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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 (6 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m 2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).

In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36 mg/kg/day in males (3 times the MRHD) 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 (4 times the MRHD) did not alter mating or fertility.

14 CLINICAL STUDIES

The efficacy of duloxetine delayed-release capsules 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, and 1 short-term trial in children and adolescents [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)] .

14.1 Major Depressive Disorder

The efficacy of duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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

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.

Study Number Treatment Group Primary Efficacy Measure: HAMD-17
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI)
Study 1Duloxetine delayed-release capsules (60 mg/day) b 21.5 (4.10)-10.9 (0.70)-4.9 (-6.8, -2.9)
Placebo21.1 (3.71)-6.1 (0.69)
Study 2Duloxetine delayed-release capsules (60 mg/day) b 20.3 (3.32)-10.5 (0.71)-2.2 (-4.0, -0.3)
Placebo20.5 (3.42)-8.3 (0.67)
Study 3Duloxetine delayed-release capsules (20 mg BID) b 18.6 (5.85)-7.4 (0.80)-2.4 (-4.7, -0.2)
Duloxetine delayed-release capsules (40 mg BID) b 18.1 (4.52)-8.6 (0.81)-3.6 (-5.9, -1.4)
Placebo17.2 (5.11)-5.0 (0.81)
Study 4Duloxetine delayed-release capsules (40 mg BID) b 19.9 (3.54)-11.0 (0.49)-2.2 (-3.6, -0.9)
Duloxetine delayed-release capsules (60 mg BID) b 20.2 (3.41)-12.1 (0.49)-3.3 (-4.7, -1.9)
Placebo19.9 (3.58)-8.8 (0.50)

In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine delayed-release capsules 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 delayed-release capsules at the same dose (N = 136) or to placebo (N = 142) for 6 months. Patients on duloxetine delayed-release capsules 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 delayed-release capsules 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)

Figure 1
(click image for full-size original)

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