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Clarinex-D 12hr

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Clarinex-D 12hr

Clarinex-D 12hr

CLINICAL PHARMACOLOGY

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 does not readily cross the blood brain barrier.

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.

Pharmacokinetics

Absorption: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately 4-5 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) of desloratadine. For pseudoephedrine, the mean Tmax occurred at 6-7 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 desloratadine or pseudoephedrine.

Following oral administrations of CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets twice daily for 14 days in normal 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 h) 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 h) of 459 ng/mL and 4658 ng•hr/mL were observed.

Distribution: Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound toplasma 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 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 2-5 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 prospectively 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.

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 55-96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.

Elimination: 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 half-life values compared to desloratadine.

The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately 3-6 or 9-16 hours when the urinary pH is 5 or 8, respectively.

Special Populations

Geriatric: The number of patients (n=10) ≥ 65 years old treated with CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets was too limited to make any clinically relevant judgment regarding the efficacy or safety of this drug product in this age group. 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: CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age.

Renally Impaired: No studies with CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets were conducted in patients with renal impairment. Following a single dose of desloratadine 7.5 mg pharmacokinetics were characterized in patients with mild (n=7; creatinine clearance 51-69 mL/min/1.73m²), moderate (n=6; creatinine clearance 34-43 mL/min/1.73m²) and severe (n=6; creatinine clearance 5-29 mL/min/1.73m²) renal impairment or hemodialysis dependent (n=6) patients. In subjects with mild and moderate 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.

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 impairment. CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets should generally be avoided in patients with renal impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION section).

Hepatically Impaired: No studies with CLARINEX-D®12 HOUR Extended Release Tablets or pseudoephedrine were conducted in patients with hepatic impairment. Following a single oral dose of desloratadine, pharmacokinetics were characterized in patients 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. 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 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 patients 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. CLARINEX-D®12 HOUR Extended Release Tablets should generally be avoided in patients with hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Effect of Gender: No clinically significant gender-related differences were observed in the pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine or pseudoephedrine following administration of CLARINEX-D®12 HOUR Extended Release Tablets. 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 clinically relevant and therefore no dosage adjustment is recommended.

Effect of Race: No studies have been conducted to evaluate the effect of race on the pharmacokinetics of CLARINEX-D®12 HOUR Extended Release Tablets. 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 and therefore no dose adjustment is recommended.

Drug Interactions

No specific interaction studies have been conducted with CLARINEX-D® 12 HOUR Extended Release Tablets. However, in two 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 coadministered 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 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 healthy male and female subjects. 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 Subjects

  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%

Due to the pseudoephedrine component, CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets should not be used by patients taking monoamine oxidase inhibitors or within 14 days after stopping such treatment. The antihypertensive effects of beta-adrenergic blocking agents, methyldopa, mecamylamine, reserpine, and veratrum alkaloids may be reduced by sympathomimetics. Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis.

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: In clinical trials for CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) 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 (desloratadine and pseudoephedrine sulfate) 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 (desloratadine and pseudoephedrine sulfate) Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in patients receiving desloratadine alone.

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 (up to 24 mg/kg, 1 and 3 months) to monkeys did not alter the QTc at an estimated desloratadine exposure (AUC) that was approximately 955 times the mean area under the plasma concentration versus time curve (AUC) in humans at the recommended daily oral dose. See OVERDOSAGE section for information on human QTc experience.

Clinical Trials

The clinical efficacy and safety of CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets was evaluated in two 2-week multicenter, randomized parallel group clinical trials involving 1248 patients 12 to 78 years of age with seasonal allergic rhinitis, 414 of whom received CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets. In the two trials patients were randomized to receive CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) Extended Release Tablets twice daily, CLARINEX® Tablets 5 mg once daily, and sustained-release pseudoephedrine tablet 120 mg twice daily for two weeks. Primary efficacy variable was twice-daily reflective patient scoring of four 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 four point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic efficacy of CLARINEX-D® 12 HOUR (desloratadine and pseudoephedrine sulfate) 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 desloratadine alone over the 2-week treatment period. Primary efficacy variable results from one of two trials are shown in Table 2.

Table 2: Changes in Symptoms in a 2-Week Clinical Trial in Patients with Seasonal Allergic Rhinitis

Treatment Group (n) Mean Baseline* (sem) Change (% change) from
Baseline**
(sem)
CLARINEX-D
12 HOUR
Comparison to components***
(P-value)
Total Symptom Score (Excluding Nasal Congestion)
CLARINEX-D® 12 HOUR Extended Release Tablets BID (199) 14.18
(0.21)
-6.54 (-46.0)
(0.30)
-
Pseudoephedrine tablet 120 mg BID (197) 14.06
(0.21)
-5.07 (-35.9)
(0.30)
P < 0.001
CLARINEX® 5 mg Tablets QD (197) 14.82
(0.21)
-5.09 (-33.5)
(0.30)
P < 0.001
Nasal Stuffiness/Congestion
CLARINEX-D® 12 HOUR Extended Release Tablets BID (199) 2.47
(0.027)
-0.93 (-37.4) (0.046) -
Pseudoephedrine tablet 120 mg BID (197) 2.46
(0.027)
-0.75 (-31.2)
(0.046)
P=0.006
CLARINEX® 5 mg Tablets QD (197) 2.50
(0.027)
-0.66 (-26.7)
(0.046)
P < 0.001
* To qualify at Baseline, the sum of the twice-daily diary reflective scores for the three 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 patients defined by gender, age, or race.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

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