Duloxetine (Page 10 of 16)

8.2 Lactation

Risk Summary

Data from published literature report the presence of duloxetine in human milk (see Data). There are reports of sedation, poor feeding, and poor weight gain in infants exposed to duloxetine through breast milk (see Clinical Considerations). There are no data on the effect of duloxetine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for duloxetine delayed-release capsules and any potential adverse effects on the breastfed child from duloxetine delayed-release capsules or from the underlying maternal condition.

Clinical Considerations

Infants exposed to duloxetine delayed-release capsules should be monitored for sedation, poor feeding and poor weight gain.

Data

Disposition of duloxetine delayed-release capsules was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of duloxetine delayed-release capsules twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of duloxetine delayed-release capsules in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day, which is less than 1% of the maternal dose. The presence of duloxetine delayed-release capsules metabolites in breast milk was not examined.

8.4 Pediatric Use

Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 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 (14.2)]. The safety and effectiveness in pediatric patients less than 7 years of age have not been established.

Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7 to 17. Neither duloxetine delayed-release capsules nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established.

The most frequently observed adverse reactions in the 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. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as duloxetine delayed-release capsules [see Adverse Reactions (6.11)].

Use of duloxetine delayed-release capsules in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)].
Animal 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).

8.5 Geriatric Use

Of the 2,418 patients in premarketing clinical studies of duloxetine delayed-release capsules for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including duloxetine delayed-release capsules have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.13)].
In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine delayed-release capsules reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly 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 treatment with duloxetine delayed-release capsules is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions (5.3) and Adverse Reactions (6.10)].

The pharmacokinetics of duloxetine delayed-release capsules 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 year). There was no difference in the Cmax, 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 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 Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration (2.6) 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, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease 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 to 80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration (2.6) and Warnings and Precautions (5.14)].

9 DRUG ABUSE AND DEPENDENCE

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 their 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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