AERIUS® AERIUS KIDS®

Transcription

PRODUCT MONOGRAPH
AERIUS®
Desloratadine Tablet 5 mg
Desloratadine Syrup 0.5 mg/mL
AERIUS KIDS®
Histamine H1-Receptor Antagonist
Schering-Plough Canada Inc.
16750, route Transcanadienne
Kirkland, Quebec
H9H 4M7
Date of Preparation:
March 26, 2014
Submission Control No: 164302
®
Registered trademark of MSD International Holdings GMbh Used under license by ScheringPlough Canada Inc.
AERIUS Tablets / AERIUS Syrup / AERIUS KIDS Syrup
Page 1 of 37
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3
SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE ..............................................................................3
CONTRAINDICATIONS ...................................................................................................3
WARNINGS AND PRECAUTIONS ..................................................................................4
ADVERSE REACTIONS....................................................................................................5
DRUG INTERACTIONS ....................................................................................................7
DOSAGE AND ADMINISTRATION ................................................................................7
OVERDOSAGE ..................................................................................................................8
ACTION AND CLINICAL PHARMACOLOGY ..............................................................8
STORAGE AND STABILITY ..........................................................................................11
SPECIAL HANDLING INSTRUCTIONS .......................................................................11
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................11
PART II: SCIENTIFIC INFORMATION ...............................................................................13
PHARMACEUTICAL INFORMATION..........................................................................13
CLINICAL TRIALS ..........................................................................................................14
DETAILED PHARMACOLOGY .....................................................................................20
MICROBIOLOGY ............................................................................................................26
TOXICOLOGY .................................................................................................................26
REFERENCES ..................................................................................................................31
PART III: CONSUMER INFORMATION..............................................................................35
Page 2 of 37
AERIUS®
AERIUS KIDS®
Desloratadine
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form /
Strength
oral
Tablet / 5 mg
Syrup / 0.5 mg/mL
Clinically Relevant Nonmedicinal
Ingredients
For a complete listing see Dosage Forms,
Composition and Packaging section.
INDICATIONS AND CLINICAL USE
AERIUS® (desloratadine) tablets are indicated for:
fast 24 hour relief of multi nasal and non-nasal symptoms associated with allergic
rhinitis, including sneezing, nasal discharge and itching, congestion/stuffiness, itching of
the palate and/or ears and/or throat and/or eyes and allergic cough, as well as tearing and
redness of the eyes.
the rapid relief of symptoms associated with chronic idiopathic urticaria, such as pruritus
and hives.
AERIUS® and AERIUS KIDS® (desloratadine) syrup are indicated for:
fast 24 hour relief of multi nasal and non-nasal symptoms associated with allergic
rhinitis, including sneezing, nasal discharge and itching, congestion/stuffiness, itching of
the palate and/or ears and/or throat and/or eyes and allergic cough, as well as tearing and
redness of the eyes.
the rapid relief of symptoms associated with chronic idiopathic urticaria, such as pruritus
and hives.
CONTRAINDICATIONS
Patients who are hypersensitive to this drug or to any ingredient in the formulation or
component of the container. For a complete listing, see the Dosage Forms, Composition
and Packaging section of the product monograph.
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WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
In the case of severe hepatic or renal insufficiency, use with caution.
Hepatic/Biliary/Pancreatic
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 5mg 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 (see
DETAILED PHARMACOLOGY / Human Pharmacokinetics / Hepatic Dysfunction).
Renal
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 (see DETAILED
PHARMACOLOGY / Human Pharmacokinetics / Renal Dysfunction).
In the case of severe renal insufficiency, AERIUS should be used with caution.
Respiratory
Use in Asthmatics: AERIUS has been safely administered to patients with mild to moderate
asthma (see CLINICAL TRIALS / Efficacy in Seasonal Allergic Rhinitis: Patients with SAR
and Concomitant Mild to Moderate Asthma).
AERIUS did not cause exacerbation of asthma symptoms (see DETAILED PHARMACOLOGY
/ Human Pharmacokinetics / Asthmatics).
Special Populations
Pregnant Women: Since no clinical data on exposed pregnancies are available with
desloratadine, the safe use of AERIUS during pregnancy has not been established. The use of
AERIUS 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 (see TOXICOLOGY).
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Nursing Women: Desloratadine passes into breast milk; therefore, breast-feeding is not
recommended in lactating women taking AERIUS.
Pediatrics (Tablets <12 years of age) and (Syrup < 2 years): The efficacy and safety of AERIUS
Tablets in children under 12 years of age and of AERIUS Syrup in children under 2 years of age
have not been established.
Geriatrics (> 65 years of age): In a multiple dose study with AERIUS 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 (see
DETAILED PHARMACOLOGY / Human Pharmacokinetics / Elderly).
ADVERSE REACTIONS
Adverse Drug Reaction Overview
No clinically relevant drug-related adverse effects including cardiovascular effects were
observed with AERIUS in clinical trials.
Very rare cases of hypersensitivity reactions including anaphylaxis and rash have been reported
during the marketing of desloratadine. In addition, cases of tachycardia, palpitations,
psychomotor hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased
bilirubin have been reported very rarely.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events and for approximating rates.
The frequency of reasonably related undesirable effects is presented as the excess incidence in
1866 patients who received AERIUS (desloratadine) 5 mg tablets 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 AERIUS allergic rhinitis and CIU clinical trials were comparable
to those reported with placebo.
At the recommended dose of 5 mg daily, undesirable effects with AERIUS 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 AERIUS. Headache was reported in only 0.6% of patients in
excess of those treated with placebo. The incidence of treatment-related adverse events reported
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by 1% of subjects treated with AERIUS 5 mg in multiple-dose clinical trials is presented in
Table 1.
Table 1.
Incidence of Treatment-Related Adverse Events Reported by > 2% of Subjects Treated with AERIUS 5 mg
in Multiple-Dose Allergic Rhinitis and Chronic Idiopathic Urticaria Studies.
Numbera (%) of Subjects
Desloratadine
5.0 mg
(n= 1866)
Placebo
(n= 1857)
281 (15.1)
232 (12.5)
Autonomic Nervous System Disorders
Dry Mouth
Fatigue
51 (2.7)
49 (2.6)
33 (1.8)
36 (1.9)
34 (1.8)
12(0.6)
Body As a Whole-General Disorders
Headache
124 (6.6)
84 (4.5)
88 (4.7)
72 (3.9)
Psychiatric Disorders
Somnolence
53 (2.8)
36 (1.9)
48 (2.6)
35(1.9)
No. of Subjects (%) with Any Related Adverse Eventb
a:
b:
Number of subjects reporting related adverse events at least once during the study. Some subjects may have reported more than one
adverse event.
Considered by the investigator to be possibly or probably related to treatment.
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.
Post-Market Adverse Drug Reactions
Very rare cases of hypersensitivity reactions, including anaphylaxis and rash have been reported
psychomotor hyperactivity, seizures, elevations of liver enzymes, hepatitis, and increased
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DRUG INTERACTIONS
Overview
AERIUS taken concomitantly with alcohol did not potentiate the performance impairing effects
of alcohol (see DETAILED PHARMACOLOGY / Human Pharmacodynamics / Psychomotor
Pharmacodynamics).
Drug-Drug Interactions
No clinically relevant interactions with AERIUS were observed in clinical trials investigating the
potential for interaction with azithromycin, erythromycin, ketoconazole, fluoxetine, and
cimetidine (see DETAILED PHARMACOLOGY / Human Pharmacokinetics / Drug-Drug
Interactions).
Drug-Food Interactions
There was no effect of food or grapefruit juice on the disposition of desloratadine (see
DETAILED PHARMACOLOGY / Human Pharmacokinetics / Effect of food).
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory test have not been established.
Drug-Lifestyle Interactions
Effects on Ability To Drive And Use Machines: None (see DETAILED PHARMACOLOGY
/ Human Pharmacodynamics / Psychomotor Pharmacodynamics).
DOSAGE AND ADMINISTRATION
Dosing Considerations
In the case of severe hepatic or renal insufficiency, AERIUS should be used with caution.
Recommended Dose and Dosage Adjustment
Tablets
Adults and adolescents (12 years of age and older): One AERIUS (desloratadine) 5 mg tablet
daily regardless of mealtime. For oral use.
Page 7 of 37
Syrup
Adults and adolescents (12 years of age and older): 10 mL (5 mg) AERIUS 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,
Do not administer AERIUS KIDS to children between 2 to 12 years of age for longer than 14
days unless recommended by a physician.
OVERDOSAGE
In the event of overdose, consider standard measures to remove unabsorbed active substance.
Symptomatic and supportive treatment is recommended. AERIUS administered at a dose of 45
mg daily (nine times the clinical dose) for ten days showed no statistically or clinically relevant
prolongation of the QTc interval. The mean changes in QTc were 0.3 msec and 4.3 msec 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.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Desloratadine is a non-sedating 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 central nervous system.
Wheal and Flare: Desloratadine 5mg 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.
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Psychomotor Pharmacodynamics: Clinical trials have demonstrated that there was no
difference in the incidence of somnolence in subjects treated with AERIUS (desloratadine) 5 mg
as compared to subjects treated with placebo.
No significant differences were found in the psychomotor test results between AERIUS and
placebo groups, whether administered alone or with alcohol. Co-administration of alcohol with
AERIUS 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 AERIUS 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
AERIUS was administered daily for 14 days to 49 healthy volunteers, no statistically or
clinically relevant cardiovascular effects were observed. In another trial, AERIUS was
administered at a dose of 45 mg daily (nine times the clinical dose) for ten days; no prolongation
of the QTc interval was seen (see OVERDOSAGE).
