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 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 does not readily cross
the blood brain barrier. The clinical significance of this finding is unknown.
Pseudoephedrine sulfate is an orally active
sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine
sulfate is recognized as an effective agent for the relief of nasal congestion
due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar
to those of ephedrine and central effects similar to, but less intense than, amphetamines.
It has the potential for excitatory side effects.
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
In clinical trials for CLARINEX-D 24 HOUR Extended
Release Tablets, ECGs were recorded at baseline and after 2 weeks of treatment
within 1 to 3 hours after dosing. No clinically meaningful changes were
observed following treatment with CLARINEX-D 24 HOUR Extended Release Tablets
for any ECG parameter, including the QTc interval. An increase in the
ventricular rate of 6.7 and 5.4 bpm was observed in the CLARINEX-D 24 HOUR
Extended Release Tablets and pseudoephedrine groups, respectively, compared to
an increase of 2.8 bpm in subjects receiving desloratadine alone. Single daily
doses of CLARINEX 45 mg were given to normal male and female volunteers for 10
All ECGs obtained in this study were manually read in a
blinded fashion by a cardiologist. In the CLARINEX-treated subjects, there was
a mean increase in the maximum heart rate of 9.2 bpm relative to placebo. The
QT interval was corrected for heart rate (QTc) by both Bazett's and Fridericia
methods. Using the QTc (Bazett), there was a mean increase of 8.1 msec in the
CLARINEXtreated subjects relative to placebo. Using QTc (Fridericia) there was
a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo.
No clinically relevant adverse events were reported.
A bioequivalence study that compared CLARINEX-D 24 HOUR
Extended Release Tablets to the monotherapy (desloratadine 5 mg, and
pseudoephedrine 240 mg) showed that CLARINEX-D 24 HOUR Extended Release Tablets
was not bioequivalent to the monotherapy (desloratadine 5 mg tablet). The
systemic exposure to desloratadine and 3-hydroxydesloratadine was 15% to 20% lower
from CLARINEX-D 24 HOUR Extended Release Tablets than those from desloratadine
5 mg tablet. Clinical trials were therefore necessary to support efficacy of
CLARINEX-D 24 HOUR Extended Release Tablets [see Clinical Studies].
In the above single dose pharmacokinetic study the mean
time to maximum plasma concentrations (Tmax) for desloratadine occurred at
approximately 6 to 7 hours post dose and mean peak plasma concentrations (Cmax)
and area under the concentrationtime curve (AUC(tf)) of approximately 1.79
ng/mL and 61.1 ng•hr/mL, respectively, were observed. In another
pharmacokinetic study, food and grapefruit juice had no effect on the
bioavailability (Cmax and AUC) of desloratadine.
For pseudoephedrine, the mean Tmax occurred at 8 to 9
hours post dose and mean peak plasma concentrations (Cmax) and AUC(tf) of 328
ng/mL and 6438 ng•hr/mL, respectively, were observed. The ingestion of
food did not affect the absorption of pseudoephedrine from CLARINEX-D 24 HOUR
Extended Release Tablets.
Following oral administration of CLARINEX-D 24 HOUR
Extended Release Tablets once daily for 14 days in healthy volunteers, steady-state
conditions were reached on Day 12 for desloratadine and 3-hydroxydesloratadine,
and Day 10 for pseudoephedrine. For desloratadine, mean steady-state Cmax and
AUC(0-24h) of approximately 2.44 ng/mL and 34.8 ng•hr/mL, respectively were observed.
For pseudoephedrine, mean steady-state peak plasma concentrations (Cmax) and
AUC(0-24h) of 523 ng/mL and 8795 ng•hr/mL, respectively, were observed.
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.
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 with
desloratadine 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 prospectively identified, a total of 94
poor metabolizers and 123 normal metabolizers were enrolled and treated with
CLARINEX Syrup 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.
Pseudoephedrine alone is incompletely metabolized (less
than 1%) in the liver by N-demethylation to an inactive metabolite. The drug
and its metabolite are excreted in the urine. About 55% to 96% of an
administered dose of pseudoephedrine hydrochloride is excreted unchanged in the
Following single dose administration of CLARINEX-D 24
HOUR Extended Release Tablets, the mean plasma elimination halflife of
desloratadine was similar to the desloratadine 5 mg tablet, approximately 24
and 27 hours, respectively. In another study, following administration of
single oral doses of desloratadine 5 mg, Cmax and AUC values increased in a
dose proportional manner 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.
The mean elimination half-life of pseudoephedrine is
dependent on urinary pH. The elimination half-life is approximately 3 to 6 or 9
to 16 hours when the urinary pH is 5 or 8, respectively.
Geriatric Subjects: 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 2 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 vs. younger subjects. These
agerelated differences are unlikely to be clinically relevant and no dosage
adjustment is recommended in elderly patients.
Pediatric Subjects: CLARINEX-D 24 HOUR Extended
Release Tablets are not an appropriate dosage form for use in pediatric patients
below 12 years of age.
