14.1 Major Depressive Disorder

The efficacy of Cymbalta 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 Cymbalta 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 Cymbalta 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 Cymbalta 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, Cymbalta demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score.

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.

In another study, 533 patients meeting DSM-IV criteria for MDD received Cymbalta 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 Cymbalta at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on Cymbalta experienced a statistically significantly longer time to relapse of depression than did patients on placebo. 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 Cymbalta in hospitalized patients with major depressive disorder has not been studied.

14.2 Generalized Anxiety Disorder

The efficacy of Cymbalta 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 Cymbalta 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 Cymbalta doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week 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, Cymbalta demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a widely used and well-validated scale that measures 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 Cymbalta 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 Cymbalta 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 Cymbalta experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

14.3 Diabetic Peripheral Neuropathic Pain

The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study 1 and 2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Cymbalta. Patients recorded their pain daily in a diary.

Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with placebo. Study 1 additionally compared Cymbalta 20 mg with placebo. A total of 457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2. Treatment with Cymbalta 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

  
14.4 Fibromyalgia

The efficacy of Cymbalta for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study 1 was three months in duration and enrolled female patients only. Study 2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). Study 1 and 2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).

Both studies compared Cymbalta 60 mg once daily or 120 mg daily (given in divided doses in Study 1 and as a single daily dose in Study 2) with placebo. Study 2 additionally compared Cymbalta 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 Cymbalta, 120 placebo) were enrolled in Study 1 and a total of 520 patients (376 Cymbalta, 144 placebo) were enrolled in Study 2 (5% male, 95% female). Treatment with Cymbalta 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increase the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.

  
Additionally, the benefit of up-titration in non-responders to Cymbalta at 60 mg/day was evaluated in a separate study. Patients were initially treated with Cymbalta 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with Cymbalta at either 60 mg once daily or 120 mg once daily. Those patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to Cymbalta 120 mg as compared to those who were blindly continued on Cymbalta 60 mg.