Mechanism of Action: Desloratadine is a long-acting tricyclic histamine antagonist
with selective H1-receptor histamine antagonist activity. Receptor
binding data indicate that at a concentration of 2-3 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.
Pharmacokinetics
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 (Cmax and AUC)
of desloratadine.
The pharmacokinetic profile of CLARINEX Syrup was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of CLARINEX Syrup containing 5 mg of desloratadine was bioequivalent to a single dose of 5 mg CLARINEX Tablet. Food had no effect on the bioavailability (AUC and Cmax) of CLARINEX Syrup.
The pharmacokinetic profile of CLARINEX RediTabs Tablets was evaluated in a three-way crossover study in 24 adult volunteers. A single CLARINEX RediTabs Tablet containing 5 mg of desloratadine was bioequivalent to a single 5 mg CLARINEX RediTabs Tablet (original formulation) for both desloratadine and 3-hydroxydesloratadine. Water had no effect on the bioavailability (AUC and Cmax) of CLARINEX RediTabs 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=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 2-5 years, 1575 subjects
aged 6-11 years, and 1196 subjects aged 12-70 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 CLARINEX
Syrup for 15-35 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.
Special Populations
Geriatric: In older subjects ( ≥ 65 years old; n=17) following
multiple-dose administration of CLARINEX 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 CLARINEX Syrup containing 2.5 mg of desloratadine resulted in desloratadine
plasma concentrations similar to those achieved in adults administered a single
5 mg CLARINEX Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL
of CLARINEX Syrup containing 1.25 mg of desloratadine resulted in desloratadine
plasma concentrations similar to those achieved in adults administered a single
5 mg CLARINEX Tablet. However, the Cmax and AUCt of 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 Cmax and AUCt obtained in
children 2-11 years of age receiving 1.25-2.5 mg of CLARINEX Syrup.
A single dose of either 2.5 mL or 1.25 mL of CLARINEX 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 CLARINEX Syrup.
The CLARINEX RediTabs Tablet 2.5 mg tablet has not been evaluated in pediatric patients. Bioequivalence of the CLARINEX RediTabs Tablet and the original CLARINEX RediTabs Tablets was established in adults. In conjunction with the dose finding studies in pediatrics described, the pharmacokinetic data for CLARINEX RediTabs Tablet supports the use of the 2.5 mg dose strength in pediatric patients 6-11 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 51-69 mL/ min/1.73 m2), moderate (n=6; creatinine clearance
34-43 mL/min/1.73 m2), and severe (n=6; creatinine clearance 5-29
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
section).
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
section).
Gender: Female subjects treated for 14 days with CLARINEX 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 CLARINEX 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
| |
Desloratadine |
3-Hydroxydesloratadine |
| Cmax |
AUC
0-24 hrs |
Cmax |
AUC
0-24 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% |
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 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 OVERDOSAGE
section for information on human QTc experience.
Clinical Trials
Seasonal Allergic Rhinitis: The clinical efficacy and safety
of CLARINEX 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 2.5-20
mg/day of CLARINEX 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 CLARINEX 5 mg in the
treatment of adult and adolescent patients with seasonal allergic rhinitis.
In a dose ranging trial, CLARINEX 2.5-20 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 5.0 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, CLARINEX Tablets 5 mg once daily improved rhinitis
symptoms, with no decrease in pulmonary function. This supports the safety of
administering CLARINEX Tablets to adult patients with seasonal allergic rhinitis
with mild to moderate asthma.
CLARINEX 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
| Treatment Group (n) |
Mean Baseline* (sem) |
Change from Baseline** (sem) |
Placebo Comparison
(P-value) |
| CLARINEX 5.0 mg (171) |
14.2 (0.3) |
-4.3 (0.3) |
P < 0.01 |
| Placebo (173) |
13.7 (0.3) |
-2.5 (0.3) |
|
* 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. |
There were no significant differences in the effectiveness of CLARINEX Tablets
5 mg across subgroups of patients defined by gender, age, or race.
Perennial Allergic Rhinitis: The clinical efficacy and safety
of CLARINEX 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 CLARINEX 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 CLARINEX 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
| Treatment Group (n) |
Mean Baseline* (sem) |
Change from Baseline** (sem) |
Placebo Comparison
(P-value) |
| CLARINEX 5.0 mg (337) |
12.37 (0.18) |
-4.06 (0.21) |
P=0.01 |
| Placebo (337) |
12.30 (0.18) |
-3.27 (0.21) |
|
* 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. |
Chronic Idiopathic Urticaria: The efficacy and safety of CLARINEX
Tablets 5 mg once daily was studied in 416 chronic idiopathic urticaria patients
12 to 84 years of age, of whom 211 received CLARINEX. In two double-blind, placebo-controlled,
randomized clinical trials of six weeks' duration, at the pre-specified one-week
primary time point evaluation, CLARINEX 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 CLARINEX 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
| Treatment Group (n) |
Mean Baseline (sem) |
Change from Baseline* (sem) |
Placebo Comparison
(P-value) |
| CLARINEX 5.0 mg (115) |
2.19 (0.04) |
-1.05 (0.07) |
P < 0.01 |
| Placebo (110) |
2.21 (0.04) |
-0.52 (0.07) |
|
Pruritus scored 0 to 3 where 0=no symptom to 3=maximal symptom.
*Mean reduction in pruritus averaged over the first week of treatment. |
The clinical safety of CLARINEX Syrup was documented in three, 15-day, double-blind,
placebo-controlled safety studies in pediatric subjects with a documented history
of allergic rhinitis, chronic idiopathic urticaria, or subjects who were candidates
for antihistamine therapy. In the first study, 2.5 mg of CLARINEX Syrup was
administered to 60 pediatric subjects 6 to 11 years of age. The second study
evaluated 1.25 mg of CLARINEX Syrup administered to 55 pediatric subjects 2
to 5 years of age. In the third study, 1.25 mg of CLARINEX Syrup was administered
to 65 pediatric subjects 12 to 23 months of age and 1.0 mg of CLARINEX Syrup
was administered to 66 pediatric subjects 6 to 11 months of age. The results
of these studies demonstrated the safety of CLARINEX Syrup in pediatric subjects
6 months to 11 years of age.
Last reviewed on RxList: 7/10/2009
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