BUPROPION HYDROCHLORIDE tablet, film coated

BUPROPION HYDROCHLORIDE by

Drug Labeling and Warnings

BUPROPION HYDROCHLORIDE by is a Prescription medication manufactured, distributed, or labeled by DirectRX. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • Drug Interactions

    7.1 Potential for Other Drugs to Affect Bupropion

    Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6.

    Inhibitors of CYP2B6:Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride tablets may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].

    Inducers of CYP2B6:Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride tablets may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.

    Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded.

    7.2 Potential for Bupropion to Affect Other Drugs

    Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion hydrochloride tablets, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

    Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride tablets and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].

    7.3 Drugs that Lower Seizure Threshold

    Use extreme caution when coadministering bupropion hydrochloride tablets with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Contraindications (4), Warnings and Precautions (5.3)].

    7.4 Dopaminergic Drugs (Levodopa and Amantadine)

    Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering bupropion hydrochloride tablets concomitantly with these drugs.

    7.5 Use with Alcohol

    In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion hydrochloride tablets. The consumption of alcohol during treatment with bupropion hydrochloride tablets should be minimized or avoided.

    7.6 MAO Inhibitors

    Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion hydrochloride tablets. Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride tablets before starting an MAOI antidepressant [see Dosage and Administration (2.4, 2.5), Contraindications (4)].

    7.7 Drug-Laboratory Test Interactions

    False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

  • Use in Specific Populations

    8.1 Pregnancy

    Pregnancy Category C

    Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Clinical Considerations: Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

    Human Data: Data from the international bupropion Pregnancy Registry (675 first- trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.

    No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.

    Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.

    Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.

    For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.

    Animal Data: In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). 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, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater.

    When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

    8.3 Nursing Mothers

    Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion hydrochloride tablets are administered to a nursing woman.

    8.4 Pediatric Use

    Safety and effectiveness in the pediatric population have not been established [see Boxed Warning, Warnings and Precautions (5.1)].

    8.5 Geriatric Use

    Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

    Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

    8.6 Renal Impairment

    Consider a reduced dose and/or dosing frequency of bupropion hydrochloride tablets in patients with renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets is 75 mg daily. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage and Administration (2.2),Clinical Pharmacology (12.3)].

  • Drug Abuse and Dependence

    9.1 Controlled Substance

    Bupropion is not a controlled substance.

    9.2 Abuse

    Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.

    In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.

    Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.

    Bupropion hydrochloride tablets are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.

    Animals: Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

  • Overdosage

    10.1 Human Overdose Experience

    Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

    Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

    10.2 Overdosage Management

    Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR). Call 1-800-222-1222 or refer to www.poison.org.

    There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended

  • Description

    Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNOHCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:

    molecule

    Bupropion hydrochloride tablets, USP are supplied for oral administration as 75-mg and 100-mg lavender film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, hydroxypropyl methylcellulose, microcrystalline cellulose, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triethyl citrate.

  • Clinical Pharmacology

    12.1 Mechanism of Action

    The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

    12.3 Pharmacokinetics

    Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

    Absorption: The absolute bioavailability of bupropion hydrochloride tablets in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

    In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use.

    Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

    Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.

    Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 3 hours after administration of bupropion hydrochloride tablets and are approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.

    Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.

    Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

    Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

    Renal Impairment: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Bupropion hydrochloride tablets should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations (8.6)].

    Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal.

    The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 3).

    Table 3. Pharmacokinetics of Bupropion and Metabolites in Patients with Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls
    Cmax AUC t½ Tmax*

    *
    = Difference.


    Bupropion


    1.69


    3.12


    1.43


    0.5 h


    Hydroxybupropion


    0.31


    1.28


    3.88


    19 h


    Threo/erythrohydrobupropion amino alcohol


    0.69


    2.48


    1.96


    20 h

    Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x- ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers.

    Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].

    Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown.

    Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

    Drug Interactions:Potential for Other Drugs to Affect Bupropion: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

    Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (Cmax and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.

    Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively.

    Cimetidine: The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively of the combined moieties of threohydrobupropion and erythrohydrobupropion.

    Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

    Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.

    In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.

    In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively.

    Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.

    Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.

    Potential for Bupropion to Affect Other Drugs: Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of co-administered drugs.

    Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

    Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.

    Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

  • Nonclinical Toxicology

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

    Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations 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.

