Bupropion Hydrochloride (Page 7 of 9)

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/kg/day, respectively. These doses are approximately 6 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 6 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.

There were no effects on male and female fertility when rats were administered oral doses of bupropion up to 300 mg/kg/day (approximately 6 times the MRHD on a mg/m2 basis) to females prior to mating and either through Day 13 of gestation or through lactation, and to males for 60 days prior to and through mating. However, doses of 200 mg/kg/day (approximately 4 times the MRHD on a mg/m2 basis) or greater, caused transient ataxia or behavioral changes in adult female rats. There were also no adverse effects on fertility, reproduction, or growth and development of male or female offspring.

14 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/day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg/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/day) and placebo. This trial demonstrated the effectiveness of bupropion hydrochloride tablets for only the 450-mg/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/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

Trial Number

Treatment Group

Primary Efficacy Measure: HDRS

Mean Baseline Score (SD)

LS Mean Score at Endpoint Visit (SE)

Placebo-subtracted Differencea (95% CI)

Bupropion hydrochloride tablets 300-600 mg/dayb (n = 48)

28.5 (5.1)

14.9 (1.3)

-4.7 (-8.8, -0.6)

Trial 1

Placebo (n = 27)

29.3 (7.0)

19.6 (1.6)

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Trial 2

Bupropion hydrochloride tablets 300 mg/day (n = 36)

32.4 (5.9)

-15.5 (1.7)

-4.1

Bupropion hydrochloride tablets 450 mg/dayb (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 hydrochloride tablets 300 mg/dayb (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.

a 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.

b Doses that are demonstrated to be statistically significantly superior to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING


Bupropion hydrochloride tablets, USP 100 mg are available for oral administration as purple, round, unscored, film coated tablets, imprinted “APO” on one side and “BUP” over “100” on the other side. They are supplied as follows:
Bottles of 30 (NDC 68788-7988-3)

Bottles of 60 (NDC 68788-7988-6)

Bottles of 90 (NDC 68788-7988-9)
Store at 20ºC to 25ºC (68ºF to 77ºF): excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

Protect from moisture.

Store in a tight, light resistant container [see USP].

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