DESLORATADINE: Package Insert and Label Information (Page 2 of 3)

9 DRUG ABUSE AND DEPENDENCE

There is no information to indicate that abuse or dependency occurs with desloratadine tablets.

10 OVERDOSAGE

In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Desloratadine and 3-hydroxydesloratadine are not eliminated by hemodialysis.

Information regarding acute overdosage is limited to experience from post-marketing adverse event reports and from clinical trials conducted during the development of the desloratadine product. In a dose-ranging trial, at doses of 10 mg and 20 mg/day somnolence was reported.

In another study, no clinically relevant adverse events were reported in normal male and female volunteers who were given single daily doses of desloratadine 45 mg for 10 days [See CLINICAL PHARMACOLOGY (12.2)].

11 DESCRIPTION

Desloratadine tablets USP, 5 mg are light blue, circular, biconvex, film-coated tablets debossed “LU” on one side and “S71” on other side, containing 5 mg desloratadine, an antihistamine, to be administered orally. Desloratadine tablets USP also contain the following excipients: anhydrous lactose, colloidal silicon dioxide, FD&C Blue#2/Indigo Carmine Aluminium Lake, hydrogenated vegetable oil, hypromellose, microcrystalline cellulose, polyethylene glycol, pregelatinised starch and titanium dioxide.

Desloratadine is a white to off-white crystalline powder that is freely soluble in dichloromethane and in methanol. It has an empirical formula: C19 H19 ClN2 and a molecular weight of 310.8. The chemical name is 8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H -benzo[5,6]cyclohepta[1,2-b ]pyridine and has the following structure:

1
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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Desloratadine is a long-acting tricyclic histamine antagonist with selective H1 -receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2 to 3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H1 -receptor. Desloratadine inhibited histamine release from human mast cells in vitro. Results of a radiolabeled tissue distribution study in rats and a radioligand H1 -receptor binding study in guinea pigs showed that desloratadine did not readily cross the blood brain barrier. The clinical significance of this finding is unknown.

12.2 Pharmacodynamics

Wheal and Flare

Human histamine skin wheal studies following single and repeated 5 mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5 mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc

Single daily doses of 45 mg were given to normal male and female volunteers for 10 days. All ECGs obtained in this study were manually read in a blinded fashion by a cardiologist. In desloratadine-treated subjects, there was an increase in mean heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both the Bazett and Fridericia methods. Using the QTc (Bazett) there was a mean increase of 8.1 msec in desloratadine-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in desloratadine-treated subjects relative to placebo. No clinically relevant adverse events were reported.

12.3 Pharmacokinetics

Absorption

Following oral administration of a desloratadine 5 mg tablet once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (Tmax ) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (Cmax ) and AUC of 4 ng/mL and 56.9 ng∙hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (Cmax and AUC) of desloratadine.

The pharmacokinetic profile of desloratadine oral solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of desloratadine oral solution containing 5 mg of desloratadine was bioequivalent to a single dose of 5 mg desloratadine tablet. Food had no effect on the bioavailability (AUC and Cmax ) of desloratadine oral solution.

Distribution

Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89% bound to plasma proteins, respectively. Protein binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism

Desloratadine (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1,462) and Hispanics (2%, n=1,063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with desloratadine oral solution for 15 to 35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.

Elimination

The mean plasma elimination half-life of desloratadine was approximately 27 hours. Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14 C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to desloratadine.

Special Populations

Geriatric Subjects:

In older subjects (≥65 years old; n=17) following multiple-dose administration of desloratadine tablets, the mean Cmax and AUC values for desloratadine were 20% greater than in younger subjects (<65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the two age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects ≥65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects:

In subjects 6 to 11 years old, a single dose of 5 mL of desloratadine oral solution containing 2.5 mg of desloratadine, resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg desloratadine tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of desloratadine oral solution containing 1.25 mg of desloratadine, resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg desloratadine tablet. However, the Cmax and AUC of the metabolite (3-hydroxydesloratadine) were 1.27 and 1.61 times higher for the 5 mg dose of oral solution administered in adults compared to the Cmax and AUC obtained in children 2 to 11 years of age receiving 1.25 to 2.5 mg of desloratadine oral solution.

