Bupropion hydrochloride

Description

Bupropion hydrochloride extended-release tablets (XL) are an antidepressant belonging to the aminoketone class, distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The chemical structure 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 active ingredient, bupropion hydrochloride, is presented as a white, crystalline powder that is highly soluble in water. It possesses a bitter taste and can induce a sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride extended-release tablets (XL) are formulated for oral administration and are available in dosages of 150 mg and 300 mg. These tablets are round, white to off-white in appearance and contain the labeled amount of bupropion hydrochloride along with inactive ingredients, including dehydrated alcohol, ethylcellulose, hydrochloric acid, hydroxypropylcellulose, methacrylic acid copolymer, povidone, silicon dioxide, hydrogenated vegetable oil, and ethyl alcohol.

Each tablet is printed with edible black ink. The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is excreted in the feces. USP drug release testing is currently pending.

Uses and Indications

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

Additionally, bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients diagnosed with seasonal affective disorder. The efficacy for this indication was demonstrated in three controlled trials involving adult outpatients who have a history of major depressive disorder with an autumn-winter seasonal pattern.

There are no teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

Bupropion hydrochloride extended-release tablets (XL) should be administered whole and must not be crushed, divided, or chewed. The medication may be taken without regard to meals.

For the treatment of Major Depressive Disorder, the initial dose is 150 mg per day, administered as a single daily dose in the morning. If the patient tolerates this dose, it may be increased to 300 mg per day as a single daily dose in the morning as early as day 4. It is essential to maintain an interval of at least 24 hours between doses. If no clinical improvement is observed after several weeks at the 300 mg per day dosage, a maximum dose of 450 mg per day may be considered.

Maintenance treatment for Major Depressive Disorder typically extends beyond the acute episode and may last several months or longer.

For Seasonal Affective Disorder, treatment should be initiated in the autumn prior to the onset of depressive symptoms and continued through winter. Tapering should occur in early spring, with patients taking 300 mg per day during the autumn-winter season tapering to 150 mg per day for 2 weeks prior to discontinuation.

When switching patients from WELLBUTRIN Tablets or WELLBUTRIN SR Sustained-Release Tablets, it is recommended to maintain the same total daily dose if possible. For example, patients on WELLBUTRIN 300 mg per day may transition to 300 mg of bupropion hydrochloride extended-release tablets (XL) once daily.

For patients with impaired hepatic function, particularly those with severe hepatic cirrhosis, the maximum dose should not exceed 150 mg every other day. In patients with impaired renal function, bupropion should be used with caution, and consideration should be given to reducing the frequency and/or dose.

Contraindications

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

Patients with a seizure disorder should not use bupropion XL due to the risk of seizures. The use of bupropion XL is also contraindicated in individuals currently or previously treated with ZYBAN, WELLBUTRIN (immediate-release), WELLBUTRIN SR, or any other bupropion-containing medications, as the incidence of seizures is dose-dependent.

Patients with a current or prior diagnosis of bulimia or anorexia nervosa are contraindicated for bupropion XL due to an increased risk of seizures associated with treatment for bulimia using the immediate-release formulation. Additionally, bupropion XL is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives, including benzodiazepines, due to the potential for seizure activity.

The concurrent use of bupropion XL with monoamine oxidase (MAO) inhibitors is contraindicated. A minimum of 14 days should elapse between the discontinuation of an MAO inhibitor and the initiation of bupropion XL therapy. Lastly, bupropion XL is contraindicated in patients with a known allergic response to bupropion or any of its components.

Warnings and Precautions

Patients diagnosed with major depressive disorder (MDD), both in adult 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, regardless of whether they are receiving antidepressant therapy. This risk may persist until significant remission is achieved. It is important to note that antidepressants can contribute to the worsening of depression and the emergence of suicidality, particularly during the initial phases of treatment.