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 co-administered 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 co-administered 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 co-administered 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 mg to 20 mg.
Equivalent exposure (AUC) to desloratadine, 3-hydroxy desloratadine, and 3-hydroxy
desloratadine glucuronide was achieved after desloratadine 5mg and loratadine 10 mg.
Page 9 of 37
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.
Distribution: No information available.
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 cannot 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 5mg for 28 days, the approximate two-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
AERIUS (5 mg to 20 mg) for 14 days.
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Results from a single dose trial of 7.5 mg AERIUS 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
14
C-desloratadine dose, which was equally distributed in urine and feces as metabolic products.
Special Populations and Conditions
See DETAILED PHARMACOLOGY/ Human Pharmacokinetics for:
Pediatrics
Geriatrics
Gender
Race
Hepatic Insufficiency
Renal Insufficiency
STORAGE AND STABILITY
Temperature and Moisture
Tablets: Store between 15 and 30 C. Protect from excessive moisture.
Syrup: Store between 15 and 30 C.
Others
Keep in a safe place out of the reach of children.
SPECIAL HANDLING INSTRUCTIONS
None.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Dosage Forms
AERIUS (desloratadine) Tablets: 5 mg tablet for oral administration.
AERIUS and AERIUS KIDS (desloratadine) Syrup: 0.5 mg/mL for oral administration.
Page 11 of 37
Composition
AERIUS tablets are formulated as blue, round, film-coated tablets for immediate release. Each
tablet contains 5 mg of active ingredient, desloratadine.
Non-medicinal ingredients: carnauba wax, microcrystalline cellulose, corn starch, dibasic
calcium phosphate dihydrate, FD & C Blue #2 Lake, hydroxypropyl methylcellulose, lactose
monohydrate, polyethylene glycol, talc, titanium dioxide, white beeswax.
AERIUS and AERIUS KIDS syrup are formulated as clear, orange coloured liquid with
bubblegum flavouring. Each mL of syrup contains 0.5 mg of desloratadine. Non-medicinal
ingredients: bubblegum flavour, citric acid anhydrous, disodium edetate, dye FD&C yellow
No. 6, propylene glycol, purified water, sodium benzoate, sodium citrate dihydrate, sorbitol
solution, and sucrose.
Packaging
AERIUS tablets are packaged in PVC/aluminum blisters in boxes of 2’s (as professional sample)
10’s, 20’s, 30’s and 50’s. AERIUS tablets are also available in HDPE bottles of 90 and 100
tablets.
AERIUS and AERIUS KIDS syrup are packaged in amber glass bottles of 50 mL (professional
sample) and 100 mL.
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PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name:
Desloratadine
Chemical Name:
8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine
Molecular Formula:
C19H19CIN2
Molecular Mass:
310.8
Structural Formula:
Cl
N
N
H
Physicochemical properties:
Physical Form:
White to off-white powder
Solubility:
ethanol
methylene chloride
methanol
octanol
0.1N HCl
DMSO
water
pH 7.4 phosphate buffer
0.1N NaOH
>100 mg/mL (freely soluble)
39.7 mg/mL (soluble)
0.1mg/mL (very slightly soluble)
1.5 mg/mL (slightly soluble)
<0.1 mg/mL (practically insoluble)
pKa Values:
pyridine functional group
piperidine functional group
4.2
9.7
Partition Coefficient:
Melting Point:
log KO/W
n-octanol/0.1N HCl
n-octanol/pH 3 buffer
-2.27
-1.44
0.342
1.02
0.944
Form I
156.0 to 157.5 C
Page 13 of 37
CLINICAL TRIALS
Efficacy in Seasonal Allergic Rhinitis
Study demographics and trial design
The clinical efficacy of AERIUS in the treatment of seasonal allergic rhinitis (SAR) was
demonstrated in four multiple-dose, placebo-controlled clinical trials (C98-001, C98-223, C98224, and C98-225). A total of 2499 subjects with SAR were randomized to treatment with either
AERIUS or placebo. Of these, 1838 patients received active treatment. Efficacy endpoints in
the clinical trials included Total Symptom Score, Total Nasal Symptom Score, Total Non-Nasal
Symptom Score, and Quality of Life analysis. AERIUS 5 mg once daily significantly reduced
the Total Symptom Scores (the sum of individual scores for rhinorrhea, sneezing,
congestion/stuffiness, nasal itching, itchy/burning eyes, tearing, ocular redness, and itchy
ears/palate).
Study Results
AERIUS 5 mg was significantly more effective than placebo in reducing Total Nasal Symptoms
including congestion and Total Non-Nasal Symptoms. Instantaneous assessments of efficacy at
the end of the dosing interval demonstrated that reductions in symptoms which were observed
following the first dose of AERIUS 5 mg were maintained for the full 24 hour dosing interval.
There was no significant difference in the effectiveness of AERIUS 5 mg across subgroups of
patients defined by gender, age, or race.
Onset of Action Studies: Results from onset of action studies utilizing controlled-exposure
chambers indicated that subjects first became aware of significant improvements in their SAR
symptoms as early as 1 hour and 15 minutes following a 5.0 mg dose of AERIUS.
Quality of Life (QOL) Assessments: Exploratory assessments of quality of life in clinical trials
indicated that SAR produced a consistent burden of disease. Improvements in therapeutic
responses with AERIUS 5 mg were also associated with improvements in various QOL domains
including but not limited to: activity limitations, sleep problems, general problems, practical
problems, nasal symptoms, ocular problems, emotional function, vitality and social functioning
(see Table 2).
Page 14 of 37
Table 2: AERIUS (5 mg desloratadine) effectiveness in alleviating the burden of SAR:
improvement in QOL domains.
Study
Pradalier
A. et al.
(2007)
Study Description
Results
Methods: A multicenter, double-blind, randomized,
placebo-controlled, parallel-group study of
desloratadine 5 mg vs placebo in patients with
symptomatic SAR.
Objective: To compare the effects of desloratadine and
placebo on QOL in seasonal AR
Study duration: Two weeks.
Population: ITT population consisted of 483 subjects
(234 patients in the desloratadine 5 mg arm vs 249
patients in the placebo arm).
Validated QOL measurement tool: French-language
version of RQLQ. The questionnaire includes 28 items
in seven domains (activity limitations, sleep problems,
general problems, practical problems, nasal symptoms,
ocular symptoms, and emotional function). Patients
rated experiences over the previous week using a 7point scale: 0 (not bothered at all) to 6 (extremely
bothered); the total score was the mean of the domain
scores.
Secondary efficacy variables: The change from
baseline to D14 in TNSS.
Primary efficacy variable: QOL assessment, and
change from baseline in TNSS, TNNSS, TSS and
individual symptom score and diary symptom score.
Mean total RQLQ score at D14: desloratadine was
associated with a significantly larger improvement
from baseline vs placebo (P=0.0003).
Compared to placebo, desloratadine demonstrated
significant improvement (decrease in symptoms) in all
RQLQ sub-domains (activity limitations, sleep
problems, general problems, practical problems, nasal
symptoms, ocular problems, and emotional function)
vs placebo (P 0.043).
The desloratadine group demonstrated significant
decrease in TNSS (P=0.0003), TNNSS (P=0.001) and
TSS (P=0.0001) at D14 compared to D0 vs placebo.
The desloratadine group demonstrated a significant
decrease in morning and evening AR symptoms after
just 1 day of treatment (P 0.02).
*QOL: Quality of Life
ITT: Intent-To-Treat
D0: day 0;
D14: day 14;
RQLQ: French-language version of Rhinoconjunctivitis Quality of Life Questionnaire.
TNSS: Total Nasal Symptoms Score;
TNNSS: Total Non-Nasal Symptoms Score;
TSS: Total Symptoms Score.
Efficacy in Perennial Allergic Rhinitis
The clinical efficacy of AERIUS (desloratadine) in the treatment of perennial allergic rhinitis
(PAR) was evaluated in two multiple-dose, placebo-controlled clinical trials (P00218 and
P00219). A total of 1374 subjects with PAR were randomized to treatment with either AERIUS
or placebo. Of these, 685 patients received active treatment.
Study Results
One of the two perennial allergic rhinitis trials supported efficacy of desloratadine, compared
with placebo, for the primary efficacy endpoint (average am/pm instantaneous total symptom
score excluding nasal stuffiness/congestion expressed as change from baseline). In that study, the
Page 15 of 37
majority of the secondary efficacy endpoints supported treatment efficacy. The second pivotal
trial did not achieve statistical significance for the primary efficacy endpoint "average am/pm
instantaneous total symptom score excluding nasal stuffiness/congestion, expressed as change
from baseline". A statistically significant difference between desloratadine and placebo was
shown in this trial for one of the secondary efficacy variables “joint investigator-subject
evaluation of therapeutic response”.
Efficacy in Seasonal Allergic Rhinitis: Patients With SAR and Concomitant Mild to
Moderate Asthma.
Berger et al (2002) published results from a study evaluating safety and efficacy of (5 mg
desloratadine) in patients with SAR and mild seasonal allergic asthma. The four week multicenter, double-blind, placebo-controlled study included 331 patients (ages 15 or older) with a
two year history of SAR and increased asthma signs or symptoms in conjunction with fall/winter
allergy season. Patients were clinically symptomatic at screening and were assigned to take
either 5 mg desloratadine or placebo once daily for 4 weeks. The following symptoms were
evaluated in the study: rhinorrhea, nasal stuffiness/congestion, nasal itching, sneezing,
itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate. Patients
evaluated symptoms twice daily (morning/evening) and the primary efficacy parameter was
difference from baseline in AM/PM reflective total symptom scores. The results showed that
compared to placebo, desloratadine significantly reduced SAR total symptom scores with first
dose, which continued throughout the study duration (p < 0.001). Desloratadine was safe and
well tolerated in patients with SAR and mild seasonal allergic asthma. The number and type of
treatment-related adverse events were similar between the desloratadine and placebo groups.
