Bupropion Hydrochloride SR (Page 8 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 10 and 2 times the MRHD, respectively, on a mg per m2 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 3 to 10 times the MRHD on a mg per 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 per kg per day revealed no evidence of impaired fertility.

14 CLINICAL STUDIES

The efficacy of bupropion hydrochloride extended-release tablets (SR) as an aid to smoking cessation was demonstrated in 3 placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n = 1,940, greater than or equal to 15 cigarettes per day). In these trials, bupropion hydrochloride extended-release tablets (SR) were used in conjunction with individual smoking cessation counseling.

The first trial was a dose-response trial conducted at 3 clinical centers. Subjects in this trial were treated for 7 weeks with 1 of 3 doses of bupropion hydrochloride extended-release tablets (SR) (100, 150, or 300 mg per day) or placebo; quitting was defined as total abstinence during the last 4 weeks of treatment (Weeks 4 through 7). Abstinence was determined by subject daily diaries and verified by carbon monoxide levels in expired air.

Results of this dose-response trial with bupropion hydrochloride extended-release tablets (SR) demonstrated a dose-dependent increase in the percentage of subjects able to achieve 4-week abstinence (Weeks 4 through 7). Treatment with bupropion hydrochloride extended-release tablets (SR) at both 150 and 300 mg per day was significantly more effective than placebo in this trial.

Table 5 presents quit rates over time in the multicenter trial by treatment group. The quit rates are the proportions of all subjects initially enrolled (i.e., intent-to-treat analysis) who abstained from Week 4 of the trial through the specified week. Treatment with bupropion hydrochloride extended-release tablets (SR) (150 or 300 mg per day) was more effective than placebo in helping subjects achieve 4-week abstinence. In addition, treatment with bupropion hydrochloride extended-release tablets (SR) (7 weeks at 300 mg per day) was more effective than placebo in helping subjects maintain continuous abstinence through Week 26 (6 months) of the trial.

Table 5. Dose-Response Trial: Quit Rates by Treatment Group

Abstinence from Week 4 through Specified Week

Treatment Groups
Placebo (n = 151) % (95% CI)

Bupropion Hydrochloride Extended-Release Tablets (SR)

100 mg/day

( n = 153)

%

(95% CI)

Bupropion Hydrochloride Extended-Release Tablets (SR)

150 mg/day

( n = 153)

%

(95% CI)

Bupropion Hydrochloride Extended-Release Tablets (SR)

300 mg/day

( n = 156)

%

(95% CI)

Week 7 (4-week quit) 17%

(11 to 23)

22%

(15 to 28)

27%a

(20 to 35)

36%a

(28 to 43)

Week 12 14%

(8 to 19)

20%

(13 to 26)

20%

(14 to 27)

25%a

(18 to 32)

Week 26 11%

(6 to 16)

16%

(11 to 22)

18%

(12 to 24)

19%a

(13 to 25)

a Significantly different from placebo (P ≤0.05).

The second trial was a comparator trial conducted at 4 clinical centers. Four treatments were evaluated: bupropion hydrochloride extended-release tablets (SR) 300 mg per day, nicotine transdermal system (NTS) 21 mg per day, combination of bupropion hydrochloride extended-release tablets (SR) 300 mg per day plus NTS 21 mg per day, and placebo. Subjects were treated for 9 weeks. Treatment with bupropion hydrochloride extended-release tablets (SR) was initiated at 150 mg per day while the subject was still smoking and was increased after 3 days to 300 mg per day given as 150 mg twice daily. NTS 21 mg per day was added to treatment with bupropion hydrochloride extended-release tablets (SR) after approximately 1 week when the subject reached the target quit date. During Weeks 8 and 9 of the trial, NTS was tapered to 14 and 7 mg per day, respectively. Quitting, defined as total abstinence during Weeks 4 through 7, was determined by subject daily diaries and verified by expired air carbon monoxide levels. In this trial, subjects treated with any of the 3 treatments achieved greater 4-week abstinence rates than subjects treated with placebo.

Table 6 presents quit rates over time by treatment group for the comparator trial.