  • Clinical Studies

    The efficacy of bupropion hydrochloride tablets in the treatment of major depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 4) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 4). In the first trial, the dose range of bupropion hydrochloride tablets was 300 mg to 600 mg per day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion hydrochloride tablets as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of bupropion hydrochloride tablets (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of bupropion hydrochloride tablets for only the 450-mg-per-day dose. The efficacy results were statistically significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third trial, outpatients were treated with 300 mg per day of bupropion hydrochloride tablets. This trial demonstrated the efficacy of bupropion hydrochloride tablets as measured by the HDRS total score, the HDRS item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI- Improvement Scale (CGI-I) score. Effectiveness of bupropion hydrochloride tablets in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.

    Table 4. Efficacy of Bupropion Hydrochloride Tablets for the Treatment of Major Depressive Disorder

    *
    Difference (drug minus placebo) in least-squares estimates with respect to the primary efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline to the endpoint visit.
    †
    Doses that are demonstrated to be statistically significantly superior to placebo.

    Trial

    Number

    Treatment Group

    Primary Efficacy Measure: HDRS

    Mean Baseline

    Score (SD)

    LS Mean Score at

    Endpoint Visit

    (SE)

    Placebo­subtracted Difference* (95% CI)

    Trial 1

    Bupropion

    300-600 mg/day†

    (n = 48)

    28.5 (5.1)

    14.9 (1.3)

    -4.7 (-8.8, -0.6)

    Placebo (n = 27)

    29.3 (7.0)

    19.6 (1.6)

    -­

    Mean Baseline

    Score (SD)

    LS Mean Change from Baseline (SE)

    Placebo-subtracted Difference* (95% CI)

    Trial 2

    Bupropion

    300 mg/day

    (n = 36)

    32.4 (5.9)

    -15.5 (1.7)

    -4.1

    Bupropion

    450 mg/day†

    (n = 34)

    34.8 (4.6)

    -17.4 (1.7)

    -5.9 (-10.5, -1.4)

    Placebo (n=39)

    32.9 (5.4)

    -11.5 (1.6)

    -­

    Trial 3

    Bupropion

    300 mg/day†

    (n = 110)

    26.5 (4.3)

    -12.0 (NA)

    -3.9 (-5.7, -1.0)

    Placebo (n = 106)

    27.0 (3.5)

    -8.7 (NA)

    -­

    n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available.

  • Medication Guide

    Bupropion Hydrochloride Tablets, USP

    (bue proe' pee on)

    Read this Medication Guide carefully before you start taking bupropion hydrochloride tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about bupropion hydrochloride tablets, ask your healthcare provider or pharmacist.

    IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of suicidal thoughts and actions with antidepressant medicines; the second section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; and the third section is entitled “What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?”

    Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions

    This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your healthcare provider or your family member’s healthcare provider about:


    all risks and benefits of treatment with antidepressant medicines

    all treatment choices for depression or other serious mental illness

    What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

    1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment.

    2. Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic- depressive illness) or suicidal thoughts or actions.

    3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?


    Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.

    Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.

    Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

    Call your healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:


    thoughts about suicide or dying

    attempts to commit suicide

    new or worse depression

    new or worse anxiety

    feeling very agitated or restless

    panic attacks


    trouble sleeping (insomnia)

    new or worse irritability

    acting aggressive, being angry, or violent

    acting on dangerous impulses

    an extreme increase in activity and talking (mania)

    other unusual changes in behavior or mood

    What else do I need to know about antidepressant medicines?


    Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.

    Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.

    Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.

    Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.

    It is not known if bupropion hydrochloride tablets are safe and effective in children under the age of 18.

    Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions

    This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.

    Although bupropion hydrochloride tablets are not a treatment for quitting smoking, it contains the same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.

    Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or actions while taking bupropion to help them quit smoking. These symptoms can develop during treatment with bupropion or after stopping treatment with bupropion.

