Cymbalta ® (duloxetine) delayed-release capsules

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Cymbalta® (duloxetine): Efficacy and Safety in Adolescents With Fibromyalgia

The safety and efficacy of Cymbalta in adolescents age 13 to 17 years old with fibromyalgia has been established and is now indicated for use.

Detailed Information

The safety and effectiveness of duloxetine has been established for treatment of JFM in patients 13 to 17 years of age; however, it has not been established in patients less than 13 years of age.1

Efficacy and Safety of Duloxetine Vs Placebo in Adolescents With Juvenile Fibromyalgia

Study Design

A 13-week randomized, double-blind, placebo controlled, multi-site study (N=184) evaluated the safety and efficacy of duloxetine 30/60mg daily (N=91) compared to placebo (N=93) in adolescent patients aged 13 to 17 years with JFM.2

Patients randomized to the duloxetine treatment group received 30 mg daily during week 1; then the dose was increased to 60 mg, two 30-mg capsules, daily. Investigators were able to adjust the dose back to 30 mg, if necessary, based on the patient's response. No dose adjustment were permitted after week 7 and the dose was decreased to 30 mg.2

Following the double-blind study, an open-label extension phase [weeks 14-39 (N=106)] was completed to measure the secondary endpoints. During the open-label treatment

  • patients who received duloxetine 30 mg daily were increased to 60 mg daily, and

  • patients who received duloxetine 60 mg daily were tapered to 30 mg daily.2

Key Inclusion/Exclusion Criteria

The study included patients

  • 13 to 17 years old

  • diagnosed with JPFS, and

  • with pain scores ≥4 on the average pain severity item of the BPI.2

Patients were excluded from the study if they 

  • had recently given birth, pregnant, or nursing

  • were treated with duloxetine 6 months prior

  • experienced duloxetine hypersensitivity

  • had evidence of an autoimmune disease or rheumatologic disorder

  • experienced a DSM-IV axis I psychiatric disorder within the past year, excluding a few disorders with PI approval

  • were diagnosed with and required pharmacologic treatment for a secondary DSM-IV axis I condition

  • were diagnosed with any DSM-IV axis II psychiatric disorder, or

  • were diagnosed with DSM-IV axis I psychosis, bipolar disorder, or schizoaffective disorder during lifetime.2

Outcome Measures

The study evaluated the mean change in 24-hour BPI average pain severity from baseline to week 13 between duloxetine 30/60 mg daily and placebo.2

The secondary endpoints measured improvements at the end of double-blind treatment period [Week 13 (N=149)] and open-label extension [Weeks 14–39 (N=106)] in

  • BPI severity and interference scores

  • treatment response (≥30%, ≥50% reductions on BPI average pain severity)

  • PPQ

  • CGI-S (overall and mental illness)

  • FDI: child and parent versions

  • CDI

  • Multidimensional Anxiety Scale for Children

  • safety, and

  • tolerability.2

Baseline Characteristics

A total of 184 patients were randomized (Table 1).2

Table 1. Patient Demographics and Baseline Characteristicsa,2


Placebo

n=93

Duloxetine

n=91

Age (y)

15.33 (1.42)

15.74 (1.38)

Female, n (%)

65 (69.89)

73 (80.22)

Race, n (%)

Caucasian

70 (75027)

72 (79.12)

African American

8 (8.60)

7 (7.69)

Asian

7 (7.53)

6 (6.59)

American Indian or Alaska

0 (0)

1 (1.10)

Native Hawaiian or others

1 (1.08)

0 (0)

Multiracial

6 (6.45)

4 (4.40)

BMI (kg/m2)

24.10 (5.92)

24.11 (7.09)

Time since diagnosis for fibromyalgia, y, mean (SD)

0.38 (1.24)

0.19 (0.47)

Abbreviation: BMI = body mass index.

a Intent-to-treat population.

Efficacy

From baseline to week 13, the change in 24-hour average BPI pain severity score was not statistically significant (p=.052) between the duloxetine treatment group and placebo treatment group.2

Duloxetine showed improvement over placebo on the primary endpoint with a p-value of .052 from the prespecified primary analysis,1,2 and p values ranging from .011 to .020 from sensitivity analyses which assigned baseline values to missing assessments of some patients who did not complete the trial for various reasons.1

During the open-label extension phase (weeks 14-39), statistical significance was seen at the LS mean change from baseline in BPI average score in patients who switched to duloxetine in open-label trial from placebo during double-blind treatment (p<.001) (Table 2).2

Table 2. Secondary Endpoints at Double-Blind and Open-Label Treatment Period2

 

Placebo

n=93

Duloxetine

n=91

Treatment Difference

P Value

Placebo/Duloxetine

n=75

Duloxetine/Duloxetine

n=91


LS Means for Change From Baseline (SE)


Double-Blind Treatment Period



Open-Label Treatment Period

BPI severity and interference ratings

Worst pain score

-0.96 (0.267)

-1.43 (0.275)

-0.47

0.175

-0.8 (0.256)a

-0.65 (0.262)b

Least pain score

-0.60 (0.242)

-0.96 (0.247)

-0.35

0.255

-0.45 (0.212)b

-0.29 (0.218)

Pain score right now

-1.17 (0.270)

-1.44 (0.276)

-0.26

0.446

-0.29 (0.252)

-0.38 (0.259)