Table 3: Published clinical trial evaluating safety and efficacy of AERIUS (5 mg desloratadine)
in treating SAR in patients with SAR and concomitant mild to moderate asthma.
Study
Study Description
Berger WE. et
al. (2002)
Methods: A multicenter, parallel-group, double-blind,
placebo-controlled, study of desloratadine 5 mg vs placebo in
patients with SAR and mild seasonal allergic asthma.
Objective: To evaluate the safety and efficacy of
desloratadine 5 mg in patients experiencing moderate SAR,
nasal congestion, and symptoms of seasonal allergic asthma.
Study duration: Four weeks.
Population: ITT population consisted of 331 subjects (168
patients in the desloratadine 5 mg arm vs 163 patients in the
placebo arm).
Primary efficacy variable: The mean AM/PM reflective TSS,
expressed as the change from baseline for the averages of
days 1 to 15, with additional analyses at days 1 to 29.
Results
Desloratadine significantly reduced mean
AM/PM reflective TSS for SAR, beginning
with the first dose (P<0.001) and continuing
throughout days 1 to 15 (-4.90 vs -2.98;
P<0.001) and days 1 to 29 (-5.47 vs -3.73;
P<0.001).
SAR: Seasonal allergic rhinitis;
ITT: Intent-To-Treat;
TSS: Total Symptoms Score;
Page 16 of 37
Efficacy in Chronic Idiopathic Urticaria
The clinical efficacy of AERIUS (desloratadine) in the treatment of chronic idiopathic urticaria
(CIU) was documented in over 400 chronic idiopathic urticaria patients 12 to 84 years of age in 2
double- blind, placebo-controlled, randomized clinical trials of 6 weeks duration as demonstrated
by reduction of associated itching and hives.
Study Results
AERIUS Tablets significantly reduced the severity of pruritus, number of hives, size of largest
hive, and total symptom score when compared to placebo. Symptoms were effectively reduced
as early as one day after initiation of treatment with AERIUS and were sustained for the full 24hour dosing interval.
Treatment with AERIUS also improved sleep and daytime functions as measured by reduced
interference with sleep and routine daily activities.
There was no significant difference in the effectiveness of AERIUS 5 mg across subgroups of
patients defined by gender, age, or race.
Quality of Life (QOL) Assessment
A number of published clinical trials, evaluating the impact of AERIUS (5 mg desloratadine) on
chronic idiopathic urticaria on QOL have demonstrated that AERIUS 5 mg significantly
improves a variety of QOL domains. A summary is provided in Table 4.
Table 4: Clinical trials demonstrating AERIUS (5 mg; desloratadine) effectiveness in alleviating
the burden of chronic idiopathic urticaria: improvement in QOL domains.
Study
Study Description
Grob JJ et
al (2008)
Methods: A multicentered, double-blinded, randomized,
placebo-controlled study of desloratadine 5 mg vs placebo
in patient with a history of CIU.
Objective: To evaluate the effect of desloratadine 5 mg on
QOL scores in patients with CIU.
Study duration: Six weeks.
Population: ITT population consisted of 137 subjects
(65 patients in the desloratadine arm vs 72 patients in the
placebo arm).
Validated QOL measurement tool: DLQI comprises 10
equally weighted items that evaluate the effect of skin
problems on patients’ lives: itchiness/soreness/ pain;
embarrassment; interference with shopping; clothes
purchases; social leisure; difficulty playing sports;
difficulty with work or study; problems with partner;
sexual difficulties; and problems at home caused by
treatment. Each item is scored on a continuum from 0
(least impairment) to 3 (worst impairment), with total
DLQI scores ranging from 0 to 30) and VQ-Dermato
Results
A significantly greater improvement from D0 to
D24 was associated with desloratadine treatment
compared to placebo in DLQI overall score (18.5
vs. 29.1 points; P=0.009).
Desloratadine treated patients had a significantly
lower mean VQ-Dermato scores vs the placebo
group in daily activities (18.1 vs. 32.6; P=0.001),
mood (7.5 vs. 14.7; P=0.027), social life (10 vs. 21;
P=0.005) and physical pain (42.3 vs. 58.2;
P=0.006) from D1 to end of study.
Desloratadine demonstrated trend toward
significance in a fifth domain, self-image (21.5 vs.
30; P=0.075).
Page 17 of 37
Study
Study Description
Results
questionnaire comprises 28 items in seven domains (selfperception, daily living activity, mood state, social
functioning, leisure activity, treatment induced restriction
and physical discomfort), with each item scored on a scale
of 0 to 4. Total VQ-Dermato scores range from 0 (least
serious effect) to 112 (worst effect).
Monroe E.
et al.
(2003)
Methods: A multicentered, double-blinded, randomized,
placebo-controlled, parallel-group study of desloratadine 5
mg vs placebo in patient with moderate to severe CIU.
Objective: To determine the efficacy (including secondary
efficacy QOL sleep and daily activities parameters) and
safety of desloratadine 5 mg in patients with moderate to
severe CIU.
Population: ITT population consisted of 226 subjects (116
patients in the desloratadine arm vs 110 patients in the
placebo arm).
Primary efficacy measure: The change in average
reflective AM/PM pruritus scores from baseline.
Secondary efficacy outcomes: The reflective average
AM/PM scores for number of hives, size of largest hive, and
total symptom score (sum of pruritus, number of hives,
and size of largest hive scores) as well as, QOL
measurements, interference with sleep (AM reflective), and
interference with daily activities (PM reflective).
There was a significant improvement with
desloratadine for pruritus (58.4% vs 40.4%
placebo; P=0.004), the number of hives (40.8% vs
19.9% placebo; P<0.001), and the size of the
largest hive (39% vs 19.3% placebo; P<0.001);
Desloratadine significantly reduced interference of
CIU on sleep. Days 1 to 8 resulted in a 44.0%
improvement in sleep from baseline compared to a
14.4% improvement in the placebo group
(P=0.007). As early as 24 hours after the first dose,
interference with sleep was improved by 30.6% vs
2.8% for placebo (P=0.044).
Desloratadine significantly reduced interference of
CIU on daily activity performance as early as D2
(40.9% improvement vs 5.6% for placebo group;
P=0.002). The effect was also sustained for the
entire treatment duration (46.9%for desloratadine
vs 17.2% for placebo group; P=0.001).
Lachapelle
JM et al.
2006
Methods: A multicentered, open label study of
desloratadine 5 mg in patient with CIU.
Objective: To assess the effect of once daily desloratadine
5 mg on the QOL of patients suffering from CIU.
Population: ITT population consisted of 121 patients.
Validated QOL measurement tool: DLQI comprises 10
DLQI scores ranging from 0 to 30); pruritus, number and
maximum size of hives, sleep quality and activity
impairment were also assessed.
Desloratadine demonstrated a statistically
significant decrease in the Mean DLQI at baseline,
D7, and D42 (13.4, 9.1, and 6.6 respectively). The
mean proportional scores observed with
desloratadine-treatment at D0, D7 and D42 (44.5%,
30.3%, and 21.9% respectively). The relative
proportional changes from baseline were observed
with desloratadine on both D7 and D42 (-31.6%
and -50.9% respectively). All these changes were
statistically significant (P<0.0001).
A clinically significant change (i.e. a decrease of at
least 2 points) from baseline was observed with
desloratadine for 66% of patients at D7 and 77% of
patient at D42. (P<0.0001)
There was complete relief by D2 in 33.3% of
patients, marked relief by D2 in 35.1% of patients
and approximately 9.6% who experienced no relief.
Pruritus and size of the hives significantly
improved with desloratadine-treatment (P<0.005).
Grob JJ
and
Lachapelle
JM (2008)
Methods: A structured search of the MEDLINE database
was conducted to identify papers published between 1
January 1991 and 30 September 2007 on the treatment of
CIU with the second-generation antihistamines cetirizine,
desloratadine, fexofenadine, and levocetirizine, and their
Desloratadine 5 mg significantly lowered QOL
scores in three studies (n=364) (P<0.05).
Three 6-week double-blind, placebo-controlled
trials (n=553) establish that desloratadine
significantly improved patient-reported pruritus,
Page 18 of 37
Study
Study Description
Results
effects on patient-reported QOL. The Following search
terms were used alone or in combination: ‘chronic
idiopathic urticaria’; ‘pruritus’; ‘wheals’; ‘hives’; ‘secondgeneration antihistamines’; ‘cetirizine’; ‘desloratadine’;
‘fexofenadine’; ‘levocetirizine’; and ‘quality of life’.
Validated QOL measurement tool: DLQI and VQDermato validated instruments.: DLQI comprises 10
DLQI scores ranging from 0 to 30) and VQ-Dermato
questionnaire comprises 28 items in seven domains (selfperception, daily living activity, mood state, social
functioning, leisure activity, treatment induced restriction
and physical discomfort), with each item scored on a scale
of 0 to 4. Total VQ-Dermato scores range from 0 (least
serious effect) to 112 (worst effect).
sleep disruption, and interference with daily
activities (P<0.05).
Significant improvements were observed in QOL
domains such as but not limited to selfconsciousness regarding skin, problems with
partner, and interference of CIU on outdoor
activity, sport, leisure, work/study, and sexual
activity (P<0.0001).
CIU: chronic idiopathic urticaria;
QOL: Quality of Life;
ITT: Intent-To-Treat;
DLQI: Dermatology Life Quality Index;
VQ-Dermato: Questionnaire; reproducible dermatology instrument designed to assess QOL outcomes in French speakers;
RQLQ: French-language version of Rhinoconjunctivitis Quality of Life Questionnaire;
D0: day 0;
D7: day 7;
D42: day 42.