    If you, your family member, or your caregiver notice agitation, hostility, depression, or changes in thinking or behavior that are not typical for you, or you have any of the following symptoms, stop taking bupropion and call your healthcare provider right away:


    thoughts about suicide or dying

    attempts to commit suicide

    new or worse depression

    new or worse anxiety

    panic attacks

    feeling very agitated or restless

    acting aggressive, being angry, or violent

    acting on dangerous impulses


    an extreme increase in activity and talking (mania)

    abnormal thoughts or sensations

    seeing or hearing things that are not there (hallucinations)

    feeling people are against you (paranoia)

    feeling confused

    other unusual changes in behavior or mood

    When you try to quit smoking, with or without bupropion, you may have symptoms that may be due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and increased appetite or weight gain. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.

    Before taking bupropion, tell your healthcare provider if you have ever had depression or other mental illnesses. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion.

    What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?


    Seizures: There is a chance of having a seizure (convulsion, fit) with bupropion hydrochloride tablets, especially in people:

    o
    with certain medical problems.
    o
    who take certain medicines.

    The chance of having seizures increases with higher doses of bupropion hydrochloride tablets. For more information, see the sections “Who should not take bupropion hydrochloride tablets?” and “What should I tell my healthcare provider before taking bupropion hydrochloride tablets?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking bupropion hydrochloride tablets unless your healthcare provider has said it is okay to take them.

    If you have a seizure while taking bupropion hydrochloride tablets, stop taking the tablets and call your healthcare provider right away. Do not take bupropion hydrochloride tablets again if you have a seizure.


    High blood pressure (hypertension). Some people get high blood pressure that can be severe, while taking bupropion hydrochloride tablets. The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.

    Manic episodes. Some people may have periods of mania while taking bupropion hydrochloride tablets, including:

    o
    Greatly increased energy
    o
    Severe trouble sleeping
    o
    Racing thoughts
    o
    Reckless behavior
    o
    Unusually grand ideas
    o
    Excessive happiness or irritability
    o
    Talking more or faster than usual

    If you have any of the above symptoms of mania, call your healthcare provider.


    Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while taking bupropion hydrochloride tablets, including delusions (believe you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your healthcare provider.

    Visual problems.

    o
    eye pain
    o
    changes in vision
    o
    swelling or redness in or around the eye


    Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

    Severe allergic reactions. Some people can have severe allergic reactions to bupropion hydrochloride tablets. Stop taking bupropion hydrochloride tablets and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction.

    What are bupropion hydrochloride tablets?

    Bupropion hydrochloride tablets are a prescription medicine used to treat adults with a certain type of depression called major depressive disorder.

    Who should not take bupropion hydrochloride tablets?

    Do not take bupropion hydrochloride tablets if you


    have or had a seizure disorder or epilepsy.

    have or had an eating disorder such as anorexia nervosa or bulimia.

    are taking any other medicines that contain bupropion, including ZYBAN ® (used to help people stop smoking) APLENZIN ® , FORFIVO XL™ , WELLBUTRIN SR ® , or WELLBUTRIN XL ®. Bupropion is the same active ingredient that is in bupropion hydrochloride tablets, USP.

    drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop using them all of a sudden.

    take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.

    o
    do not take an MAOI within 2 weeks of stopping bupropion hydrochloride tablets unless directed to do so by your healthcare provider.
    o
    do not start bupropion hydrochloride tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.


    are allergic to the active ingredient in bupropion hydrochloride tablets, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in bupropion hydrochloride tablets.

    What should I tell my healthcare provider before taking bupropion hydrochloride tablets?

    Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”

    Tell your healthcare provider about your other medical conditions including if you:


    have liver problems, especially cirrhosis of the liver.

    have kidney problems.

    have, or have had, an eating disorder, such as anorexia nervosa or bulimia.

    have had a head injury.

    have had a seizure (convulsion, fit).

    have a tumor in your nervous system (brain or spine).

    have had a heart attack, heart problems, or high blood pressure.

    are a diabetic taking insulin or other medicines to control your blood sugar.

    drink alcohol.

    abuse prescription medicines or street drugs.

    are pregnant or plan to become pregnant.

    are breastfeeding. Bupropion passes into your milk in small amounts.

    Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking bupropion hydrochloride tablets.

    How should I take bupropion hydrochloride tablets?


    Take bupropion hydrochloride tablets exactly as prescribed by your healthcare provider.

    Take bupropion hydrochloride tablets at the same time each day.

    Take your doses of bupropion hydrochloride tablets at least 6 hours apart.

    Do not chew, cut, or crush bupropion hydrochloride tablets.

