Aerius®
Desloratadine
Histamine H1-Receptor Antagonist
Schering
http://www.sch-plough.com/schering_plough/index.jsp
Aerius Monograph PDF download here.
Aerius Kids™
Desloratadine
Histamine H1-Receptor Antagonist
Schering
CPS:PIS_m009015
Pharmacology
Desloratadine is a nonsedating long-acting
antihistamine with selective peripheral H1-receptor antagonist
activity, which has demonstrated antiallergic, antihistaminic and
anti-inflammatory activity.
Desloratadine does not exacerbate
asthma.
Pharmacodynamics: After oral administration,
desloratadine selectively blocks peripheral histamine H1-receptors
as the drug is effectively excluded from entry into the CNS.
Wheal and Flare: Desloratadine 5 mg was
significantly better than placebo, as measured by a reduction in
histamine-induced wheal and flare areas for all days tested (1, 7, 14, 21, 28).
There was no evidence of tachyphylaxis over the 28-day dosing period.
Psychomotor Pharmacodynamics: Clinical trials
have demonstrated that there was no difference in the incidence of somnolence
in subjects treated with desloratadine 5 mg as compared to subjects
treated with placebo.
No significant
differences were found in the psychomotor test results between desloratadine
and placebo groups, whether administered alone or with alcohol.
Coadministration of alcohol with desloratadine did not increase the
alcohol-induced impairment in performance or increase in sleepiness. No effects
on the ability to drive and use machines have been observed. A single dose of
desloratadine did not affect standard measures of flight performance including
exacerbation of subjective sleepiness or tasks related to flying.
Cardiovascular Pharmacodynamics: In a
multiple-dose clinical trial, in which up to 20 mg of desloratadine was
administered daily for 14 days to 49 healthy volunteers, no statistically or
clinically relevant cardiovascular effects were observed. In another trial,
desloratadine was administered at a dose of 45 mg daily (9 times the clinical dose)
for 10 days; no prolongation of the QTc interval was seen (see Overdose:
Symptoms and Treatment).
The potential for
desloratadine to interact with ketoconazole (N=24), erythromycin (N=24),
azithromycin (N=90), fluoxetine (N=54), and cimetidine (N=36) was investigated
in separate interaction studies. Ketoconazole coadministered with desloratadine
increased Cmax and AUC values for desloratadine by 29% and 21%
respectively, and 3-hydroxy desloratadine Cmax and AUC values by 77%
and 110%, respectively. Erythromycin coadministered with desloratadine
increased the Cmax and AUC values for desloratadine by 24% and 14%,
respectively. The increases were 43% and 40%, respectively, for 3-hydroxy
desloratadine. Azithromycin coadministered with desloratadine increased the Cmax
and AUC values for desloratadine by 15% and 5%, respectively. The increases
were 15% and 4%, respectively, for 3-hydroxy desloratadine. Fluoxetine
coadministered with desloratadine resulted in no change in the AUC of
desloratadine and an increase of 15% in the Cmax of desloratadine.
The Cmax and AUC values for 3-hydroxy desloratadine were increased
by 17% and 13% respectively. Cimetidine coadministered with desloratadine
increased Cmax and AUC values by 12% and 19% respectively while the
Cmax and AUC of 3-hydroxy desloratadine were reduced by 11.2% and
2.8% respectively. However, as there was no evidence of change in the safety
profile of desloratadine throughout these studies, the increases in plasma
concentrations are not considered to be clinically relevant. In addition, no
clinically relevant changes in electrocardiographic pharmacodynamics (QTc) were
observed.
Pharmacokinetics
Absorption: Desloratadine plasma concentrations
can be detected within 30 minutes of desloratadine administration.
Desloratadine is well absorbed with maximum concentrations achieved after
approximately 3 hours; the mean elimination half-life is approximately
27 hours. The bioavailability of desloratadine is dose proportional over
the range of 5 to 20 mg. Equivalent exposure (AUC) to desloratadine, 3-hydroxy
desloratadine, and 3-hydroxy desloratadine glucuronide was achieved after
desloratadine 5 mg and loratadine 10 mg.
In a single dose
crossover study of desloratadine, the tablet and syrup formulations were found
to be bioequivalent.