Pediatric Efficacy
Study Results
When given at the recommended doses, the plasma concentration of desloratadine was
comparable in the pediatric (2- 11 years of age) and adult populations (>12 years of age). Thus,
since the course of seasonal allergic rhinitis, perennial allergic rhinitis and chronic idiopathic
urticaria, and the profile of desloratadine are similar in adults and pediatric patients, efficacy data
in adults can be extrapolated to the pediatric population.
Safety Evaluation
A total of 3758 subjects who received AERIUS in clinical programs for the allergic rhinitis and
CIU indications were evaluable for safety. Of these, 3045 were treated with AERIUS in
multiple-dose trials, with 2872 receiving doses of 5 mg or higher.
Page 19 of 37
Study Results
The overall incidence of treatment-related adverse events (AEs) in patients treated with AERIUS
5 mg was comparable to the incidence in patients treated with placebo (15.1% with AERIUS 5
mg vs. 12.5% with placebo).
The most common adverse event thought to be at least possibly related to treatment was
headache. Treatment-related headache was reported in 4.5% of subjects treated with AERIUS 5
mg compared with 3.9% of placebo subjects. There is no significant difference in the safety of
AERIUS among subgroups defined by gender, age or race. There were no indications of any
particular cardiovascular safety concerns during the clinical trials based on adverse events, vital
signs and ECG assessments. No particular safety concerns relevant to the hepatic system were
demonstrated. Overall, the incidence of AEs observed in this program was comparable to
placebo, giving AERIUS an acceptable safety profile.
Very rare cases of hypersensitivity reactions, including anaphylaxis and rash have been reported
during the marketing of desloratadine.
Safety Evaluation - Pediatric
The safety of desloratadine syrup was demonstrated in two pediatric trials involving 231 children
aged 2 -11 years, with a documented history of seasonal allergic rhinitis or chronic idiopathic
urticaria. Of these, 115 children received either a daily desloratadine dose of 1.25 mg (2-5 years
of age; n=55), or 2.5 mg (6-11 years of age, n=60), and 116 received placebo.
Study Results
A total of 2 (1.7%) treatment-related adverse events were reported; 1 each of headache and rash.
Both of these occurred in the desloratadine 1.25 mg 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, treatment was well tolerated as documented by clinical laboratory tests, vital signs, and
ECG interval data, including QTc.
DETAILED PHARMACOLOGY
Preclinical Pharmacology
Desloratadine is an active metabolite of loratadine that possesses qualitatively similar
pharmacodynamic activity with a relative oral potency in animals 2.5 to 4 times greater than
loratadine. In guinea pigs, the antihistamine effect after a single dose of desloratadine lasts 24
hours.
Page 20 of 37
In addition to antihistaminic activity, desloratadine has demonstrated antiallergic and antiinflammatory activity in a number of in vitro (mainly conducted on cells of human origin) and in
vivo studies. These studies have shown that desloratadine inhibits the broad cascade of events
that initiate and propagate allergic inflammation, including:
the release of proinflammatory cytokines including IL-4, IL-6, IL-8 and IL-13,
the release of important proinflammatory chemokines such as RANTES (Regulated upon
Activation, Normal T-cell Expressed and Secreted),
superoxide anion production by activated polymorphonuclear neutrophils,
eosinophil adhesion and chemotaxis,
the expression of the adhesion molecules such as P-selectin,
IgE-dependent release of histamine, prostaglandin (PGD2) and leukotriene (LTC4)
the acute allergic bronchoconstrictor response and allergic cough.
Desloratadine exhibits excellent receptor specificity for histamine H1-receptors. This selectivity
together with a limited entry to the CNS accounts for the little or no sedation liability observed in
clinical studies. Although antimuscarinic activity is significant from in vitro studies, this activity
does not seem to be relevant in vivo where anticholinergic effects are only seen at very high
doses, well in excess of the antihistamine dose.
Reports of serious cardiac arrhythmias with the use of some antihistamines prompted a careful
and extensive evaluation of the cardiovascular safety of desloratadine. Years of clinical
experience with loratadine, and indirectly with desloratadine, indicates that desloratadine has not
been associated with ventricular arrhythmias. Studies with desloratadine in rats, guinea pigs and
monkeys, at multiples of the clinical dose, have confirmed there is no effect on important
components of the ECG such as PR interval, QRS interval or QTc interval. Further studies on
cardiac K+ channels, including the important HERG channel, have shown no effect at 1
micromolar desloratadine concentration, which is well in excess of therapeutic plasma levels.
Pharmacokinetics
In laboratory animals and humans, desloratadine was extensively absorbed (> 90%) following
oral administration. In laboratory animals, accurate exposure estimates to desloratadine were
only obtained at low doses since duration (0-24 hr) of plasma sampling did not allow for an
accurate determination of AUC(0- ). In rats and monkeys, CL/F values for desloratadine
decreased with duration of dosing; however in humans, single dose and multiple dose CL/F
values were the same. The cause for the changes in CL/F in rats and monkeys is unknown. In
all species, exposure to desloratadine was greater following desloratadine administration than
following an equal dose (mg/kg or mg) of loratadine.
The low amounts of desloratadine recovered in urine and feces indicate that, in laboratory
animals and humans (normal metabolizers), desloratadine is metabolically cleared from plasma.
In vivo and in vitro metabolic profiles for desloratadine, loratadine and their metabolites were
obtained in laboratory animals and humans. The metabolic pathways for desloratadine were the
same within each species following 14C-desloratadine and 14C-loratadine administration. The
Page 21 of 37
primary pathways for desloratadine metabolism involved hydroxylation at either the 3-, 5-, or 6positions. All desloratadine metabolites identified in human plasma and excreta following
desloratadine and loratadine administration were also observed in profiles from at least one of
the preclinical species.
The major (>5%) human metabolites of desloratadine were present in all species (mouse, rat,
rabbit, monkey) after exposure to desloratadine and loratadine. In laboratory animals,
hydroxylation was primarily at the 5- and 6-position while in humans hydroxylation occurred
primarily at the 3-position.
Human Pharmacodynamics
Cardiovascular Pharmacodynamics: To confirm the cardiovascular safety of AERIUS
(desloratadine), a study to evaluate the electrocardiographic effects of desloratadine in subjects
(n=24) treated with 45 mg desloratadine (nine times the clinical dose) once daily for 10 days was
conducted. The primary endpoint of this study was the difference between Baseline (Day -1)
maximum ventricular rate, PR, QRS, QT and QTc intervals and the corresponding Day 10
maximum ECG parameters. At 9-fold the proposed clinical dose, there was no statistically or
clinically relevant prolongation of the QTc interval. The mean changes in QTc were 0.3 msec
and 4.3 msec for placebo and desloratadine, respectively (p=0.09; Lower confidence interval
(LCI) = -0.6; Upper confidence interval (UCI) = 8.7). It should be noted that in a separate rising,
multiple dose study in which up to 20 mg of AERIUS was administered daily for 14 days, no
statistically or clinically relevant cardiovascular effects were observed.
Psychomotor Pharmacodynamics: Drowsiness and somnolence, which affect psychomotor
performance, have been reported with first generation antihistamines. The co-administration of
alcohol with such products has resulted in further impairment of psychomotor performance. In a
previous study, CLARITIN (loratadine) did not increase the alcohol-induced impairment in
performance or increase in sleepiness.
In the previously mentioned clinical study, which utilized a 45 mg dose of AERIUS (nine times
the clinical dose) (see Cardiovascular Pharmacodynamics), there were no reports of
somnolence. In a separate randomized, single-dose, double-blind, placebo-controlled, 4-way
crossover study, 25 healthy volunteers were treated with desloratadine 7.5 mg/juice,
desloratadine 7.5 mg/alcohol in juice, placebo tablet/alcohol in juice and placebo tablet/juice.
No significant differences were found in the psychomotor test results between desloratadine and
placebo groups, whether given alone or with alcohol. In a study with Aerius (desloratadine) no
effects on the ability to drive and use machines have been observed. In a separate study in
normal volunteers administered a single dose of 5mg Aerius (desloratadine), no effects on
standard measures of flight performance were observed.
Human Pharmacokinetics
A multiple-dose pharmacokinetic study was conducted at the clinical dose of 5 mg in a large
cohort of subjects (n=112) comprised of a 1:1 ratio of males to females and in which patient
demographics were comparable to those of the general SAR population. Subjects received their
treatment once daily for 10 days. Steady state for desloratadine and 3-hydroxy desloratadine (3-
Page 22 of 37
OH DL) was attained by Day 7. In this study, 4% of the subjects, defined as slow metabolizers,
achieved a higher concentration of desloratadine. Maximum desloratadine concentration was
about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89
hours. In these subjects, desloratadine is cleared from plasma by elimination of parent drug in
urine and feces. The safety profile of these subjects was not different from that of the general
population. The accumulation (R=1.11-1.64) after 14 days of once daily dosing was consistent
with desloratadine half-life (~27 hours) and the once daily dosing frequency.
The influence of sex and race (Caucasian, Black) on the pharmacokinetic parameters (area under
the curve [AUC], maximum concentration [Cmax]) for desloratadine and 3-OH desloratadine
was examined in a second multiple dose study. The mean AUC and Cmax were higher in
females (desloratadine: 3 and 10%, respectively, and 3-OH desloratadine: 48% and 45%,
respectively) compared to males. With regards to race, AUC and Cmax were higher (18% and
32%, respectively) in Blacks than Caucasians. In contrast, the 3-OH desloratadine parameters
were lower (10%). Considering the magnitude of the changes and safety demonstrated following
administration of a dose of 45 mg desloratadine, the increases are not clinically relevant,
therefore, no dosage adjustment is required for race or gender.