    You may take bupropion hydrochloride tablets with or without food.

    If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time. Thi s is very important. Too much bupropion hydrochloride tablets can increase your chance of having a seizure.

    If you take too much bupropion hydrochloride tablets, or overdose, call your local emergency room or poison control center right away.

    Do not take any other medicines while taking bupropion hydrochloride tablets unless your healthcare provider has told you it is okay.

    If you are taking bupropion hydrochloride tablets for the treatment of major depressive disorder, it may take several weeks for you to feel that bupropion hydrochloride tablets is working. Once you feel better, it is important to keep taking bupropion hydrochloride tablets exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel bupropion hydrochloride tablets are working for you.

    Do not change your dose or stop taking bupropion hydrochloride tablets without talking with your healthcare provider first.

    What should I avoid while taking bupropion hydrochloride tablets?


    Limit or avoid using alcohol during treatment with bupropion hydrochloride tablets. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your risk of having seizures.

    Do not drive a car or use heavy machinery until you know how bupropion hydrochloride tablets affect you. Bupropion hydrochloride tablets can affect your ability to do these things safely.

    What are possible side effects of bupropion hydrochloride tablets?

    See “What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?”

    Bupropion hydrochloride tablets can cause serious side effects.

    The most common side effects of bupropion hydrochloride tablets include:


    Nervousness

    Dry mouth

    Constipation

    Headache

    Nausea or vomiting

    Dizziness

    Heavy sweating

    Shakiness (tremor)

    Trouble sleeping

    Blurred vision

    Fast heartbeat

    If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your medicine too close to bedtime.

    Tell your healthcare provider right away about any side effects that bother you.

    These are not all the possible side effects of bupropion hydrochloride tablets. For more information, ask your healthcare provider or pharmacist.

    Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    You may also report side effects to Sandoz Inc. at 1-800-525-8747.

    How should I store bupropion hydrochloride tablets?


    Store bupropion hydrochloride tablets at room temperature between 20ºC to 25ºC (68ºF to 77ºF).

    Keep bupropion hydrochloride tablets dry and out of the light.

    Keep bupropion hydrochloride tablets and all medicines out of the reach of children.

    General Information about bupropion hydrochloride tablets.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bupropion hydrochloride tablets for a condition for which it was not prescribed. Do not give bupropion hydrochloride tablets to other people, even if they have the same symptoms you have. It may harm them.

    If you take a urine drug screening test, bupropion hydrochloride tablets may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking bupropion hydrochloride tablets, they can do a more specific drug screening test that should not have this problem.

    This Medication Guide summarizes important information about bupropion hydrochloride tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bupropion hydrochloride tablets that is written for healthcare professionals.

    For more information about bupropion hydrochloride tablets, call Sandoz Inc. at 1-800-525-8747.

    What are the ingredients in bupropion hydrochloride tablets?

    Active ingredient: bupropion hydrochloride, USP.

    Inactive ingredients: FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, hydroxypropyl methylcellulose, microcrystalline cellulose, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triethyl citrate.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Brands listed are trademarks of their respective owners.

    For Medication Guides, please visit www.us.sandoz.com or call 1-800-507-2130.

    01-2015M

    7334

    Sandoz Inc.

    Princeton, NJ 08540

  • Package Label

    Label

  • INGREDIENTS AND APPEARANCE
    BUPROPION HYDROCHLORIDE 
    bupropion hydrochloride tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 61919-037(NDC: 0781-1053)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    BUPROPION HYDROCHLORIDE (UNII: ZG7E5POY8O) (BUPROPION - UNII:01ZG3TPX31) BUPROPION HYDROCHLORIDE75 mg
    Inactive Ingredients
    Ingredient NameStrength
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    POTASSIUM CHLORIDE (UNII: 660YQ98I10)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    Product Characteristics
    Colorpurple (Lavender) Scoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code GG929
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 61919-037-6060 in 1 BOTTLE; Type 0: Not a Combination Product11/25/2015
    2NDC: 61919-037-3030 in 1 BOTTLE; Type 0: Not a Combination Product11/25/2015
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07558411/25/2015
    Labeler - DirectRX (079254320)
    Establishment
    NameAddressID/FEIBusiness Operations
    DirectRX079254320repack(61919-037)
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