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole and not chew, divide, or crush them, as this may lead to an increased risk of adverse effects, including seizures.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

There are no specific laboratory tests recommended for patients. Additionally, there is no further information available regarding abuse, route, method, and frequency of administration, patient counseling, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)