The pharmacokinetic profile of desloratadine syrup was evaluated in a three-way crossover study
in 30 adult volunteers. A dose of 10 mL of desloratadine syrup containing 5 mg desloratadine
was bioequivalent to a single 5 mg AERIUS tablet. The Cmax and AUC for desloratadine and 3hydroxy desloratadine were comparable.
Protein Binding: The in vitro protein binding of desloratadine to human plasma protein was
determined by ultrafiltration and ranges between 82.8% to 87.2% over the concentration range of
5 to 400 ng/mL. For this degree of protein binding (free fraction 13%), interactions involving
displacement are not known to be clinically important.
Effect of Food: Results from a single dose food effect study using a 7.5 mg dose of AERIUS
demonstrated 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.
In a three-way crossover study, food (high-fat, high-caloric breakfast) had no effect on the
bioavailability of desloratadine syrup.
Drug-Drug Interactions: Two randomized, two-way crossover, third-party blind, multiple dose
(10 days), placebo-controlled studies characterized the effect of CYP3A4 inhibitors ketoconazole
(N=24) and erythromycin (N=24) on the pharmacokinetics and cardiovascular safety of
AERIUS.
A third study (N=90) with similar design, except comparing parallel groups, investigated the
effect of azithromycin, an azilide antibiotic that also inhibits CYP3A4, on the pharmacokinetics
and cardiovascular pharmacodynamics of AERIUS.
Page 23 of 37
Two additional randomized, multiple dose, parallel group studies investigated the effect of
cimetidine (N=36) and fluoxetine (N=54) on the pharmacokinetics and cardiovascular
pharmacodynamics of AERIUS.
Ketoconazole co-administered 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 increased Cmax and AUC values for
desloratadine by 24% and 14%, respectively. The increases were 43% and 40%, respectively,
for 3-hydroxy desloratadine. Azithromycin co-administered 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 Throughout these studies, there was no
evidence of change in the safety profile of desloratadine, therefore the increases in plasma
concentrations are not considered to be clinically relevant. Ketoconazole induced a small
increase in the plasma desloratadine concentrations compared with those reported for loratadine.
These data suggest that desloratadine has a reduced potential for interacting with inhibitors of
CYP3A4. The similarity of the erythromycin concentrations from this study to previous studies
suggests that desloratadine is unlikely to inhibit the metabolism of substrates of CYP3A4, which
comprise at least 50% of drugs currently marketed. Fluoxetine co-administered 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 for 3-hydroxy desloratadine were increased by 17%
and 13% respectively. Cimetidine co-administered with desloratadine increased Cmax and AUC
values by 12% and 19% respectively and the Cmax and AUC of 3-hydroxy desloratadine were
reduced by 11.2% and 2.8% respectively.
Serial ECG measurements showed no statistically significant or clinically relevant changes in
QTc intervals. Mean changes in QTc were 5.4 msec and 2.3 msec for
ketoconazole/desloratadine and desloratadine/placebo, respectively (p=0.14; LCI = -7.3; UCI=
11). Mean changes in QTc were 9.8 msec and 7.8 msec for erythromycin/desloratadine and
desloratadine/placebo, respectively (p=0.53; LCI = -8.4; UCI = 4.5). Mean changes in QTc were
-4.2 msec and -6.3 msec for desloratadine/Azithromycin and desloratadine/placebo, respectively
(p = 0.61).
Hepatic Dysfunction: In a single-dose (7.5 mg) study, the pharmacokinetics of subjects with
mild, moderate and severe hepatic dysfunction (n=4/group), as defined by the Child-Pugh
Classification (A, B or C), were compared with data from healthy subjects (n=8) without any
evidence of hepatic dysfunction. Within the various subgroups of hepatic dysfunction, there
were no significant differences in pharmacokinetics. Subjects with hepatic dysfunction had
mean AUC and Cmax values up to 2.4 times greater than healthy subjects. The pharmacokinetics
of desloratadine was evaluated in subjects with normal hepatic function (n=9) or moderate
dysfunction (n=11) following once daily administration of desloratadine 5mg for 10 days.
Subjects with hepatic dysfunction could experience a 3-fold increase in exposure (AUC) to
desloratadine. The exposure to 3-OH DL in subjects with hepatic dysfunction was similar to that
in normal subjects. The adverse event profile and electrocardiograms showed no consistent
changes of clinical relevance in any subject with hepatic dysfunction. Since the increased
Page 24 of 37
concentrations are not considered clinically relevant, no dosage adjustment is recommended for
subjects with hepatic dysfunction.
Renal Dysfunction: The pharmacokinetics of AERIUS following a single dose of 7.5 mg was
evaluated in patients with mild (n=7), moderate (n=6), and severe (n=6) renal impairment or
hemodialysis dependent (n=6) patients. There was little difference between the Cmax and AUC
values for subjects with mild and moderate insufficiency. Patients with varying degrees of renal
dysfunction including dialysis dependent subjects experienced a 1.7- to 2.5-fold increase in
desloratadine median AUC with minimal change in 3-hydroxy desloratadine concentrations.
Desloratadine and 3-hydroxy desloratadine were not removed by hemodialysis. Plasma protein
binding of desloratadine and 3-hydroxy desloratadine was unaltered by renal disease. The results
show that patients with varying degrees of renal dysfunction, including those with severe renal
impairment or on dialysis, demonstrated no clinically relevant changes from baseline in
pharmacokinetic parameters. In the case of severe renal insufficiency, AERIUS (desloratadine)
should be used with caution.
Elderly: The pharmacokinetics of AERIUS was evaluated in a subset (n= 17) of subjects >65
years of age who participated in a multiple dose (5 mg once daily x 10 days) study. The mean
AUC and Cmax were 20% greater than in subjects <65 years old. The apparent total body
clearance adjusted for body weight was similar between the two age groups. The mean plasma
elimination half-life was prolonged by approximately 30% (33.7 hours) in subjects > 65 years
old. There was no difference in the adverse event reporting frequency in this group. These age
related changes are not clinically relevant, therefore, no dosage adjustment is warranted in
subjects >65 years of age.
Asthmatics: In 2 four-week studies of 924 patients (aged 15 to 75 years) with seasonal allergic
rhinitis and concomitant asthma, AERIUS 5mg tablets improved rhinitis symptoms, with no
decrease in pulmonary function. This supports the safety of administering AERIUS 5mg tablets
to adult patients with seasonal allergic rhinitis with mild to moderate asthma.
Pediatric Population: In two separate studies, each involving 18 healthy pediatric subjects, the
pharmacokinetics of desloratadine syrup following single oral doses of 1.25 mg (2-5 years) and
2.5 mg (6-11 years) was evaluated. Exposure to 3-hydroxy desloratadine for pediatric subjects
and adults were also comparable. See Table 5 for a summary of the results.
Page 25 of 37
Table 5.
Pharmacokinetics of desloratadine syrup following single oral doses of 1.25 mg (2-5
years) and 2.5 mg (6-11 years) and 5mg (fasted adults)
Parameter
AUCtf (ng.hr/mL)
Cmax (ng/mL)
Tmax (hr)
T1/2 (hr)
Mean (CV%)
A: 41.96 (49)
B: 48.61 (88)
C: 46.22 (71)
A: 2.68 (50)
B: 2.23 (55)
C: 2.30 (51)
A: 3.17 (63)
B: 3.67 (79)
C: 3.58 (45)
A: 16.43 (55)
B: 19.42 (61)
C: 24.03 (23)
Minimum
A: 15.18
B: 13.72
C: 14.90
A: 1.39
B: 1.01
C: 0.94
A: 1.50
B: 1.50
C: 1.00
A: 9.96
B: 10.72
C: 16.11
Maximum
A: 87.07
B: 163.46
C: 192.65
A: 6.96
B: 3.85
C: 6.17
A: 8.00
B: 12.00
C: 5.00
A: 39.17
B: 51.47
C: 41.32
A = P01125 (1.25mg syrup given to 2-5 year old children)
B = P01126 (2.5mg syrup given to 6-11 year old children)
C = P00213 (5mg syrup given to adults under fasted conditions)
MICROBIOLOGY
Not applicable.
TOXICOLOGY
Acute Toxicity
The acute oral (gavage) and intraperitoneal toxicity of desloratadine was evaluated in six week
old Sprague-Dawley rats and CD-1 mice. Estimated oral and intraperitoneal LD50 values in both
rats and mice were significant multiples of a human dose of 5.0 mg desloratadine/day. Oral LD50
values were 3530 and 5490 times the daily human dose in mice and rats respectively.
Intraperitoneal LD50 values were 460 and 680 times a daily human dose in mice and rats,
respectively (Table 6).
Page 26 of 37
Table 6.
Desloratadine LD50 Values
Species
Sex
Route
LD50 Value (mg/kg) (Clin.
Dose Multiple)a
Mouse
Male
PO
353 (3530X)
Female
PO
353 (3530X)
Male
IP
49 (490X)
Female
IP
46 (460X)
Male
PO
616 (6160X)
Female
PO
549 (5490X)
Male
IP
178 (1780X)
Female
IP
68 (680X)
Mouse
Rat
Rat
PO = Oral (gavage); IP = Intraperitoneal
a: Based upon a projected desloratadine clinical dose of 5.0 mg/day (0.10 mg/kg presuming a 50 kg patient).