Renally Impaired: Following a single dose of
desloratadine 7.5 mg, pharmacokinetics were characterized in subjects 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) subjects. In
subjects 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 subjects 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.
Pseudoephedrine is primarily excreted unchanged in the
urine as unchanged drug; the remainder is apparently metabolized in the liver.
Therefore, pseudoephedrine may accumulate in patients with renal impairment.
Hepatically Impaired: Following a single oral dose
of desloratadine, pharmacokinetics were characterized in subjects with mild (n=4),
moderate (n=4), and severe (n=4) hepatic impairment as defined by the
Child-Pugh classification of hepatic impairment and 8 subjects with normal
hepatic function. Subjects 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 subjects 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
subjects with hepatic impairment was observed. For 3-hydroxydesloratadine, the
mean Cmax and AUC values for subjects with hepatic impairment were not
statistically significantly different from subjects with normal hepatic function.
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 considered to
be clinically relevant.
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 considered to be clinically
In 2 controlled crossover
clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12
in each study) subjects, desloratadine 7.5 mg (1.5 times the daily dose) once
daily was co-administered with erythromycin 500 mg every 8 hours or
ketoconazole 200 mg every 12 hours for 10 days. In 3 separate controlled,
parallel group clinical pharmacology studies, desloratadine at the clinical
dose of 5 mg has been co-administered 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
healthy male and female subjects. Although increased plasma concentrations (Cmax
and AUC0-24 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
Table 2: Changes in Desloratadine and
3-hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Subjects
|Erythromycin (500 mg Q8h)
|Ketoconazole (200 mg Q12h)
|Azithromycin (500 mg Day 1, 250 mg QD x 4 days)
|Fluoxetine (20 mg QD)
|Cimetidine (600 mg Q12h)
Animal Toxicology And/Or Pharmacology
Reproductive Toxicology Studies
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).
Seasonal Allergic Rhinitis
The clinical efficacy and safety of CLARINEX-D 24 HOUR
Extended Release Tablets was evaluated in two 2-week multicenter, randomized
parallel group clinical trials involving 2852 subjects 12 to 78 years of age
with seasonal allergic rhinitis, 708 of whom received CLARINEX-D 24 HOUR
Extended Release Tablets. In the 2 trials, subjects were randomized to receive
CLARINEX-D 24 HOUR Extended Release Tablets once daily, CLARINEX Tablets 5 mg
once daily, or sustained-release pseudoephedrine tablet 240 mg once daily for
two weeks. The majority of patients were between 18 and < 65 years of age
with a mean age of 34.3 years and were predominantly women (63%). Patient
ethnicity was 79% Caucasian, 10% Black, 8% Hispanic and 3% Asian/other
ethnicity. Primary efficacy variable was twice-daily reflective patient scoring
of 4 nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching,
and sneezing) and 4 non-nasal symptoms (itching/burning eyes, tearing/watering
eyes, redness of eyes, and itching of ears/palate) on a four point scale
(0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic
efficacy of CLARINEX-D 24 HOUR Extended Release Tablets, as measured by total
symptom score excluding nasal congestion, was significantly greater than pseudoephedrine
alone over the 2-week treatment period; and the decongestant efficacy of
CLARINEX-D 24 HOUR Extended Release Tablets, as measured by nasal
stuffiness/congestion, was significantly greater than CLARINEX (desloratadine
alone) over the 2-week treatment period. Primary efficacy variable results from
1 of 2 trials are shown in Table 3.
Table 3: Changes in Symptoms in a 2-Week Clinical
Trial in Subjects With Seasonal Allergic Rhinitis
(% change) from Baseline†,
|CLARINEX-D 24 HOUR Comparison to components‡
|Total Symptom Score (Excluding Nasal Congestion)
| CLARINEX-D 24 HOUR ExtendedRelease Tablets
| Pseudoephedrine tablet 240 mg
| CLARINEX 5 mg Tablets
| CLARINEX-D 24 HOUR Extended Release Tablets
| Pseudoephedrine tablet 240 mg
| CLARINEX 5 mg Tablets
|p < 0.001
|SEM=Standard Error of the Mean
* To qualify at Baseline, the sum of the twice-daily diary reflective scores
for the 3 days prior to Baseline and the morning of the Baseline visit were to
total ≥ 42 for total nasal symptom score (sum of 4 nasal symptoms of
rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and a
total of ≥ 35 for total non-nasal symptoms score
(sum of 4 non-nasal
symptoms of itching/burning eyes, tearing/watering eyes, redness of eyes, and
itching of ears/palate), and a score of ≥ 14 for each of the individual
symptoms of nasal stuffiness/congestion and rhinorrhea. Each symptom was scored
on a 4-point severity scale
(0=none, 1=mild, 2=moderate, 3=severe).
† Mean reduction in score averaged over the 2-week treatment period.
‡ The comparison of interest is shown bolded.
There were no significant differences in the efficacy of
CLARINEX-D 24 HOUR Extended Release Tablets across subgroups of subjects
defined by gender, age, or race.