Bupropion Hydrochloride (Page 7 of 10)

13 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 per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per 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 per kg per day (approximately 2 to 7 times the MRHD on a mg per 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 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 per kg per day revealed no evidence of impaired fertility.

14 CLINICAL STUDIES

The efficacy of the immediate-release formulation of bupropion 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 6) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion 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 the immediate-release formulation of bupropion (300 mg per day and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at the 450-mg-per-day dose. The efficacy results were 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 the immediate-release formulation of bupropion. This trial demonstrated the efficacy of the immediate-release formulation of bupropion 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.

Table 6. Efficacy of Immediate-Release Bupropion 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)

Placebo-subtracted Difference *

(95% CI)

Trial 1

Immediate-Release 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

Immediate-Release Bupropion 300 mg/day

(n = 36)

32.4 (5.9)

-15.5 (1.7)

-4.1

Immediate-Release 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

Immediate-Release 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.

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained-release formulation of bupropion, trials have demonstrated the bioequivalence of the immediate-release and sustained-release forms of bupropion under steady-state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.

In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on bupropion hydrochloride extended-release tablets (SR) (150 mg twice daily) were randomized to continuation of their same dose of bupropion hydrochloride extended-release tablets (SR) or placebo for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement 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 receiving continued treatment with bupropion hydrochloride extended-release tablets (SR) experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.

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