Duloxetine Delayed-Release (Page 8 of 15)

8.4 Pediatric Use

The safety and effectiveness of Duloxetine delayed-release capsules have been established for treatment of generalized anxiety disorder (GAD) in patients 7 to 17 years of age.

The safety and effectiveness of Duloxetine delayed-release capsules have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see Warnings and Precautions (5.1)]. Perform regular monitoring of weight and growth in pediatric patients treated with Duloxetine delayed-release capsules [see Adverse Reactions (6.1)].

Generalized Anxiety Disorder

Use of Duloxetine delayed-release capsules for the treatment of GAD in patients 7 to 17 years of age is supported by one 10-week, placebo-controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.3)].

The safety and effectiveness of Duloxetine delayed-release capsules for the treatment of GAD in pediatric patients less than 7 years of age have not been established.


The safety and effectiveness of Duloxetine delayed-release capsules for the treatment of fibromyalgia in patents less than 13 years of age have not been established.

Major Depressive Disorder

The safety and effectiveness of Duloxetine delayed-release capsules have not been established in pediatric patients for the treatment of MDD. Efficacy of Duloxetine delayed-release capsules was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with MDD (MDD-6 and MDD-7). Neither Duloxetine delayed-release capsules nor an active control (approved for treatment of pediatric MDD) was superior to placebo.

The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.

Juvenile Animal Toxicology Data

Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).

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.

8.5 Geriatric Use

Geriatric Exposure in Premarketing Clinical Trials of Duloxetine delayed-release capsules

  • Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over.
  • Of the 1041 patients in CLBP trials, 21% (221) were 65 years of age or over.
  • Of the 487 patients in OA trials, 41% (197) were 65 years of age or over.
  • Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over.
  • Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over.

In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out.

SSRIs and SNRIs, including Duloxetine delayed-release capsules have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.13)].

In an analysis of data from all placebo-controlled-trials, Duloxetine delayed-release capsules-treated patients reported a higher rate of falls compared to placebo-treated patients. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during Duloxetine delayed-release capsules treatment is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with Duloxetine delayed-release capsules use [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the C max , but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary.

8.6 Gender

Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

8.7 Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

8.8 Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

8.9 Hepatic Impairment

Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single 20 mg dose of Duloxetine delayed-release capsules, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although C max was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration (2.7) and Warnings and Precautions (5.14)].

8.10 Severe Renal Impairment

Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, C max and AUC values were approximately 100% greater in patients with ESRD receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration (2.7) and Warnings and Precautions (5.14)].


9.2 Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

While Duloxetine delayed-release capsules have not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Duloxetine delayed-release capsules (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

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