Desloratadine Information
Desloratadine ()
Desloratadine () Description
Desloratadine () orally disintegrating tablets contain either 2.5 mg or 5 mg of Desloratadine () , an antihistamine, to be administered orally. Each tablet also contains the following inactive ingredients: anhydrous citric acid, aspartame, colloidal silicon dioxide, crospovidone, ferric oxide, mannitol, lactose anhydrous, microcrystalline cellulose, polacrilex resin, sodium stearyl fumarate, talc, tutti frutti flavor.
Desloratadine () is a white to off-white powder that is soluble in dichloromethane. It has an molecular formula: CHClN 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 :
Desloratadine () Clinical Pharmacology
Desloratadine () is a long-acting tricyclic histamine antagonist with selective H-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 H-receptor. Desloratadine () inhibited histamine release from human mast cells
Results of a radiolabeled tissue distribution study in rats and a radioligand H-receptor binding study in guinea pigs showed that Desloratadine () did not readily cross the blood brain barrier.
Absorption: Following oral administration of Desloratadine () 5 mg once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (T) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (C) and area under the concentration-time curve (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 (C and AUC) of Desloratadine () .
Water had no effect on the bioavailability (AUC and C) of Desloratadine () orally disintegrating tablets.
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= 3,748), 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, 1,575 subjects aged 6 to 11 years, and 1,196 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 () . 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 elimination half-life of Desloratadine () was 27 hours. Cand 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 C-Desloratadine () dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxyDesloratadine () showed similar Tand half-life values compared to Desloratadine () .
Geriatric: 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 (
Pediatric Subjects: In subjects 6 to 11 years old, a single dose of 5 mL of Desloratadine () syrup 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 () syrup 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 C and AUCof the metabolite (3-OH Desloratadine () ) were 1.27 and 1.61 times higher for the 5 mg dose of syrup administered in adults compared to the C and AUC obtained in children 2 to 11 years of age receiving 1.25 to 2.5 mg of desloratidine syrup.
A single dose of either 2.5 mL or 1.25 mL of Desloratadine () syrup 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 () syrup.
The 2.5 mg Desloratadine () orally disintegrating tablet has not been evaluated in pediatric patients. In conjunction with the dose finding studies in pediatrics described, the pharmacokinetic data for Desloratadine () orally disintegrating tablets supports the use of the 2.5 mg dose strength in pediatric patients 6 to 11 years of age.
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 m), moderate (n=6; creatinine clearance 34 to 43 mL/min/1.73 m), and severe (n=6; creatinine clearance 5 to 29 mL/min/1.73 m) renal impairment or hemodialysis dependent (n=6) patients. In patients with mild and moderate renal impairment, median C 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, C 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 ).
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 eight 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 C 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 ).
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 (Cand AUC) of Desloratadine () and 3-hydroxyDesloratadine () were observed (see ), 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 1
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 one 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 QT:Single dose administration of Desloratadine () did not alter the corrected QT interval (QT) in rats (up to 12 mg/kg, oral), or guinea pigs (25 mg/kg, intravenous). Repeated oral administration at doses up to 24 mg/kg for durations up to 3 months in monkeys did not alter the QT at an estimated Desloratadine () exposure (AUC) that was approximately 955 times the mean AUC in humans at the recommended daily oral dose. See section for information on human QT experience.
Desloratadine () Clinical Trials
Seasonal Allergic Rhinitis:The clinical efficacy and safety of Desloratadine () tablets were evaluated in over 2,300 patients 12 to 75 years of age with seasonal allergic rhinitis. A total of 1,838 patients received 2.5 to 20 mg/day of Desloratadine () in four double-blind, randomized, placebo-controlled clinical trials of 2 to 4 weeks duration conducted in the United States. The results of these studies demonstrated the efficacy and safety of Desloratadine () 5 mg in the treatment of adult and adolescent patients with seasonal allergic rhinitis. In a dose ranging trial, Desloratadine () 2.5 to 20 mg/day was studied. Doses of 5, 7.5, 10, and 20 mg/day were superior to placebo; and no additional benefit was seen at doses above 5 mg. In the same study, an increase in the incidence of somnolence was observed at doses of 10 mg/day and 20 mg/day (5.2% and 7.6%, respectively), compared to placebo (2.3 %).
In two 4 week studies of 924 patients (aged 15 to 75 years) with seasonal allergic rhinitis and concomitant asthma, Desloratadine () tablets 5 mg once daily improved rhinitis symptoms, with no decrease in pulmonary function. This supports the safety of administering Desloratadine () tablets to adult patients with seasonal allergic rhinitis with mild to moderate asthma.
Desloratadine () tablets 5 mg once daily significantly reduced the Total Symptom Scores (the sum of individual scores of nasal and non-nasal symptoms) in patients with seasonal allergic rhinitis. See
TOTAL SYMPTOM SCORE (TSS)
Changes in a 2 Week Clinical
Trial in Patients with Seasonal Allergic Rhinitis
There were no significant differences in the effectiveness of Desloratadine () tablets 5 mg across subgroups of patients defined by gender, age, or race.
