During a chronic dosing study with bupropion in 14 depressed patients 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 to healthy volunteers.
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 studies involving patients dosed in a range of 300 to 750 mg/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 study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that in younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetic study suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].
A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion. In addition, 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 to female volunteers.
The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride 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 was no statistically significant difference in C max , half-life, T max , AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (XL)
In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) 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.
Ticlopidine and Clopidogrel: In a study in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C max and AUC) of bupropion by 40% and 60% for clopidogrel, by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion were decreased.
Prasugrel: In healthy subjects, prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and decreased C max and AUC values of hydroxybupropion by 32% and 24%, respectively.
Cimetidine: Following oral administration of bupropion 300 mg with and without cimetidine 800 mg in 24 healthy young male volunteers, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C max , respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.
Ritonavir and Lopinavir: In a healthy volunteer study, ritonavir 100 mg twice daily reduced the AUC and C max 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 study, ritonavir 600 mg twice daily decreased the AUC and C max 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 study, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C max by 57%. The AUC and C max of hydroxybupropion metabolite were decreased by 50% and 31%, respectively.
Efavirenz: In a study of healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C max of hydroxybupropion was increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers, following a 14-day administration of bupropion 100 mg three times per day, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.
In vitro , bupropion and hydroxybupropion are CYP2D6 inhibitors. In a clinical study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C max , 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 study bupropion increased the C max 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.
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m 2 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 of bupropion hydrochloride (approximately 2 to 7 times the MRHD on a mg/m 2 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 one Ames bacterial mutagenicity assay, but was negative in another. 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.
The efficacy of bupropion in the treatment of major depressive disorder was established with the immediate-release formulation of bupropion hydrochloride in two 4-week, placebo-controlled trials in adult inpatients with MDD and in one 6-week, placebo-controlled trial in adult outpatients with MDD. In the first study, the bupropion dose range was 300 mg to 600 mg per day administered in 3 divided doses; 78% of patients were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (item 1), and the Clinical Global Impressions-Severity Scale (CGI-S). The second study included 2 fixed doses of bupropion (300 mg and 450 mg per day) and placebo. This trial demonstrated the efficacy of bupropion for only the 450 mg dose. The efficacy results were significant for the HAMD total score and the CGI-S severity score, but not for HAMD item 1. In the third study, outpatients were treated with bupropion 300 mg per day. This study demonstrated the efficacy of bupropion as measured by the HAMD total score, the HAMD item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.
A longer-term, placebo-controlled, randomized withdrawal trial demonstrated the efficacy of bupropion HCl sustained-release in the maintenance treatment of MDD. The trial included adult outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open-label trial of bupropion 300 mg per day. Responders were randomized to continuation of bupropion 300 mg per day or placebo for up to 44 weeks of observation for relapse. Response during the open-label phase was defined as a CGI-Improvement Scale score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients in the bupropion group experienced significantly lower relapse rates over the subsequent 44 weeks compared to those in the placebo group.
Although there are no independent trials demonstrating the efficacy of bupropion hydrochloride extended-release tablets (XL) in the acute treatment of MDD, studies have demonstrated similar bioavailability between the immediate-, sustained-, and extended-release formulations of bupropion HCl under steady-state conditions (i.e., the exposures [C max and AUC] for bupropion and its metabolites are similar among the 3 formulations).
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