In separate single dose
studies, at the recommended doses, pediatric patients had comparable AUC and Cmax
values of desloratadine to those in adults who received a 5 mg dose of
desloratadine syrup or tablets.
Metabolism: Desloratadine is extensively
metabolized. The results of metabolic profiling indicated that hydroxylation of
desloratadine to 3-hydroxy desloratadine (3-OH desloratadine) followed by its
subsequent glucuronidation was the major pathway of metabolism of desloratadine.
The enzyme responsible for the metabolism of desloratadine has not been
identified yet, and therefore some interactions with other drugs can not be
fully excluded. In vivo studies with specific inhibitors of CYP3A4 and CYP2D6
have shown that these enzymes are not important in the metabolism of
desloratadine. Desloratadine does not inhibit CYP3A4 and CYP2D6 and is neither
a substrate nor an inhibitor of p-glycoprotein.
Data from clinical
pharmacology studies indicate that a subset of the general adult and pediatric
patient population has a decreased ability to form 3-hydroxydesloratadine.
Ninety pediatric and 440 adult subjects were phenotyped for the polymorphism in
clinical pharmacology studies. The incidence of the trait was approximately 8.6%
in adults and 15.6% in pediatric subjects. In both pediatric and adult studies
the slow metabolizer trait is more frequent in subjects of African descent than
Caucasians. The desloratadine exposure (AUC) associated with the slow
metabolizer phenotype has been well characterized (~4 times that of normal
metabolizers) in single dose studies and is similar in pediatric and adult
subjects at various doses. Median (range) AUC in pediatric normal and slow
metabolizers was 31.9 (14-74) ng.hr/mL and 116 (72-210) ng.hr/mL, respectively.
The corresponding values for adult normal and slow metabolizers were 33.5
(8.7-99) ng.hr/mL and 139 (82-393) ng.hr/mL, respectively. In adults
characterized as slow metabolizers, desloratadine exposure (AUC) after multiple
doses has been demonstrated to be about six fold higher than that of normal
metabolizers. The desloratadine exposure after multiple doses has not been
documented for children. The safety profile of adult and pediatric slow
metabolizers of desloratadine was not different from that of the general
population.
Desloratadine is
moderately bound (83 to 87%) to plasma proteins.
Following
administration of desloratadine 5 mg for 28 days, the approximate 2-fold
degree of accumulation of desloratadine and 3-OH desloratadine is consistent
with the half-life of DL and its active metabolite and a once daily dosing
frequency. This accumulation is not clinically meaningful. The
pharmacokinetics of desloratadine and 3-OH desloratadine do not change after
daily dosing for 7 consecutive days.
There is no evidence of
clinically relevant drug accumulation following once-daily dosing of
desloratadine (5 to 20 mg) for 14 days.
Results from a
single-dose trial of 7.5 mg of desloratadine demonstrate that there was no
effect of food (high-fat, high-caloric breakfast) on the disposition of
desloratadine. In another study, grapefruit juice had no effect on the
disposition of desloratadine.
Excretion: 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.
Indications
Aerius (desloratadine) tablets are indicated for
the fast relief of nasal and non-nasal symptoms associated with allergic
rhinitis, including sneezing, nasal discharge and itching,
congestion/stuffiness, itching of the palate, and coughing associated with
these symptoms, as well as itching, tearing and redness of the eyes.
Aerius Kids
(desloratadine) syrup is indicated for the fast relief of nasal and non-nasal
symptoms associated with seasonal allergic rhinitis, including sneezing, nasal
discharge and itching, congestion/stuffiness, itching of the palate, and
coughing associated with these symptoms, as well as itching, tearing and redness
of the eyes.
Aerius tablets and
Aerius Kids (desloratadine) syrup are also indicated for the rapid relief of
symptoms associated with chronic idiopathic urticaria, such as pruritus and
hives.
Contraindications
Hypersensitivity to the active substance or any
of the excipients contraindicates its use.
Warnings
No data supplied by the manufacturer.
Precautions
Hepatic Dysfunction: In a single-dose
(7.5 mg) pharmacokinetic study, subjects with mild to severe hepatic
dysfunction (n=4/group) had mean AUC and Cmax values up to
2.4 times higher than healthy subjects (n=8); however, these findings are
not considered to be clinically relevant.