In an oral (gavage) rising-dose tolerance study in young adult cynomolgus monkeys, emesis was
observed at doses 23.5 and 93.75 mg/kg in males and females, respectively. Emesis
occurred approximately 15 minutes after and/or up to three hours post dose. The maximum dose
that did not produce emesis in male monkeys (11.75 mg/kg) still represents an 118-fold multiple
of the human dose (0.10 mg desloratadine/kg/day), and an 92-fold monkey-to-human systemic
exposure multiple compared to an arithmetic mean Cmax value of 4.0 ng/mL in humans
following a 5.0 mg/day dose of desloratadine.
Repeated-Dose Toxicity
Two-week, one-month and three-month desloratadine studies were conducted in rats at doses of
up to 240 mg/kg for an initial pilot two-week study, up to 8 mg/kg for the second two-week
study and up to 120 mg/kg for one- and three-months. Desloratadine systemic exposure at 60
mg/kg is similar to that achieved with a 120 mg/kg dose of loratadine. The no-effect level for
the three-month study was 3 mg/kg (low-dose) but less than 30 mg/kg. Mortality was
observed in the 30, 60 and 120 mg/kg dose groups and in the comparative control (120 mg
loratadine/kg) dose group in the three-month study. Fecal changes were observed and were
considered related to the anticholinergic effect of this class of compounds. Clinical pathology
changes occurred at desloratadine doses 30 mg/kg (systemic exposure multiple of at least 458
times). The findings associated with target organs/tissues consisted mainly of vacuolation
corresponding to phospholipidosis. Phospholipidosis is a common finding of amphiphilic
compounds like desloratadine and loratadine. Centrilobular hepatocyte hypertrophy occurred at
Page 27 of 37
desloratadine doses of 30 mg/kg and at 120 mg/kg of loratadine. There was no evidence of
phospholipidoses at the 3 mg/kg dose.
Renal tubular cell necrosis and/or renal tubular dilatation were observed at desloratadine doses
60 mg/kg (systemic exposure multiple of at least 605 times) or at a loratadine dose of
120 mg/kg (desloratadine systemic exposure multiple of at least 663 times).
Renal tubular casts were seen in males given either 60 mg/kg of desloratadine or 120 mg/kg of
loratadine. Myofiber degeneration, muscle fibrosis and/or mononuclear infiltrates in muscle
occurred at desloratadine doses of 60 mg/kg and at 120 mg/kg of loratadine. Luminal cellular
debris was seen in the seminiferous tubules of the testes at a desloratadine dose of 60 mg/kg and
at 120 mg/kg dose of loratadine.
Hypospermatogenesis occurred in the testes of one or more males given 120 mg loratadine/kg or
desloratadine doses 30 mg/kg. Luminal cellular debris was present in the epididymides of the
loratadine-dosed males and in the desloratadine-dosed males at doses 30 mg/kg. Oligospermia
was also seen in the epididymides of one male given 30 mg/kg of desloratadine, in one male
given 60 mg/kg of desloratadine, and in some males given 120 mg/kg of desloratadine or
loratadine. However, there were no testicular changes observed in the one-month study at doses
up to 120 mg/kg. Furthermore, these testicular-related changes were consistent with those
previously observed with loratadine at doses as low as 2 mg loratadine/kg in rats but with a
loratadine no effect dose of 1 mg loratadine/kg for similar findings after one year of dosing. This
effect on rat testes has been reported with other antihistamines. With loratadine and
desloratadine, this effect is only observed in rats. In the three-month study, granulosa cell
necrosis was seen in the ovaries of many females given 120 mg/kg of desloratadine and in some
females given 120 mg/kg of loratadine. Uterine immaturity occurred in some females given 60
mg/kg of desloratadine and in many females given 120 mg/kg of desloratadine or loratadine.
A seven-day, a two-week, two one-month and a three-month study were conducted in monkeys
with desloratadine. Desloratadine doses of up to 12 mg/kg (systemic exposure multiple of at
least 182 times) were well tolerated for up to three-months of dosing and was the no-effect dose
in the one-month studies. Doses
36 mg/kg (systemic exposure multiple of at least 842 times)
in the repeat one-month study caused emesis.
In the three-month study, the high dose of 18 mg/kg of desloratadine was increased to 24 mg/kg
and the loratadine dose was increased from 22 mg/kg to 72 mg/kg on Day 36. Clinical signs,
including few or no feces, extended abdomen, hunched posture and/or lethargy, at the 18/24
mg/kg of desloratadine (systemic exposure multiple of at least 953 times) and 22/72 mg/kg of
loratadine (desloratadine systemic exposure multiple of at least 1147 times) doses were attributed
to the anticholinergic effects of this class of compounds. Decreases in serum cholesterol and
alkaline phosphatase were noted in the 18/24 mg/kg desloratadine group and in the 22/72 mg/kg
loratadine group. Evaluation of histopathologic findings from the desloratadine 18/24 mg/kg
dose group suggests that this dose produces phospholipidosis similar to that produced by the
22/72 mg/kg loratadine dose. There was no evidence of phospholipidosis following
desloratadine doses of 6 mg/kg. There were no testicular changes observed in monkeys dosed
Page 28 of 37
for three months at doses up to 18/24 mg desloratadine/kg or 22/72 mg loratadine/kg. In this
three-month study, the only effects observed at the 12 mg/kg dose of desloratadine were
vacuolation in the salivary glands and lungs. A dose of 6 mg/kg (systemic exposure multiple 204
times) was the no-effect dose. The toxicity studies demonstrate adequate exposure multiples at
the no-effect levels and ensure an acceptable safety profile for desloratadine (Table 7).
Table 7. Systemic Exposure of Desloratadine in Animals Following PO Dose Repeated Administration of Desloratadine.
Species
Study
Dose Route/
Gender
AUC(0-24 hr)
(ng hr/mL)
Animal to Human
Exposure Ratio
(5.0 mg/day
human dose)
No-Effect Dose
(mg/kg)
Rat
3 Month Toxicity
(Day 57)
Gavage
3
M
F
1950
1890
34
33
Monkey
2-Week Toxicity
(Day 14)
Gavage
6.5
M,Fa
5115
90
Monkey
1-Month Toxicity
(Day 15)
Gavage
12
M,F
10388
182
Monkey
1-Month Toxicity
Repeat
(Day 15)
Gavage
12
M,F
16002
281
Monkey
3-Month Toxicity
(Day 57)
Gavage
6
M,F
11623
204
a: M,F equals values for males and females combined.
Carcinogenicity
Since animals and humans are exposed to desloratadine through metabolism of loratadine,
carcinogenicity studies conducted with loratadine also assessed the carcinogenic risk of
desloratadine.
In an 18-month carcinogenicity study in mice and a 2-year study in rats, loratadine was
administered in the diet at doses up to 40 mg/kg/day (mice) and 25 mg/kg/day (rats).
Pharmacokinetic assessments were carried out to determine the animal exposure to desloratadine
as well as to loratadine in the carcinogenicity studies. Desloratadine AUC data demonstrated
that the exposure of mice given 40 mg/kg/day loratadine was 33 times higher than in humans
given the maximum recommended daily oral dose of desloratadine. Desloratadine exposure of
rats given 25 mg/kg/day of loratadine was 123 times higher than in humans given the highest
recommended dose of desloratadine (5mg/day). Male mice given 40 mg/kg/day of loratadine
had a significantly higher incidence of hepatocellular tumors (adenomas and carcinomas
combined) than concurrent controls. In rats, a significantly higher incidence of hepatocellular
tumors (adenomas and carcinomas combined) was observed in males given 10 mg/kg/day and in
males and females given 25 mg/kg/day. The liver tumors observed in the loratadine
carcinogenicity studies were considered to be due to nongenotoxic mechanism(s) that were
observed only at high doses of loratadine; thus, these animal carcinogenicity findings were not
Page 29 of 37
considered relevant to humans taking recommended therapeutic doses of either loratadine or
desloratadine.
Mutagenicity
In mutagenicity studies with desloratadine, there was no evidence of mutagenic potential in a
reverse point mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity
assay) or in two assays for chromosomal aberrations (human peripheral blood lymphocyte
clastogenicity assay and mouse bone marrow micronucleus assay).
Reproductive Toxicology
There was no effect on female fertility at doses up to 24 mg/kg/day which produced systemic
exposure levels in female rats which were at least 506 times those in humans given the highest
recommended clinical dose of desloratadine. In a separate study, decreased fertility in male rats
was shown by lower female conception rates associated with decreases in sperm numbers and
motility and histopathologic testicular changes, which occurred at an oral dose of desloratadine
of 12 mg/kg (systemic exposure approximately 175 times higher than in humans given the
maximum recommended dose of desloratadine). Although there was no overall effect on mean
sperm motility or concentration, a few rats given desloratadine at a dose of 3 mg/kg/day
appeared to have testicular findings consistent with those observed previously with loratadine,
which had a no effect dose of 1 mg/kg/day for similar findings after one year of administration.
There was no effect on fertility at 3 mg/kg/day, which produced plasma levels (AUC) in rats that
were 34 times higher than in humans receiving the maximum clinical dose of desloratadine. This
effect on rat testes has been reported with other antihistamines but as with desloratadine and
loratadine, this effect is not observed in other laboratory animal species and appears to be unique
to the rat.
Page 30 of 37
REFERENCES
1. Agrawal DK. Pharmacology and clinical efficacy of desloratadine as an ant-allergic and
anti-inflammatory drug. Exp. Opin. Invest. Drugs. 10, 547-560; 2001.
2. Bachert C. Decongestant efficacy of desloratadine in patients with seasonal allergic
rhinitis. Allergy, Supplement 65. 56, 14-20; 2001.
3. Bachert C. The role of histamine in allergic disease: reappraisal of its inflammatory
potential. Allergy. 57: 287-296; 2002.