Table 6. Comparator Trial: Quit Rates by Treatment Group

Abstinence from Week 4 through Specified Week

Treatment Groups
Placebo (n = 160) % (95% CI) Nicotine Transdermal System (NTS) 21 mg/day (n = 244) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 244) % (95% CI)

Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day and NTS 21 mg/day ( n = 245) % (95% CI)

Week 7 (4-week quit)

23%

(17 to 30)

36%

(30 to 42)

49%

(43 to 56)

58%

(51 to 64)

Week 10 20%

(14 to 26)

32%

(26 to 37)

46%

(39 to 52)

51%

(45 to 58)

When subjects in this trial were followed out to 1 year, the superiority of bupropion hydrochloride extended-release tablets (SR) and the combination of bupropion hydrochloride extended-release tablets (SR) and NTS over placebo in helping them to achieve abstinence from smoking was maintained. The continuous abstinence rate was 30% (95% CI: 24 to 35) in the subjects treated with bupropion hydrochloride extended-release tablets (SR) and 33% (95% CI: 27 to 39) for subjects treated with the combination at 26 weeks compared with 13% (95% CI: 7 to 18) in the placebo group. At 52 weeks, the continuous abstinence rate was 23% (95% CI: 18 to 28) in the subjects treated with bupropion hydrochloride extended-release tablets (SR) and 28% (95% CI: 23 to 34) for subjects treated with the combination, compared with 8% (95% CI: 3 to 12) in the placebo group. Although the treatment combination of bupropion hydrochloride extended-release tablets (SR) and NTS displayed the highest rates of continuous abstinence throughout the trial, the quit rates for the combination were not significantly higher (P >0.05) than for bupropion hydrochloride extended-release tablets (SR) alone.

The comparisons between bupropion hydrochloride extended-release tablets (SR), NTS, and combination treatment in this trial have not been replicated, and, therefore should not be interpreted as demonstrating the superiority of any of the active treatment arms over any other.

The third trial was a long-term maintenance trial conducted at 5 clinical centers. Subjects in this trial received open-label bupropion hydrochloride extended-release tablets (SR) 300 mg per day for 7 weeks. Subjects who quit smoking while receiving bupropion hydrochloride extended-release tablets (SR) (n = 432) were then randomized to bupropion hydrochloride extended-release tablets (SR) 300 mg per day or placebo for a total trial duration of 1 year. Abstinence from smoking was determined by subject self-report and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months, continuous abstinence rates were significantly higher for subjects continuing to receive bupropion hydrochloride extended-release tablets (SR) than for those switched to placebo (P <0.05; 55% versus 44%).

Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates. Quit rates for bupropion hydrochloride extended-release tablets (SR) were similar in subjects with and without prior quit attempts using nicotine replacement therapy.

Treatment with bupropion hydrochloride extended-release tablets (SR) reduced withdrawal symptoms compared with placebo. Reductions on the following withdrawal symptoms were most pronounced: irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending on the trial and the measure used, treatment with bupropion hydrochloride extended-release tablets (SR) showed evidence of reduction in craving for cigarettes or urge to smoke compared with placebo.

Use in Patients with Chronic Obstructive Pulmonary Disease (COPD)Bupropion hydrochloride extended-release tablets (SR) were evaluated in a randomized, double-blind, comparator trial of 404 subjects with mild–to­-moderate COPD defined as FEV1 greater than or equal to 35%, FEV1 /FVC less than or equal to 70%, and a diagnosis of chronic bronchitis, emphysema, and/or small airways disease. Subjects aged 36 to 76 years were randomized to bupropion hydrochloride extended-release tablets (SR) 300 mg per day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with bupropion hydrochloride extended-release tablets (SR) was initiated at 150 mg per day for 3 days while the subject was still smoking and increased to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was determined by subject daily diaries and verified by carbon monoxide levels in expired air. Quitters were defined as subjects who were abstinent during the last 4 weeks of treatment. Table 7 shows quit rates in the COPD Trial.