Desloratadine 5 mg
was administered for 10 days to subjects with normal hepatic function (n=9) or
moderate dysfunction (n=11). Subjects with hepatic dysfunction could experience
a 3-fold increase in exposure (AUC) to desloratadine, but these findings are
not considered to be clinically relevant. Therefore, no dosage modification is
recommended in individuals with hepatic dysfunction.
Renal Dysfunction: In a single-dose
(7.5 mg) pharmacokinetic study, subjects (n=25) with varying degrees of
renal insufficiency (mild, moderate, severe and hemodialysis) had 1.7- to
2.5-fold increases in desloratadine mean AUC with minimal change in 3-hydroxy
desloratadine concentrations. However, these findings are not considered to be
clinically relevant. In the case of severe renal insufficiency, desloratadine
should be used with caution.
Pregnancy
Since no clinical data on exposed pregnancies
are available with desloratadine, the safe use of desloratadine during
pregnancy has not been established. The use of desloratadine during pregnancy
is therefore not recommended.
No overall effect on
rat fertility was observed with desloratadine at an exposure that was
34 times higher than the exposure in humans at the recommended clinical
dose. No teratogenic or mutagenic effects were observed in animal trials with
desloratadine.
Lactation
Desloratadine passes into breast milk;
therefore, breast-feeding is not recommended in lactating women taking
desloratadine.
Children
The efficacy and safety of desloratadine tablets
in children under 12 years of age and of desloratadine syrup in children
under 2 years of age have not been established.
Geriatrics
In a multiple-dose study with desloratadine
5 mg, subjects >65 years of age (n=17) had AUC and Cmax
values 20% greater and plasma elimination half-life approximately 30% longer
than in younger subjects; however, these changes are not considered to be
clinically relevant and no dosage adjustment is warranted in this age subgroup.
Use in Asthmatics
Desloratadine has been safely administered to
patients with mild to moderate asthma. Desloratadine did not cause exacerbation
of asthma symptoms.
Drug Interactions
No clinically relevant interactions with
desloratadine were observed in clinical trials investigating the potential for
interaction with azithromycin, erythromycin, ketoconazole, fluoxetine and
cimetidine.
Desloratadine taken
concomitantly with alcohol did not potentiate the performance-impairing effects
of alcohol.
Occupational Hazards
Effects on Ability To Drive And Use Machines:
none.
Adverse Effects
No clinically relevant drug-related adverse
effects including cardiovascular effects, were observed with desloratadine.
Very rare cases of hypersensitivity reactions including anaphylaxis and rash
have been reported during the marketing of desloratadine.
The frequency of
reasonably related undesirable effects is presented as the excess incidence in
1866 patients who received desloratadine 5 mg compared to that seen in
1857 patients who received placebo in multiple-dose clinical trials evaluating
the treatment of seasonal and allergic rhinitis and chronic idiopathic
urticaria. The type and frequency of undesirable effects reported throughout
the desloratadine allergic rhinitis and CIU clinical trials were comparable to
those reported with placebo.
At the recommended dose
of 5 mg daily, undesirable effects with desloratadine were reported in only 3%
of patients in excess of those treated with placebo. No excess incidence of
somnolence was reported in patients treated with desloratadine. Headache was
reported in only 0.6% of patients in excess of those treated with placebo. The
incidence of treatment-related adverse events reported by ≥ 1% of
subjects treated with desloratadine 5 mg in multiple-dose clinical trials
is presented in Table 1.
In pediatric clinical
trials, 115 patients received desloratadine syrup and 116 received placebo.
Possibly related undesirable effects were reported in only 1.7% (n=2) of
subjects treated with desloratadine syrup. Both of these events (1 each of
rash and headache) occurred among the 2-5 year old subjects (desloratadine
1.25 mg treatment group). There were no reports of reasonably related undesirable
effects among the 6-11 year old subjects in either treatment group. A total of
11 treatment emergent adverse events (fever, headache, viral infection,
Varicella, rash, and urinary tract infection) were reported in 8 subjects
(0.8%) treated with 1.25 or 2.5 mg of desloratadine. Overall, there were no
reports of somnolence, fatigue, paradoxical excitability, parakinesia,
insomnia, or hyperkinesia.