4. Bachert C. A Review of the Efficacy of Desloratadine, Fexofenadine, and Levocetirizine
in the Treatment of Nasal Congestion in Patients with Allergic Rhinitis. Clin
Therapeutics. 31(5): 921-44; 2009.
5. Baena-Cagnani C.E. Desloratadine activity in concurrent seasonal allergic rhinitis and
asthma. Allergy. 56, 21-27; 2001.
6. Berger WE, Schenkel EJ, Mansfield LE. Safety and efficacy of desloratadine 5 mg in
asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma
Immunol. 89(5): 485-91; 2002.
7. Berger WE, Lumry WR, Meltzer EO and Pearlman DS. Efficacy of desloratadine, 5 mg,
compared with fexofenadine, 180 mg, in patients with symptomatic seasonal allergic
rhinitis.Allergy Asthma Proc. 24(3): 214-23; 2006.
8. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic
Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World
Health Organization, GA(2)LEN* and AllerGen**). Allergy. 63 (Suppl 86): 8-160; 2008.
9. Day J. Pros and cons of the use of antihistamines in managing allergic rhinitis. J All Clin
Immunol 103:S395-399, 1999.
10. Geha RS, and Meltzer,EO: Desloratadine : A new, nonsedating, oral antihistamine. J
Allergy Clin Immunol. 107, 752-762; 2001.
11. Grob JJ, Auquier P, Dreyfus I, and Ortonne JP. Quality of life in adults with chronic
idiopathic urticaria receiving desloratadine: a randomized, double-blind, multicentre,
placebo-controlled study. J Eur Acad Dermatol Venereol. 22(1): 87-93; 2008.
12. Gupta S, Banfield C, Kantesaria B et al. Pharmacokinetic and Safety Profile of
Desloratadine and Fexofenadine When Coadministered with Azithromycin: A
Randomized, Placebo-Controlled, Parallel-Group Study. Clinical Therapeutics. 23,451466: 2001.
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13. Henz BM: The pharmocological profile of desloratadine: a review. Allergy, Supplement
65. 56:7-13; 2001.
14. Juhlin L. Inhibition of cold urticaria by desloratadine. J Derm Treat. 15:51-54; 2004.
15. Kaplan AP, Gray L, Shaff RE, Horakova Z, and Beaven MA. In vivo studies of mediator
release in cold urticaria and cholinergic urticaria. J Allergy Clin Immunol. 55:394-402;
1975.
16. Kennard CD, Ellis CN. Pharmacological therapy for urticaria. J Am Acad Dermatol
25:176-189, 1991.
17. Kim K, Sussman G, Hebert J, William Lumry W, Lutsky B, and Gates D. Desloratadine
therapy for symptoms associated with perennial allergic rhinitis. Ann Allergy Asthma
Immunol. 96:460–5, 2006.
18. Kreutner W, Hey JA, Anthes J et al. Preclinical pharmacology of desloratadine, a
selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor
selectivity, antihistamine activity and antiallergic effects. Arzneim.-Forsch./Drug Res. 50
(I), 345-352; 2000.
19. Kreutner W, Hey JA, Chiu P et al. Preclinical pharmacology of desloratadine, a selective
and nonsedating histamine H1 receptor antagonist. 2nd communication: Lack of central
nervous system and cardiovascular effects. Arzneim.-Forsch./Drug Res. 50 (I), 441-448;
2000.
20. Lachapelle JM, Decroix J, Henrijean A, Roquet-Gravy PP, De Swerdt A. Boonen H,
Lecuyer M, Suys E, Speelman G, and Vastesaeger N. Desloratadine 5 mg once daily
improves the quality of life of patients with chronic idiopathic urticaria. J Eur Acad
Dermatol Venereol. 20(3):288-92, 2006.
21. McClellan K, and Jarvis B; Desloratadine. Drugs 2001; 61 (6): 789-796.
22. Meltzer E. Comparative safety of H1 antihistamines. Ann Allergy 67:625, 1991.
23. Meltzer EO, Prenner BM, Nayak A, et al: Efficacy and tolerability of once-daily 5 mg
desloratadine, an H1-receptor antagonist, in patients with seasonal allergic rhinitis. Clin
Drug Invest. 21, 25-32; 2001.
24. Meltzer EO, Jalowayski AA, Vogt K, Iezzoni D, and Harris AG. Effect of desloratadine
therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis:
results of a single-center, placebo-controlled trial. Ann Allergy Asthma Immunol. 96:36368, 2006.
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25. Monroe E, Finn A, Patel P, Guerrero R, Ratner P, and Bernstein D. Efficacy and safety of
desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: A doubleblind, randomized, placebo controlled trial*. J Am Acad Dermatol. 48:535-41, 2003.
26. Monroe EW. The role of antihistamines in the treatment of chronic urticaria. J Allergy
Clin Immunol 86:662-665, 1990.
27. Nayak A.S., Schenkel E. Desloratadine reduces nasal congestion in patients with
intermittent allergic rhinitis. Allergy 56, 1077-1080; 2001.
28. Naclerio RM. Allergic rhinitis, N Engl J Med 325:860-869, 1991.
29. Nettis E, Colanardi MC, Soccio AL, Ferrannini A, and Vacca A. Desloratadine in
combination with montelukast suppresses the dermographometer challenge test papule,
and is effective in the treatment of delayed pressure urticaria: a randomized, doubleblind, placebo-controlled study. Br J Dermatol. 155:1279-1282; 2006.
30. Ortonne JP, Grob, JJ, Pascal Auquier P, and Dreyfus I. Efficacy and Safety of
Desloratadine in Adults with Chronic Idiopathic Urticaria: A Randomized, Double-Blind,
Placebo-Controlled, Multicenter Trial. Am J Clin Dermatol. 8(1):37-42, 2007.
31. Pradalier A, Neukirch C, Dreyfus I, and Devillier P. Desloratadine improves quality of
life and symptom severity in patients with allergic rhinitis. Allergy. 62:1331–34, 2007.
32. Ring J, Hein R, Gauger A, Bronsky E, Miller B, et al: Once-daily desloratadine improves
the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind,
placebo-controlled study. Intl J Dermatol. 40:1-5; 2001.
33. Salmun LM and Lorber R. 24-hour efficacy of once-daily desloratadine therapy in
patients with seasonal allergic rhinitis [ISRCTN32042139]. BMC Family Practice . 3:16, 2002.
34. Siebenhaar F, Degener F, Zuberbier T, Martus P, Maurer M. Up-dosing of desloratadine
results in better improvement of temperature and exposure time thresholds in patients
with cold urticaria. Allergy. 63 (Suppl 88):539; 2008.
35. Zuberbier T. Urticaria. Allergy. 58:1224-1234; 2003.
36. Zuberbier T, Ifflander J, Semmler C, Henz BM. Acute urticaria: clinical aspects and
therapeutic responsiveness. Acta Derm Venereol. 76:295-297; 1996.
37. Zuberbier T, Bendslev-Jensen C, Canonica W, Grattan CEH, Greaves MW, Henz BM, et
al. EAACI/GA2LEN/EDF guideline: definition, classification and diagnosis of urticaria.
Allergy. 61:316-320; 2006.
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38. Zuberbier T, Bendslev-Jensen C, Canonica W, Grattan CEH, Greaves MW, Henz BM, et
al. EAACI/GA2LEN/EDF guideline: management of urticaria. Allergy. 61:321-331;
2006.
Page 34 of 37
IMPORTANT: PLEASE READ
AERIUS
Desloratadine Tablet 5 mg
Most people will feel relief of allergy symptoms
within 75 minutes of taking AERIUS or AERIUS
KIDS.
Symptom relief will be maintained for 24 hours.
AERIUS or AERIUS KIDS®
AERIUS or AERIUS KIDS does not cause
drowsiness.
This leaflet is part III of a three-part "Product
Monograph" published when AERIUS or AERIUS
KIDS was approved for sale in Canada and is
designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about
AERIUS or AERIUS KIDS. Contact your doctor or
pharmacist if you have any questions about the drug.
AERIUS or AERIUS KIDS can be used by people
with mild to moderate asthma.
PART III: CONSUMER INFORMATION
ABOUT THIS MEDICATION
What the medication is used for:
AERIUS tablets provide:
fast 24 hour relief from seasonal allergies (trees,
grass, pollen and ragweed) and year round
allergies (dust mites, animal dander and moulds)
resulting in symptoms including nasal congestion,
sneezing, runny nose, itchy nose, stuffiness, itchy
palate, itchy ears, itchy throat and allergic cough,
as well as itchy watery red eyes.
fast relief of allergic skin conditions, such as skin
itch and hives.
AERIUS or AERIUS KIDS syrup provides:
fast 24 hour relief from seasonal allergies (trees,
grass, pollen and ragweed) and year round
allergies (dust mites, animal dander and moulds)
resulting in symptoms including nasal congestion,
sneezing, runny nose, itchy nose, stuffiness, itchy
palate, itchy ears, itchy throat and allergic cough,
as well as itchy watery red eyes.
fast relief of allergic skin conditions, such as skin
itch and hives.
What it does:
AERIUS or AERIUS KIDS is a long-acting
antihistamine – it blocks the action of histamine and
relieves allergy symptoms. Histamine is a chemical
released by the immune system – the body’s defence
against invading substances – when the body is
affected by substances that you are allergic to
(allergens).
When it should not be used:
AERIUS or AERIUS KIDS should not be used:
if you are allergic to desloratadine or to any of the
other product ingredients (See What the
nonmedicinal ingredients are).
if you are pregnant or nursing.