Perennial Allergic Rhinitis:The clinical efficacy and safety of Desloratadine () tablets 5 mg were evaluated in over 1,300 patients 12 to 80 years of age with perennial allergic rhinitis. A total of 685 patients received 5 mg/day of Desloratadine () in two double blind, randomized, placebo controlled clinical trials of 4 weeks duration conducted in the United States and internationally. In one of these studies Desloratadine () tablets 5 mg once daily was shown to significantly reduce symptoms of perennial allergic rhinitis ().
TOTAL SYMPTOM SCORE (TSS)
Changes in a 4 Week Clinical
Trial in Patients with Perennial Allergic Rhinitis
Desloratadine () Contraindications
Desloratadine () orally disintegrating tablets are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients, or to loratadine.
Desloratadine () Precautions
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 (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated Desloratadine () and Desloratadine () metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. 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, did not show significant increases in the incidence of any tumors. The estimated Desloratadine () and metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.
In genotoxicity studies with Desloratadine () , there was no evidence of genotoxic potential in a reverse mutation assay ( mammalian microsome bacterial mutagenicity assay) or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).
There was no effect on female fertility in rats at Desloratadine () doses up to 24 mg/kg/day (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). A male specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral Desloratadine () dose of 12 mg/kg in rats (estimated Desloratadine () exposures were approximately 45 times the AUC in humans at the recommended daily oral dose).Desloratadine () had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).
Desloratadine () was not teratogenic in rats at doses up to 48 mg/kg/day (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 210 times the AUC in humans at the recommended daily oral dose) or in rabbits at doses up to 60 mg/kg/day (estimated Desloratadine () exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). In a separate study, an increase in pre-implantation loss and a decreased number of implantations and fetuses were noted in female rats at 24 mg/kg (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). Reduced body weight and slow righting reflex were reported in pups at doses of 9 mg/kg/day or greater (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Desloratadine () had no effect on pup development at an oral dose of 3 mg/kg/day (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 7 times the AUC in humans at the recommended daily oral dose). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Desloratadine () should be used during pregnancy only if clearly needed.
Clinical studies of Desloratadine () did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see ).
Patients should be instructed to use Desloratadine () tablets as directed. As there are no food effects on bioavailability, patients can be instructed that Desloratadine () orally disintegrating tablets may be taken without regard to meals. Patients should be advised not to increase the dose or dosing frequency as studies have not demonstrated increased effectiveness at higher doses and somnolence may occur.
Phenylketonurics: Desloratadine () orally disintegrating tablets contain phenylalanine 2.55 mg per 5 mg Desloratadine () orally disintegrating tablet or 1.28 mg per 2.5 mg Desloratadine () orally disintegrating tablet.
Desloratadine () Adverse Reactions
Allergic Rhinitis:In multiple-dose placebo-controlled trials, 2,834 patients ages 12 years or older received Desloratadine () tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between Desloratadine () and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the Desloratadine () group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving Desloratadine () . All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of Desloratadine () tablets (5 mg once-daily), and that were more common with Desloratadine () tablets than placebo, are listed in Table 4.
Table 4
Incidence of Adverse Events Reported by 2% or More of Adult and Adolescent Allergic Rhinitis Patients in Placebo-Controlled, Multiple-Dose Clinical Trials with the Tablet Formulation of Desloratadine ()
The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in Desloratadine () and placebo-treated patients.
There were no differences in adverse events for subgroups of patients as defined by gender, age, or race.
The following spontaneous adverse events have been reported during the marketing of Desloratadine () : tachycardia, palpitations, rare cases of hypersensitivity reactions (such as rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis), psychomotor hyperactivity, seizures, and elevated liver enzymes including bilirubin, and very rarely, hepatitis.
Desloratadine () Overdosage
Information regarding acute overdosage is limited to experience 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.
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 (QT) by both the Bazett and Fridericia methods. Using the QT (Bazett) there was a mean increase of 8.1 msec in Desloratadine () -treated subjects relative to placebo. Using QT (Fridericia) there was a mean increase of 0.4 msec in Desloratadine () -treated subjects relative to placebo. No clinically relevant adverse events were reported.
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.
Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated Desloratadine () and Desloratadine () metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). The oral median lethal dose in mice was 353 mg/kg (estimated Desloratadine () exposures were approximately 290 times the human daily oral dose on a mg/m basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated Desloratadine () exposures were approximately 810 times the human daily oral dose on a mg/m basis).
Desloratadine () Dosage And Administration
NOTE: Desloratadine () orally disintegrating tablets are not recommended for use in pediatric patients under 6 years of age as Desloratadine () syrup is better suited for these patients.
In adult patients with liver or renal impairment, a starting dose of one 5 mg tablet every other day is recommended based on pharmacokinetic data. Dosing recommendation for children with liver or renal impairment cannot be made due to lack of data.
Desloratadine () How Supplied
Unit dose packages of 30 (5 x 6) NDC 55111-551-31
Unit dose packages of 30 (5 x 6) NDC 55111-360-31
Rx Only
Manufactured by:
Issued: 1207