Very rare cases of
hypersensitivity reactions, including anaphylaxis and rash have been reported
during the marketing of desloratadine. In addition, cases of tachycardia,
palpitations, elevations of liver enzymes, and increased bilirubin have been
reported very rarely.
CPS:Aerius_t1Click here for Table 1
Table 1: Aerius
Incidence of Treatment-related Adverse Events
Reported by ≥ 2% of Subjects Treated with Aerius 5 mg in
Multiple-dose Seasonal Allergic Rhinitis and Chronic Idiopathic Urticaria
Studies
|
|
Numbera
(%) of Subjects
|
|
|
Desloratadine
|
|
|
5 mg
(n=1866)
|
Placebo
(n=1857)
|
|
|
No. of Subjects (%) with Any Related
Adverse Eventb
|
281 (15.1)
|
232 (12.5)
|
|
|
Autonomic Nervous System Disorders
|
51 (2.7)
|
36 (1.9)
|
|
|
Dry Mouth
|
49 (2.6)
|
34 (1.8)
|
|
|
Fatigue
|
33 (1.8)
|
12(0.6)
|
|
|
Body As a Whole-General Disorders
|
124 (6.6)
|
88 (4.7)
|
|
|
Headache
|
84 (4.5)
|
72 (3.9)
|
|
|
Psychiatric Disorders
|
53 (2.8)
|
48 (2.6)
|
|
|
Somnolence
|
36 (1.9)
|
35(1.9)
|
|
a Number of subjects reporting
related adverse events at least once during the study. Some subjects may have
reported more than 1 adverse event.
b Considered by the investigator to
be possibly or probably related to treatment.
Overdose
For management of a
suspected drug overdose, CPhA recommends that you contact your regional
Poison Control Centre. See the CPS Directory section for a list of
Poison Control Centres.
Symptoms
In the event of overdose, consider standard
measures to remove unabsorbed active substance. Symptomatic and supportive
treatment is recommended. Desloratadine administered at a dose of 45 mg
daily (9 times the clinical dose) for 10 days showed no statistically or clinically
relevant prolongation of the QTc interval. The mean changes in QTc were
0.3 ms and 4.3 ms for placebo and desloratadine, respectively (p=0.09;
Lower confidence interval (LCI)=− 0.6; Upper confidence interval
(UCI)=8.7).
Desloratadine is not
eliminated by hemodialysis; it is not known if it is eliminated by peritoneal
dialysis.
Treatment
See Symptoms.
Dosage
Tablets
Adults and adolescents (12 years of age and
older): One 5 mg tablet daily regardless of mealtime. For oral use.
Syrup
Adults and adolescents (12 years of age and
older): 10 mL (5 mg) of Aerius Kids syrup once a day, regardless of mealtime.
Children 6 through 11 years of age: 5 mL (2.5
mg) Aerius Kids syrup once a day, regardless of mealtime.
Children 2 through 5 years of age: 2.5 mL (1.25
mg) Aerius Kids syrup once a day, regardless of mealtime.
Do not administer
Aerius Kids to children between 2 to 12 years of age for longer than 14 days
unless recommended by a physician.
Supplied
Syrup
Each mL of clear, orange colored liquid with
bubblegum flavoring, contains: desloratadine 0.5 mg. Nonmedicinal ingredients:
bubblegum flavor, citric acid anhydrous, disodium edetate, FD&C yellow No.
6, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate,
sorbitol solution, and sucrose. Amber glass bottles of 100 mL. Store between 15
and 30°C.
Tablets
Each blue, round, film-coated tablet for
immediate release contains: desloratadine 5 mg. Nonmedicinal ingredients:
carnauba wax, cornstarch, dibasic calcium phosphate dihydrate, FD&C Blue #2
lake, hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline
cellulose, polyethylene glycol, talc, titanium dioxide and white beeswax.
PVC/aluminum blisters in boxes of 10, 20 and 30. HDPE bottles of 100. Store
between 15 and 30°C. Protect from excessive moisture.
