desloratadine tablet, film coated Sun Pharmaceutical Industries Limited
DESLORATADINE Tablets are blue, round, film-coated tablets containing 5 mg desloratadine, an antihistamine, to be administered orally. It also contains the following excipients: corn starch NF, microcrystalline cellulose NF, meglumine USP, pregelatinized starch NF, sodium starch glycolate NF and sodium stearyl fumarate NF, coating material consisting of hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80 and FD&C Blue #2 Aluminum Lake.
Desloratadine is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It has a molecular formula: C19 H19 Cl N2 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:
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.
Absorption: Following oral administration of desloratadine 5 mg 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 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 (Cmaxand AUC) of desloratadine.
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=1462) and Hispanics (2%, n=1063). 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 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 elimination half-life of desloratadine was 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 14C-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.
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 (< 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 hrs 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.
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).
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 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).
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 0-24 hrs) of desloratadine and 3-hydroxydesloratadine were observed (see Table 1), 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 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
AUC 0-24 hrs
AUC 0-24 hrs
Erythromycin (500 mg Q8h)
Ketoconazole (200 mg Q12 h)
Azithromycin (500 mg day 1, 250 mg QD x 4 days)
Fluoxetine (20 mg QD)
Cimetidine (600 mg Q12 h)
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 QTc : Single dose administration of desloratadine did not alter the corrected QT interval (QTc) 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 QTc at an estimated desloratadine exposure (AUC) that was approximately 955 times the mean AUC in humans at the recommended daily oral dose. See OVERDOSAGEsection for information on human QTc experience.
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 Table 2.
Table 2 TOTAL SYMPTOM SCORE (TSS) Changes in a 2-week Clinical Trial in Patients with Seasonal Allergic Rhinitis
At baseline, a total nasal symptom score (sum of 4 individual symptoms) of at least 6 and a total non-nasal symptom score (sum of 4 individual symptoms) of at least 5 (each symptom scored 0 to 3 where 0=no symptom and 3=severe symptoms) was required for trial eligibility. TSS ranges from 0=no symptoms to 24=maximal symptoms.
Mean reduction in TSS averaged over the 2 week treatment period.
5 mg (171)
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 (Table 3).
Table 3 TOTAL SYMPTOM SCORE (TSS) Changes in a 4 Week Clinical Trial in Patients with Perennial Allergic Rhinitis
At baseline, average of total symptom score (sum of 5 individual nasal symptoms and 3 non-nasal symptoms, each symptom scored 0 to 3 where 0=no symptom and 3=severe symptoms) of at least 10 was required for trial eligibility. TSS ranges from 0=no symptoms to 24=maximal symptoms.
Mean reduction in TSS averaged over the 4 week treatment period.
Desloratadine 5 mg (337)
Chronic Idiopathic Urticaria: The efficacy and safety of desloratadine tablets 5 mg once daily was studied in 416 chronic idiopathic urticaria patients 12 to 84 years of age, of whom 211 received desloratadine. In two double-blind, placebo-controlled, randomized clinical trials of six weeks duration, at the pre-specified one-week primary time point evaluation, desloratadine tablets significantly reduced the severity of pruritus when compared to placebo (Table 4). Secondary endpoints were also evaluated and during the first week of therapy desloratadine tablets 5 mg reduced the secondary endpoints, "Number of Hives" and the "Size of the Largest Hive" when compared to placebo.
Table-4 PRURITUS SYMPTOM SCORE Changes in the First Week of a Clinical Trial in Patients with Chronic Idiopathic Urticaria
Mean reduction in pruritus averaged over the first week of treatment.
Desloratadine 5 mg (115)
INDICATIONS AND USAGE
Seasonal Allergic Rhinitis: Desloratadine tablets 5 mg are indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 12 years of age and older. Perennial Allergic Rhinitis: Desloratadine tablets 5 mg are indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 12 years of age and older. ChronicIdiopathic Urticaria: Desloratadine tablets are indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 12 years of age and older.
Desloratadine tablets 5 mg are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients, or to loratadine.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
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 (Salmonella/E. coli 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).
Pregnancy Category C:
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.
Desloratadine passes into breast milk, therefore a decision should be made whether to discontinue nursing or to discontinue desloratadine, taking into account the importance of the drug to the mother.
The safety and effectiveness of desloratadine tablets have not been demonstrated in pediatric patients less than 6 months of age.
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 CLINICAL PHARMACOLOGY : Special Populations).
Information for Patients:
Patients should be instructed to use desloratadine tablets as directed. As there are no food effects on bioavailability, patients can be instructed that desloratadine 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.
Adults and Adolescents
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 5.
Table 5 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.
Desloratadine Tablets 5 mg (n=1,655)
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.
Chronic Idiopathic Urticaria: In multiple-dose, placebo-controlled trials of chronic idiopathic urticaria, 211 patients ages 12 years or older received desloratadine tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received desloratadine tablets and that were more common with desloratadine than placebo were (rates for desloratadine and placebo, respectively): headache (14%, 13%), nausea (5%, 2%), fatigue (5%, 1%), dizziness (4%, 3%), pharyngitis (3%, 2%), dyspepsia (3%, 1%), and myalgia (3%, 1%).
Observed During Clinical Practice: 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.
DRUG ABUSE AND DEPENDENCE
There is no information to indicate that abuse or dependency occurs with desloratadine tablets.
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 (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.
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/m2 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/m2 basis).
DOSAGE AND ADMINISTRATION
Adults and Children 12 years of Age and Over: The recommended dose of desloratadine tablets is one 5 mg tablet once daily.
NOTE: Desloratadine tablets are not recommended for use in pediatric patients under 12 years of age as other dosage forms are better suited for younger 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 Tablets: Blue colored circular shaped, biconvex, coated tablets with “5” on one side and plain on other side; that are packaged in high-density polyethylene plastic bottles:
Bottle of 30’s with child Resistant Cap…..NDC 62756-523-83 Bottle of 100’s with child Resistant Cap…..NDC 62756-523-88 Bottle of 100’s with Non child Resistant Cap…..NDC 62756-523-08 Bottle of 1000’s with Non child Resistant Cap…..NDC 62756-523-18
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] Heat sensitive. Avoid exposure at or above 30°C (86°F). Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Distributed by: Caraco Pharmaceutical Laboratories, Ltd. 1150 Elijah McCoy Drive, Detroit, MI 48202
Manufactured by: Sun Pharmaceutical Industries Ltd. Acme Plaza, Andheri-Kurla Road, Andheri (East) Mumbai-400 059, India
PJPI0170 ISS. 11/2010
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 62756-523-88 Desloratadine Tablets 5 mg Rx only 100 TABLETS SUN PHARMACEUTICAL INDUSTRIES LTD.
tablet, film coated
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
Route of Administration
Active Ingredient/Active Moiety
Basis of Strength
SODIUM STARCH GLYCOLATE TYPE A POTATO
SODIUM STEARYL FUMARATE
HYPROMELLOSE 2910 (15 MPA.S)
FD&C BLUE NO. 2
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date
Labeler - Sun Pharmaceutical Industries Limited