Incidence of treatment response, n (%)c

30% reduction

33 (36.26)

47 (52.22)

--

0.032d

27 (37.50)

25 (36.23)

50% reduction

22 (24.18)

36 (40.00)

--

0.029d

18 (25.00)

17 (24.64)

PPQ score 

Average pain score

-9.41 (2.946)

-11.03 (2.982)

-1.62

0.669

-6.44 (3.296)

-10.65 (3.080)a

Worst pain score

-8.46 (3.322)

-14.36 (3.367)

-5.90

0.169

-8.06 (3.677)b

-4.15 (3.427)

Pain score right now

-7.20 (3.065)

-8.99 (3.092)

-1.79

0.647

-6.34 (3.335

-4.74 (3.075)

CGI-S score

Overall

-0.66 (0.118)

-0.88 (0.121)

-0.22

0.146

-0.67 (0.121)a

-0.67 (0.125)a

Mental illness

-0.15 (0.087)

-0.16 (0.089)

-0.01

0.927

-0.24 (0.101)b

-0.20 (0.104)

FDI total score

Child total score

-5.00 (1.021)

-3.97 (1.038)

1.03

0.431

-1.03 (1.267)

-1.71 (1.202)

Parent total score

-4.17 (1.139)

-3.25 (1.152)

0.92

0.529

-2.27 (1.327)

-3.49 (1.227)a

CDI total score 

-2.45 (0.674)

-3.28 (0.682)

-0.83

0.335

-1.41 (0.681)b

-0.42 (0.703)

MASC total score 

-4.99 (1.558)

-6.21 (1.575)

-1.21

0.540

-0.78 (1.432)

-0.55 (1.478)

Abbreviations: BPI = Brief Pain Inventory; CDI = Children's Depression Inventory; CGI-S = Clinical Global Impression-Severity; FDI = Functional Disability Inventory; MASC = Multidimensional Anxiety Scale for Children; PPQ = Pediatric Pain Questionnaire.

a p≤.01.

b p≤.05.

c Defined as reduction in BPI average pain for open-label and double-blind + open-label periods, only within group change was tested.

d From the Cochran-Mantel-Haenszel test controlling for pooled investigator sites.

Safety Results

In this study, duloxetine's observed safety was similar to previous pediatric duloxetine trials used to establish other indications.2

Frequently reported AEs were nausea, headache, vomiting and decreased appetite Table 3.2

Table 3. Overall Safety During Double-blind Treatment Period2

 

Placebo n=93

n (%)

Duloxetine n=91

n (%)

TEAEs≥1, total

Mild

58 (62.37)

75 (82.42)

Moderate

29 (26.88)

34 (37.36)

Severe

4 (4.30)

8 (8.79)

Most frequently reported TEAEs (≥10%)

Nausea

14 (15.05)

23 (25.27)

Headache

10 (10.75)

13 (14.29)

Vomiting

5 (5.38)

14 (15.38)

Decreased appetite 

3 (3.23)

14 (15.38)

Columbia suicidal-severity rating scale

Suicidal ideation or behavior

3 (3.23)

6 (6.59)

Non-suicidal self-injurious behavior

1 (1.08)

5 (5.49)

Serious adverse events

0

2 (2.2)

Discontinuation due to adverse events, total

1 (1.08)

5 (5.49)

Diarrhea

1 (1.08)

0

Nausea

0

1 (1.1)

Somnolence

0

1 (1.1)

Anxiety

0

1 (1.1)

Depressed mood

0

1 (1.1)

Suicidal behavior 

0

1 (1.1)

Death(s)

0

0

Abbreviation: TEAE = treatment-emergent adverse events.

The top frequently reported discontinuation reason during the double-blind treatment period are in Table 4 and during the open-label extension period are in Table 5.2

Table 4. Frequently Reported Reasons for Discontinuation During Double-Blind Treatment Period2

Discontinuations

Duloxetine (N=17)

Placebo (N=18)

Adverse event

5

1

Lack of efficacy

1

3

Parent/caregiver decision

2

4

Lost to follow-up

2

3

Protocol violation

4

3

Withdrawal by patient

3

4

Table 5. Frequently Reported Reasons for Discontinuation During Open-Label Extension Period2

Discontinuations

Duloxetine (N=18)

Placebo (N=25)

Adverse event

5

5

Lack of efficacy

2

4

Parent/guardian decision

2

4

Lost to follow-up

4

3

Sponsor decision

1

5

Physician decision

4

4

Enclosed Prescribing Information

CYMBALTA® (duloxetine) tablets, for oral use, Lilly

References

The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).

1. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

2. Upadhyaya HP, Arnold LM, Alaka K, et al. Efficacy and safety of duloxetine versus placebo in adolescents with juvenile fibromyalgia: results from a randomized controlled trial. Pediatr Rheumatol Online J. 2019;17(1):27. http://dx.doi.org/10.1186/s12969-019-0325-6.

Glossary

AE = adverse event

BPI = Brief Pain Inventory

CDI = Children's Depression Inventory

CGI-S = Clinical Global Impression-Severity

DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition

FDI = Functional Disability Inventory

JFM = juvenile fibromyalgia

JPFS = juvenile primary fibromyalgia syndrome

LS = least squares

PI = Principal Investigator

PPQ = Pediatric Pain Questionnaire

Date of Last Review: April 21, 2020

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