Duloxetine (Page 8 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (3 times the maximum recommended human dose (MRHD) of 120 mg/day given to children on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (1 time the MRHD given to children). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (2 times the MRHD given to children).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (1 time the MRHD given to children) and up to 36 mg/kg/day in males (1.4 times the MRHD given to children) did not increase the incidence of tumors.
Mutagenesis — Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (3 times the MRHD given to adolescents on a mg/m2 basis) did not alter mating or fertility.

14 CLINICAL STUDIES

The efficacy of duloxetine has been established in the following adequate and well-controlled trials:

Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies (14.1)].
Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults [see Clinical Studies (14.2)].
Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults [see Clinical Studies (14.3)].
Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies (14.5)].

Pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. However, due to Eli Lilly and Company, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

14.1 Major Depressive Disorder

The efficacy of duloxetine as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits.
In all 4 studies, duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1-4 in Table 7).
In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Table 7: Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder

Study Number

Treatment Group

Primary Efficacy Measure: HAMD-17

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

Duloxetine (60 mg/day)b Placebo

21.5 (4.10)21.1 (3.71)

-10.9 (0.70)-6.1 (0.69)

-4.9 (-6.8, -2.9)-

Study 2

Duloxetine (60 mg/day)b Placebo

20.3 (3.32)20.5 (3.42)

-10.5 (0.71)-8.3 (0.67)

-2.2 (-4.0, -0.3)-

Study 3

Duloxetine (20 mg BID)b Duloxetine (40 mg BID)b Placebo

18.6 (5.85)18.1 (4.52)17.2 (5.11)

-7.4 (0.80)-8.6 (0.81)-5.0 (0.81)

-2.4 (-4.7, -0.2)-3.6 (-5.9, -1.4)–

Study 4

Duloxetine (40 mg BID)b Duloxetine (60 mg BID)b Placebo

19.9 (3.54)20.2 (3.41)19.9 (3.58)

-11.0 (0.49)-12.1 (0.49)-8.8 (0.50)

-2.2 (-3.6, -0.9)-3.3 (-4.7, -1.9)–

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included.
a Difference (drug minus placebo) in least-squares mean change from baseline.
b Doses statistically significantly superior to placebo.
In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of duloxetine at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo (Study 5 in Figure 1). Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of duloxetine in hospitalized patients with major depressive disorder has not been studied.
Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5)

duloxetine-figure1
(click image for full-size original)

14.2 Generalized Anxiety Disorder

The efficacy of duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.
In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.
The 2 flexible-dose studies involved dose titration with duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.
In all 3 studies, duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1-3 in Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.
In another study, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2).
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. Table 8: Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder

Study Number

Treatment Group

Primary Efficacy Measure: HAMD-17

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1(HAM-A)

Duloxetine (60 mg/day)b Duloxetine (120 mg/day)b Placebo

25.1 (7.18)25.1 (7.24)25.8 (7.66)

-12.8 (0.68)-12.5 (0.67)-8.4 (0.67)

-4.4 (-6.2, -2.5)-4.1 (-5.9, -2.3)–

Study 2(HAM-A)

Duloxetine (60-120 mg/day)b Placebo

22.5 (7.44)23.5 (7.91)

-8.1 (0.70)-5.9 (0.70)

-2.2 (-4.2, -0.3)-

Study 3(HAM-A)

Duloxetine (60-120 mg/day)b Placebo

25.8 (5.66)25.0 (5.82)

-11.8 (0.69)-9.2 (0.67)

-2.6 (-4.5, -0.7)—

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included.

a Difference (drug minus placebo) in least squares mean change from baseline.

b Dose statistically significantly superior to placebo
Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4)

duloxetine-figure2
(click image for full-size original)

Pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. However, due to Eli Lilly and Company, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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