Duloxetine Delayed-Release (Page 10 of 15)


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


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/m 2 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.


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/m 2 basis) did not alter mating or fertility.


14.1 Overview of the Clinical Trials

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

  • Major Depressive Disorder (MDD): 4 short-term (Studies MDD-1, MDD-2, MDD-3, and MDD-4) and 1 maintenance trial (Study MDD-5) in adults [see Clinical Studies (14.2)].
  • Generalized Anxiety Disorder (GAD): 3 short-term trials in adults (Studies GAD-1, GAD-2, and GAD-3), 1 maintenance trial in adults (Study GAD-4), 1 short-term trial in geriatric patients (Study GAD-5), and 1 short-term trial in pediatric patients 7 to 17 years of age (Study GAD-6) [see Clinical Studies (14.3)].
  • Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults (Studies DPNP-1 and DPNP-2) [see Clinical Studies (14.4)].
  • Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration) (Studies FM-1 and FM-2) [see Clinical Studies (14.5)].
  • Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) (Studies CLBP-1 and CLBP-3) and one 13-week trial in adult patients with chronic pain due to osteoarthritis (OA) (Study OA-1) [see Clinical Studies (14.6)].

Additionally, a summary of the following trials that did not demonstrate efficacy are presented below: Study FM-3 (a 16-week trial in adult patients with fibromyalgia), Study CLBP-2 (a 13-week trial in adult patients with CLBP), and Study OA-2 (a 13-week trial in adult patients with chronic pain due to OA).

Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (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.

14.2 Major Depressive Disorder in Adults

The efficacy of Duloxetine delayed-release capsules as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD:

  • In Studies MDD-1 and MDD-2, 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 Study MDD-3, 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 Study MDD-4, 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.

In all four trials, Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 8). There is no evidence that doses greater than 60 mg/day confer additional benefits.

In all of these clinical trials, 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 8: Summary of the Primary Efficacy Results for Adult Trials in MDD
Study NumberTreatment GroupPrimary Efficacy Measure: HAMD-17
Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Difference * (95% CI)
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.
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses statistically significantly superior to placebo.
Study MDD-1Duloxetine delayed-release capsules (60 mg/day) 21.5 (4.10)-10.9 (0.70)-4.9 (-6.8, -2.9)
Placebo21.1 (3.71)-6.1 (0.69)
Study MDD-2Duloxetine delayed-release capsules (60 mg/day) 20.3 (3.32)-10.5 (0.71)-2.2 (-4.0, -0.3)
Placebo20.5 (3.42)-8.3 (0.67)
Study MDD-3Duloxetine delayed-release capsules (20 mg BID) 18.6 (5.85)-7.4 (0.80)-2.4 (-4.7, -0.2)
Duloxetine delayed-release capsules (40 mg BID) 18.1 (4.52)-8.6 (0.81)-3.6 (-5.9, -1.4)
Placebo17.2 (5.11)-5.0 (0.81)
Study MDD-4Duloxetine delayed-release capsules (40 mg BID) 19.9 (3.54)-11.0 (0.49)-2.2 (-3.6, -0.9)
Duloxetine delayed-release capsules (60 mg BID) 20.2 (3.41)-12.1 (0.49)-3.3 (-4.7, -1.9)
Placebo19.9 (3.58)-8.8 (0.50)

In Study MDD-5, 533 adult 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 dosage (N=136) or to placebo (N=142) for 6 months.

In Study MDD-5, patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo (see 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.

Kaplan-Meier estimator method.
Figure 1: Cumulative Proportion * of Adult Patients with MDD Relapse (Study MDD-5)
Figure 1
(click image for full-size original)

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