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 12 HOUR Extended
Release Tablets, ECGs were recorded at baseline and endpoint within 1 to 3 hours
after the last dose. The majority of ECGs were normal at both baseline and
endpoint. No clinically meaningful changes were observed following treatment
with CLARINEX-D 12 HOUR Extended Release Tablets for any ECG parameter,
including the QTc interval. An increase in the ventricular rate of 7.1 and 6.4
bpm was observed in the CLARINEX-D 12 HOUR Extended Release Tablets and
pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in
subjects receiving desloratadine alone. Single daily doses of CLARINEX 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 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 CLARINEX-treated
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.
In a single dose pharmacokinetic study, the mean time to
maximum plasma concentrations (Tmax) for desloratadine occurred at approximately
4 to 5 hours post dose and mean peak plasma concentrations (Cmax) and area
under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6
ng•hr/mL, respectively, were observed. In another pharmacokinetic study,
food and grapefruit juice had no effect on the bioavailability (Cmax and AUC)
For pseudoephedrine, the mean Tmax occurred at 6 to 7
hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time
curve (AUC) of approximately 263 ng/mL and 4588 ng•hr/mL, respectively,
were observed. Food had no effect on the bioavailability (Cmax and AUC) of
Following oral administration of CLARINEX-D 12 HOUR
Extended Release Tablets twice daily for 14 days in healthy volunteers,
steady-state conditions were reached on Day 10 for desloratadine,
3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean
steady-state peak plasma concentrations (Cmax) and area under the
concentration-time curve AUC 0-12 hrs of approximately 1.7 ng/mL and 16
ng•hr/mL were observed, respectively.
For pseudoephedrine, mean steady-state peak plasma
concentrations (Cmax) and AUC 0-12 hrs of 459 ng/mL and 4658 ng•hr/mL were
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
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 12
HOUR Extended Release Tablets, the mean plasma elimination half-life of desloratadine
was approximately 27 hours. In another study, following administration of
single oral doses of desloratadine 5 mg, 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 halflife 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.
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 age-related differences are unlikely to be
clinically relevant and no dosage adjustment is recommended in elderly
CLARINEX-D 12 HOUR Extended Release Tablets are not an appropriate
dosage form for use in pediatric patients below 12 years of age.
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 with the remainder apparently being metabolized in the
liver. Therefore, pseudoephedrine may accumulate in patients with renal
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 combined were not statistically
significantly different from subjects with normal hepatic function.
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
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 relevant.
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 AUC 0-24 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 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 12 HOUR
Extended Release Tablets was evaluated in two 2-week multicenter, randomized
parallel group clinical trials involving 1248 subjects 12 to 78 years of age
with seasonal allergic rhinitis, 414 of whom received CLARINEX-D 12 HOUR
Extended Release Tablets. In the 2 trials, subjects were randomized to receive
CLARINEX-D 12 HOUR Extended Release Tablets twice daily, CLARINEX Tablets
5 mg once daily, or sustained-release pseudoephedrine
tablet 120 mg twice daily for 2 weeks. The majority of patients were between 18
and < 65 years of age with a mean age of 35.8 years and were predominantly
women (64%). Patient ethnicity was 82% Caucasian, 9% Black, 6% 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 four non-nasal symptoms (itching/burning eyes,
tearing/watering eyes, redness of eyes, and itching of ears/palate) on a 4
point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the
antihistaminic efficacy of CLARINEX-D 12 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 12 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 12 HOUR Comparison to Components‡
|Total Symptom Score (Excluding Nasal Congestion)
| CLARINEX-D 12 HOUR Extended Release Tablets BID (199)
| Pseudoephedrine tablet 120 mg BID (197)
|P < 0.001
| CLARINEX 5 mg Tablets QD (197)
|P < 0.001
| CLARINEX-D 12 HOUR Extended Release Tablets BID (199)
| Pseudoephedrine tablet 120 mg BID (197)
| CLARINEX 5 mg Tablets QD (197)
|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 12 HOUR Extended Release Tablets across subgroups of subjects
defined by gender, age, or race.