All patients undergoing treatment with antidepressants for any indication should be closely monitored for clinical worsening, suicidality, and unusual behavioral changes, especially during the first few months of therapy or following any dose adjustments. Families and caregivers should be informed of the necessity to observe patients for signs of agitation, irritability, unusual behavioral changes, and the emergence of suicidality, and to report any such symptoms to healthcare providers without delay.

Bupropion is associated with a dose-dependent risk of seizures, which can be influenced by patient-specific factors, clinical circumstances, and concomitant medications. In patients who experience a seizure while on bupropion hydrochloride extended-release tablets (XL), the medication should be discontinued and not restarted. Caution is advised when prescribing bupropion hydrochloride extended-release tablets (XL) to patients with severe hepatic cirrhosis.

Increased restlessness, agitation, anxiety, and insomnia have been reported, particularly shortly after the initiation of bupropion treatment. Patients with depression treated with bupropion may exhibit a range of neuropsychiatric symptoms, including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion. Additionally, antidepressants can trigger manic episodes in patients with bipolar disorder during depressive phases and may activate latent psychosis in other susceptible individuals.

Anaphylactoid and anaphylactic reactions, characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical intervention, have been documented in clinical trials involving bupropion. Furthermore, hypertension, which can be severe and necessitate acute treatment, has been observed in patients receiving bupropion, both as monotherapy and in conjunction with nicotine replacement therapy.

While there are no specific laboratory tests recommended for monitoring, it is crucial for patients and caregivers to seek immediate medical assistance if the patient using bupropion for smoking cessation exhibits agitation, depressed mood, or atypical changes in behavior or thinking, or if suicidal ideation or behavior develops. Patients should also be advised to discontinue bupropion hydrochloride extended-release tablets (XL) and consult a healthcare provider if they experience any allergic or anaphylactoid/anaphylactic reactions, such as skin rash, pruritus, hives, chest pain, edema, or shortness of breath during treatment.

Side Effects

Patients receiving treatment for Major Depressive Disorder may experience a range of adverse reactions, some of which may lead to discontinuation of therapy. Notable adverse events leading to discontinuation include rash, nausea, agitation, migraine, vomiting, seizures, and sleep disturbances.

Common adverse reactions occurring at an incidence of 1% or more encompass various body systems. General body-related reactions include headache, infection, abdominal pain, asthenia, chest pain, pain, and fever. Cardiovascular events such as palpitations, flushing, migraine, and hot flashes have also been reported. Digestive system reactions include dry mouth, nausea, constipation, diarrhea, anorexia, vomiting, and dysphagia. Musculoskeletal complaints consist of myalgia, arthralgia, arthritis, and twitching.

Nervous system-related adverse reactions are particularly noteworthy, with insomnia, dizziness, agitation, anxiety, tremor, nervousness, somnolence, irritability, decreased memory, paresthesia, and central nervous system stimulation being reported. Respiratory issues such as pharyngitis, sinusitis, and increased cough have been observed. Skin reactions include sweating, rash, pruritus, and urticaria. Additionally, special senses may be affected, with reports of tinnitus, taste perversion, and blurred vision or diplopia. Urogenital adverse reactions include urinary frequency, urinary urgency, vaginal hemorrhage, and urinary tract infections.

Additional adverse events reported include cardiac arrhythmias, hypertension, hypotension, tachycardia, appetite increase, dyspepsia, menstrual complaints, akathisia, impaired sleep quality, sensory disturbances, confusion, decreased libido, hostility, auditory disturbances, and gustatory disturbances.

For patients with Seasonal Affective Disorder, adverse events leading to treatment discontinuation primarily include insomnia and headache. Common adverse reactions occurring at an incidence of 2% or more include dry mouth, nausea, constipation, abdominal pain, fatigue, migraine, and palpitations.

Infrequent adverse reactions across various systems include chills, facial edema, musculoskeletal chest pain, and photosensitivity in the general body category; postural hypotension, stroke, tachycardia, and vasodilation in the cardiovascular category; and abnormal liver function, bruxism, gastric reflux, and increased salivation in the digestive category. Rare events include malaise, syncope, edema of the tongue, and maculopapular rash.

