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 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 adult patient is not necessary.
Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.
No specific pharmacokinetic study was conducted to investigate the effects of race.
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 (2.7) and Warnings and Precautions (5.14)].
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 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)].
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).
In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.
In postmarketing experience, fatal outcomes have been reported for acute duloxetine overdoses, primarily with mixed overdoses, but also with duloxetine only, including 1000 mg of duloxetine (approximately 8.3 times the maximum recommended dosage). Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
There is no specific antidote to a Duloxetine delayed-release capsules overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered.
In case of acute overdose with Duloxetine delayed-release capsules, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Induction of emesis is not recommended.
Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease duloxetine AUC and Cmax by an average of one-third, although some patients had a limited effect of activated charcoal. Due to the large volume of distribution of duloxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.
In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who overdose with Duloxetine delayed-release capsules, and tricyclic antidepressants. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7)].
Consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of overdosage.
Duloxetine delayed-release capsules, USP are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) for oral administration. Its chemical designation is (+)-(S )-N -methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C18 H19 NOS∙HCl, which corresponds to a molecular weight of 333.88. The structural formula is:
Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.
Each capsule contains enteric-coated pellets of 22.4, 33.7, 44.9 or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, 40 or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include ammonium hydroxide, black iron oxide, hypromellose, methacrylic acid copolymer dispersion (methacrylic acid-ethyl acrylate copolymer, polysorbate 80, sodium lauryl sulfate), potassium hydroxide, propylene glycol, shellac, sucrose, sugar spheres (maize starch, sucrose), talc, titanium dioxide, triethylcitrate, and hard gelatin capsules (gelatin, titanium dioxide). The 20 mg hard gelatin capsule colorant is yellow iron oxide. The 30 mg hard gelatin capsule colorants are FD&C Blue No. 1, FD&C Yellow No. 6, and FD&C Yellow No. 10. The 40 mg hard gelatin capsule colorants are FD&C Blue No. 2, red iron oxide, and yellow iron oxide. The 60 mg hard gelatin capsule colorants are FD&C Blue No. 1, FD&C Yellow No. 6, FD&C Yellow No.10, and yellow iron oxide.
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