Table 7. COPD Trial: Quit Rates by Treatment Group

4-Week Abstinence Period

Treatment Groups

Placebo (n = 200) % (95% CI)

Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 204) % (95% CI)

Weeks 9 through 12 12%

(8 to 16)

22%a

(17 to 27)

a Significantly different from placebo (P <0.05).

Postmarketing Neuropsychiatric Safety Outcome TrialBupropion hydrochloride extended-release tablets (SR) were evaluated in a randomized, double-blind, active-and placebo-controlled trial that included subjects without a history of psychiatric disorder (non-psychiatric cohort, n = 3,912) and subjects with a history of psychiatric disorder (psychiatric cohort, n = 4003). Subjects aged 18 to 75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily, varenicline 1 mg twice daily, nicotine replacement therapy patch (NRT) 21 mg per day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment [see Warnings and Precautions (5.2)].

A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse events including the following NPS adverse events: anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, irritability, suicidal ideation, suicidal behavior, or completed suicide.

The use of bupropion hydrochloride extended-release tablets (SR), varenicline, and NRT in the non-psychiatric cohort was not associated with an increased risk of clinically significant NPS adverse events compared with placebo (Table 8).

Table 8. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group among Patients without a History of Psychiatric Disorder

Treatment Group

Bupropion Hydrochloride Extended-Release Tablets (SR) (n = 968) n (%)

Varenicline (n = 975) n (%)

NRT (n = 987) n (%)

Placebo (n = 982) n (%)

Clinically significant NPS 34 (3.5) 30 (3.1) 33 (3.3) 40 (4.1)
Serious NPS 5 (0.5) 1 (0.1) 1 (0.1) 4 (0.4)
Psychiatric hospitalizations 2 (0.2) 1 (0.1) 0 (0.0) 1 (0.1)

There were more clinically significant NPS adverse events reported in patients in the psychiatric cohort in each treatment group compared with the non-psychiatric cohort (Table 9). The incidence of events in the composite endpoint was higher for each of the active treatments compared with placebo: Risk Differences (RDs) (95% CI) vs. placebo were 2.2 % (-0.5, 4.9) for bupropion hydrochloride extended-release tablets (SR); 2.7% (-0.05, 5.4) for varenicline, and 0.4% (-2.2, 3.0) for NRT transdermal nicotine.

Table 9. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group among Patients with a History of Psychiatric Disorder
Treatment Group Bupropion Hydrochloride Extended-Release Tablets (SR) (n = 1,004) n (%) Varenicline(n = 1,007)n (%) NRT(n = 995)n (%) Placebo(n = 997) n (%)
Clinically significant NPS 118 (11.8) 123 (12.2) 98 (9.8) 95 (9.5)
Serious NPS 8 (0.8) 6 (0.6) 4 (0.4) 6 (0.6)
Psychiatric hospitalizations 8 (0.8) 5 (0.5) 4 (0.4) 2 (0.2)

There was one completed suicide, which occurred during treatment in a patient treated with placebo in the non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort.

In both cohorts, subjects treated with bupropion hydrochloride extended-release tablets (SR) had a superior rate of CO-confirmed abstinence during Weeks 9 through 12 and 9 through 24 compared with subjects treated with placebo.

Table 10: Continuous Abstinence (95% Confidence Interval), Study in Patients with or without a History of Psychiatric Disorder

Bupropion Hydrochloride Extended-Release Tablets (SR) 150 mg Twice Daily

Varenicline1 mgTwice Daily NRT21 mg/daywith Taper Placebo
Weeks 9 through 12
Non-Psychiatric Cohort 26% (23%, 29%) 38%(35%, 41%) 26%(24%, 29%) 14%(12%, 16%)
Psychiatric Cohort 19%(17%, 22%) 29%(26%, 32%) 20%(18%, 23%) 11%(10%, 14%)
Weeks 9 through 24
Non-Psychiatric Cohort 19%(16%, 21%)

25%(23%, 28%)

18%(16%, 21%) 11%(9%, 13%)
Psychiatric Cohort 14%(12%, 16%) 18%(16%, 21%) 13%(11%, 15%) 8%(7%, 10%)

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