Neuropsychiatric symptoms, including suicidal ideation, have been reported, particularly in patients taking bupropion for smoking cessation. There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults, necessitating careful monitoring of patients of all ages for clinical worsening, suicidality, or unusual changes in behavior. Additionally, bupropion is associated with a dose-related risk of seizures, which may be influenced by patient factors and clinical situations.

Patients with major depressive disorder may also experience clinical worsening and/or emergence of suicidal ideation and behavior during treatment.

Drug Interactions

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

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. In vitro studies indicate that drugs such as orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel may interact with bupropion.

Cimetidine has been shown to have no significant effect on the pharmacokinetics of bupropion and its active metabolites; however, it may increase the AUC and Cmax of its minor metabolites, threohydrobupropion and erythrohydrobupropion by 16% and 32%, respectively.

Ritonavir and efavirenz have been observed to reduce the exposure of bupropion and its metabolites significantly, by approximately 20% to 80% and 55%, respectively. This reduction is attributed to the induction of bupropion metabolism. Patients receiving these medications may require increased doses of bupropion, but the maximum recommended dose should not be exceeded. Other drugs, such as carbamazepine, phenobarbital, and phenytoin, may also induce bupropion metabolism, although this has not been systematically studied.

Pharmacodynamic Interactions

Bupropion is an inhibitor of the CYP2D6 isoenzyme, which is responsible for the metabolism of many drugs, including certain antidepressants (e.g., 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). Coadministration of bupropion with these medications should be approached with caution, and it is advisable to initiate treatment at the lower end of the dose range for the concomitant medication. If bupropion is added to a regimen that includes a CYP2D6 substrate, consideration should be given to reducing the dose of the original medication, particularly for those with a narrow therapeutic index.

Additionally, drugs requiring metabolic activation by CYP2D6, such as tamoxifen, may exhibit reduced efficacy when used with bupropion.

Bupropion has been shown to increase the Cmax and AUC of citalopram by 30% and 40%, respectively, although citalopram does not significantly affect bupropion pharmacokinetics.

Other Considerations

The combination of bupropion with levodopa or amantadine may lead to a higher incidence of adverse effects; therefore, caution is advised, with small initial doses and gradual increases recommended. Concurrent use of bupropion with agents that lower seizure threshold, such as antipsychotics, other antidepressants, theophylline, and systemic steroids, should also be approached with extreme caution, employing low initial dosing and gradual dose increases.

In postmarketing experience, rare reports of adverse neuropsychiatric events and reduced alcohol tolerance have been noted in patients consuming alcohol during bupropion treatment. It is recommended that alcohol consumption be minimized or avoided during therapy.

Lastly, false-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. Confirmatory tests, such as gas chromatography/mass spectrometry, are necessary to distinguish bupropion from amphetamines, as false-positive results may persist even after discontinuation of bupropion therapy.

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). 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

Clinical trials involving approximately 6,000 patients, including 275 individuals aged 65 years and older and 47 individuals aged 75 years and older, have been conducted with bupropion sustained-release tablets for the treatment of depression and smoking cessation. Additionally, several hundred patients aged 65 and over participated in clinical trials utilizing the immediate-release formulation of bupropion for depression.

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

Pharmacokinetic studies indicate that the disposition of bupropion and its metabolites in elderly subjects is similar to that of younger subjects following a single dose. Nonetheless, other studies have suggested that elderly patients may be at an increased risk for the accumulation of bupropion and its metabolites, particularly with multiple dosing. 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 experience 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 the risk of adverse effects 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 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 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 same period or to bupropion outside of the first trimester. However, these results have not been corroborated.

Bupropion hydrochloride extended-release tablets (XL) 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 (XL). 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 (XL) 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 150 mg every other day. Monitoring for potential adverse effects is advised in this group to ensure patient safety.

Hepatic Impairment

Bupropion hydrochloride extended-release tablets (XL) 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 accumulation in these patients to a greater extent than usual. Therefore, the dose should not exceed 150 mg every other day in patients with severe hepatic cirrhosis. Regular monitoring of liver function is recommended to ensure patient safety and to adjust dosing as necessary.