A single dose of either 2.5 mL or 1.25 mL of desloratadine oral solution containing 1.25 mg or 0.625 mg, respectively, of desloratadine was administered to subjects 6 to 11 months of age and 12 to 23 months of age. The results of a population pharmacokinetic analysis indicated that a dose of 1 mg for subjects aged 6 to 11 months and 1.25 mg for subjects 12 to 23 months of age is required to obtain desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg dose of desloratadine oral solution.

Renally Impaired:

Desloratadine pharmacokinetics following a single dose of 7.5 mg were characterized in patients with mild (n=7; creatinine clearance 51 to 69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34 to 43 mL/min/1.73 m2), and severe (n=6; creatinine clearance 5 to 29 mL/min/1.73 m2) renal impairment or hemodialysis dependent (n=6) patients. In patients with mild and moderate renal impairment, median Cmax and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who were hemodialysis dependent, Cmax and AUC values increased by approximately 1.7- and 2.5-fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended [see DOSAGE AND ADMINISTRATION (2.5)].

Hepatically Impaired:

Desloratadine pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in patients with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of desloratadine in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Dosage adjustment for patients with hepatic impairment is recommended [see DOSAGE AND ADMINISTRATION (2.5)].

Gender:

Female subjects treated for 14 days with desloratadine tablets had 10% and 3% higher desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine Cmax and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race:

Following 14 days of treatment with desloratadine tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

Drug Interactions:

In two controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) volunteers, desloratadine 7.5 mg (1.5 times the daily dose) once daily was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In three separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of 5 mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady-state conditions to normal healthy male and female volunteers. Although increased plasma concentrations (Cmax and AUC 0 to 24 hrs ) of desloratadine and 3-hydroxydesloratadine were observed (see Table 2), there were no clinically relevant changes in the safety profile of desloratadine, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs, and adverse events.

Table 2 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
Desloratadine 3-Hydroxydesloratadine
Cmax AUC 0 to 24 hrs Cmax AUC 0 to 24 hrs
Erythromycin (500 mg Q8h) + 24% + 14% + 43% + 40%
Ketoconazole (200 mg Q12h) + 45% + 39% + 43% + 72%
Azithromycin (500 mg day 1, 250 mg QD x 4 days) + 15% + 5% + 15% + 4%
Fluoxetine (20 mg QD) + 15% + 0% + 17% + 13%
Cimetidine (600 mg Q12h) + 12% + 19% — 11% — 3%

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity Studies

The carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (approximately 45 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD) and in males and females given 25 mg/kg/day of loratadine. The clinical significance of these findings during long-term use of desloratadine is not known. In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day desloratadine, respectively (approximately 30 and 70 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD, respectively), did not show significant increases in the incidence of any tumors.

Genotoxicity Studies

In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

Impairment of Fertility

In a female fertility study, desloratadine was given to female rats orally 14 days prior to and throughout mating until Gestation Day 7 at doses of 6, 12 and 24 mg/kg/day. An increase in preimplantation loss and a decrease in number of implantations and fetuses noted at 24 mg/kg (approximately 200 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD) was likely due to maternal toxicities including reduced body weight gain and food consumption. In a male fertility study in rats, desloratadine was given orally to male rats for 70 days prior to mating and throughout the mating period (total dosing period 106 to 108 days) at doses of 3, 12 and 40 mg/kg/day. Reduced body weight gain, food consumption, and absolute organ weights of testes, epididymis, and cauda epididymis were noted at 40 mg/kg/day. A male-specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic changes in testes and epididymis, occurred at a dose of 12 mg/kg or greater (approximately 65 times or greater than the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Desloratadine had no effect on male fertility in rats at 3 mg/kg/day (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD).

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