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, 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, there have been fatalities linked to 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 clinical experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the treatment 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 (XL), hospitalization should be considered following a suspected overdose. Based on animal studies, seizures should be treated with intravenous benzodiazepines and other supportive measures as necessary.

It is important to consider the potential for multiple drug involvement in cases of overdose. Physicians are encouraged to contact a poison control center for further guidance on the management of any overdose situation. Contact information for certified poison control centers can be found in the Physicians’ Desk Reference (PDR).

Nonclinical Toxicology

Pregnancy Category C. In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively, during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day) and greater. Decreased fetal weights were noted at doses of 50 mg/kg and higher. When rats were administered bupropion at oral doses of up to 300 mg/kg/day prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. A retrospective managed-care database study in pregnant women assessed the risk of congenital malformations following exposure to bupropion in the first trimester. This study included 7,005 infants, with 1,213 exposed to bupropion during the first trimester. The results indicated no greater risk for congenital malformations overall or specifically for cardiovascular malformations compared to exposure to other antidepressants in the first trimester or bupropion outside of the first trimester. The findings of this study have not been corroborated. Bupropion hydrochloride extended-release tablets (XL) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study, there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower doses were not tested. The significance of these lesions as potential precursors of neoplasms of the liver remains unresolved. No similar liver lesions were observed in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study. Bupropion produced a positive response in 2 of 5 strains in the Ames bacterial mutagenicity test, indicating a 2 to 3 times control mutation rate, and an increase in chromosomal aberrations was observed in 1 of 3 in vivo rat bone marrow cytogenetic studies. A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.

Postmarketing Experience

Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation. These events include, but are not limited to, depression, suicidal ideation, suicide attempts, and completed suicides. Patients treated with bupropion for smoking cessation should be closely monitored for neuropsychiatric symptoms, which may encompass changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempts.

In the postmarketing experience, symptoms have been reported in patients attempting to quit smoking while using ZYBAN, with some cases indicating a worsening of pre-existing psychiatric conditions. While most reported symptoms occurred during treatment with ZYBAN, there have also been instances where symptoms emerged following the discontinuation of the medication.

These neuropsychiatric events have been documented in both patients with and without a history of psychiatric illness, with some individuals experiencing exacerbation of their psychiatric conditions. In many cases, resolution of symptoms was noted after discontinuation of ZYBAN; however, there were instances where 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 with bupropion hydrochloride extended-release tablets (XL). 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 (XL): 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 quitting smoking, with or without ZYBAN, may be associated with nicotine withdrawal symptoms, including depression or agitation, or exacerbation of pre-existing psychiatric illness. They should contact their healthcare provider immediately if they develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if they develop suicidal ideation or behavior.

It is important for patients to understand that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient found in ZYBAN, which is used as an aid to smoking cessation treatment, and should not be used in combination with ZYBAN or any other medications that contain bupropion. Patients should also be informed that bupropion hydrochloride extended-release tablets (XL) should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be advised that any CNS-active drug like bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. They should refrain from driving or operating complex machinery until they are certain of the drug's effects. Additionally, patients should minimize or avoid alcohol consumption, as excessive use or abrupt discontinuation of alcohol or sedatives may alter the seizure threshold.

Patients should inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs, as bupropion hydrochloride extended-release tablets (XL) and other drugs may affect each other’s metabolism. They should also notify their physicians if they become pregnant or intend to become pregnant during therapy.

Patients should be instructed to swallow bupropion hydrochloride extended-release tablets (XL) whole and not to chew, divide, or crush the tablets. It is normal for patients to notice something that looks like a tablet in their stool, as the medication is contained in a non-absorbable shell designed to slowly release the drug in the body.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20-25°C (68-77°F), as defined by the United States Pharmacopeia (USP). It is essential to ensure that the storage environment maintains these temperature conditions to preserve 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)