What the medicinal ingredient is:
Desloratadine
What the nonmedicinal ingredients are:
Tablets: Carnauba wax, corn starch, dibasic calcium
phosphate dihydrate, FD&C Blue #2 Lake,
hydroxypropyl methylcellulose, lactose monohydrate,
microcrystalline cellulose, polyethylene glycol, talc,
titanium dioxide, white beeswax.
Syrup: Bubblegum flavour, citric acid anhydrous,
disodium edetate, dye FD&C Yellow No.6,
propylene glycol, purified water, sodium benzoate,
sodium citrate dihydrate, sorbitol solution, sucrose.
What dosage forms it comes in:
Tablet 5 mg or Syrup 0.5 mg/mL
Tell your doctor if you have severe liver or kidney
disease.
BEFORE you use AERIUS or AERIUS KIDS talk
to your doctor or pharmacist if you have:
severe liver disease
severe kidney disease
any allergies to this drug or its ingredients or
components of the container.
Page 35 of 37
INTERACTIONS WITH THIS MEDICATION
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
None of the drugs tested have been found to interact
with AERIUS or AERIUS KIDS.
Symptom / effect
If you are taking any medication, it is important to
ask your physician or pharmacist before taking
AERIUS or AERIUS KIDS.
Only
if
severe
Rare
PROPER USE OF THIS MEDICATION
Usual dose:
AERIUS tablets: Adults and adolescents (12 years
of age and older): Swallow one tablet with water,
once daily, regardless of mealtime.
AERIUS syrup:
Adults and adolescents (12 years of age and older):
Swallow 2 teaspoonfuls (10 mL), once daily,
In case of overdose, contact your Poison Control
Centre, physician or pharmacist immediately, even if
there are no symptoms.
Missed Dose:
If you miss taking your dose on time, do not worry;
take your dose when you remember. Do not exceed
more than one dose in 24 hours.
Allergic reaction
(rash, difficulty
in breathing)
Restlessness
with increased
body movement
Very Rare
Seizures
Liver
dysfunction - i.e.
inflammation of
the liver
(appearance of
jaundice yellowing of the
skin)
Urinary tract
infection
Children 2 to 5 years of age: Swallow 1/2 teaspoonful
(2.5 mL), once daily, regardless of mealtime.
Overdose:
In all
cases
Stop taking
drug and
call your
doctor or
pharmacist
Fast heart rate
or heart
palpitations
AERIUS KIDS syrup:
Children 6 to 11 years of age: Swallow 1 teaspoonful
(5 mL), once daily, regardless of mealtime.
Do not give AERIUS or AERIUS KIDS syrup to
children between 2 and 12 years of age for longer
than 14 days unless recommended by your doctor.
Talk with your
doctor or
pharmacist
Children Uncommon
Fever,
headache, viral
infection,
varicella
(chicken pox),
and rash
This is not a complete list of side effects. For any
unexpected effects while taking AERIUS or
AERIUS KIDS, contact your doctor or pharmacist.
HOW TO STORE IT
Store between 15 and 30 C.
Protect tablets from excessive moisture.
Keep out of reach of children.
SIDE EFFECTS AND WHAT TO DO ABOUT
THEM
Along with its desired effects, AERIUS or AERIUS
KIDS may cause undesirable effects.
Side effects that may occur include, dry mouth,
fatigue and headache.
Page 36 of 37
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions
associated with the use of health products to the
Canada Vigilance Program by one of the following 3
ways:
Report online at www.healthcanada.gc.ca/medeffect
Call toll-free at 1-866-234-2345
Complete a Canada Vigilance Reporting Form and:
Fax toll-free to 1-866-678-6789, or
Mail to:
Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, Ontario
K1A 0K9
Postage paid labels, Canada Vigilance Reporting Form
and the adverse reaction reporting guidelines are
available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the
management of side effects, contact your health
professional. The Canada Vigilance Program does not
provide medical advice.
MORE INFORMATION
This document plus the full product monograph,
prepared for health professionals can be found by
contacting the sponsor, Schering-Plough Canada Inc.,
at:
1-866-241-3891.
This leaflet was prepared by Schering-Plough Canada
Inc.
Last revised: March 26, 2014
®
Registered trademark of MSD
Holdings GmbH Used under license
International
Kirkland (Québec) H9H 4M7
www.aerius.ca
©
2014 Schering-Plough Canada Inc, a subsidiary of
Merck & Co., Inc. All rights reserved.
Page 37 of 37
PRODUCT MONOGRAPH
®
AERIUS DUAL ACTION 12 HOUR™
Desloratadine 2.5 mg / Pseudoephedrine Sulfate 120 mg
Extended Release Tablets
Histamine H1 Receptor Antagonist / Sympathomimetic Amine
Kirkland, Québec
H9H 4M7
Date of Preparation:
June 3, 2009
Submission Control No: 129220
®
/™ Schering-Plough Ltd., used under license by Schering-Plough Canada Inc.
AERIUS DUAL ACTION 12 HOUR Extended Release Tablets
Page 1 of 33
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3
SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE..............................................................................3
CONTRAINDICATIONS ...................................................................................................4
WARNINGS AND PRECAUTIONS..................................................................................4
ADVERSE REACTIONS....................................................................................................6
DRUG INTERACTIONS ....................................................................................................9
DOSAGE AND ADMINISTRATION ..............................................................................11
OVERDOSAGE ................................................................................................................11
ACTION AND CLINICAL PHARMACOLOGY ............................................................12
STORAGE AND STABILITY..........................................................................................16
SPECIAL HANDLING INSTRUCTIONS .......................................................................16
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................16
PART II: SCIENTIFIC INFORMATION ...............................................................................17
PHARMACEUTICAL INFORMATION..........................................................................17
CLINICAL TRIALS..........................................................................................................19
DETAILED PHARMACOLOGY .....................................................................................22
MICROBIOLOGY ............................................................................................................25
TOXICOLOGY .................................................................................................................25
REFERENCES ..................................................................................................................30
PART III: CONSUMER INFORMATION..............................................................................31
Page 2 of 33
®
AERIUS DUAL ACTION™ 12 HOUR
Desloratadine / Pseudoephedrine Sulfate
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
For a complete listing see DOSAGE FORMS,
COMPOSITION AND PACKAGING section.
extended release
tablet* / 2.5 mg
desloratadine & 120
mg pseudoephedrine
sulfate
*desloratadine is for immediate release and pseudoephedrine sulfate is for extended release,
allowing for twice-daily oral administration
oral
INDICATIONS AND CLINICAL USE
®
AERIUS DUAL ACTION 12 HOUR (desloratadine/pseudoephedrine sulfate) is indicated for:
$
The symptomatic treatment of seasonal allergic rhinitis including rhinorrhea, nasal
itching and sneezing, itching/burning eyes, tearing/watering eyes, redness of the eyes,
and itching of the ears or palate when accompanied by nasal congestion.
AERIUS DUAL ACTION 12 HOUR is not recommended for use in pregnant or lactating
women.
AERIUS DUAL ACTION 12 HOUR is not recommended for use in patients with severe hepatic
or renal impairment.
AERIUS DUAL ACTION 12 HOUR should be administered when the antihistaminic properties
of desloratadine and the nasal decongestant activity of pseudoephedrine are desired.
Geriatrics ( 65 years of age):
AERIUS DUAL ACTION 12 HOUR should be used with caution in patients 65 years of age and
above.
Pediatrics (<12 years of age):
AERIUS DUAL ACTION 12 HOUR is not recommended for use in children below the age of
12 years due to lack of data on safety and efficacy.
Page 3 of 33
CONTRAINDICATIONS
Patients who are hypersensitive to this drug or to any ingredient in the formulation or
component of the container. For a complete listing, see the DOSAGE FORMS,
COMPOSITION AND PACKAGING section of the product monograph.
Patients who are hypersensitive to adrenergic agents or to loratadine.
Due to its pseudoephedrine content, it is also contraindicated in patients:
who are receiving irreversible monoamine oxidase (MAO) inhibitor therapy or during the
2 weeks following the stopping of such treatment (see DRUG INTERACTIONS)
with narrow-angle glaucoma
with urinary retention
with cardiovascular diseases such as severe coronary artery disease, tachyarrhythmia and
severe hypertension
with hyperthyroidism
with a history of haemorrhagic stroke or with risk factors which could increase the risk of
haemorrhagic stroke.
AERIUS DUAL ACTION 12 HOUR is not recommended for use in patients with severe
hepatic or renal impairment.
General
Do not exceed the recommended dosage and the duration of treatment.
Do not use concurrently with other over-the counter antihistamines and decongestants.
Cardiovascular
Use with caution in patients with cardiovascular disease and hypertension. Treatment should be
discontinued in case of hypertension, tachycardia, palpitations or cardiac arrhythmias.
Dependence/Tolerance
As with other CNS stimulants, pseudoephedrine sulfate carries the risk of abuse. Increased doses
may ultimately produce toxicity. Continuous use can lead to tolerance and an increased risk of
overdosing. Depression may follow rapid withdrawal.
Endocrine and Metabolism
Use with caution in patients with diabetes mellitus.
Gastrointestinal
Use with caution in patients with stenosing peptic ulcer and pyloroduodenal obstruction.
Page 4 of 33
Genitourinary
Use with caution in patients with hypertrophy of the prostate or bladder neck obstruction.
Hepatic/Biliary/Pancreatic
The safety and efficacy of AERIUS DUAL ACTION 12 HOUR has not been established in
patients with impaired hepatic function, and there are insufficient data to give adequate dose
recommendations. The combination product is not recommended for use in patients with
impaired hepatic function (See ACTION AND CLINICAL PHARMACOLOGY).
In a desloratadine single-dose (7.5 mg) pharmacokinetic study, subjects with mild to severe
hepatic dysfunction had mean AUC and Cmax values up to 2.4 times higher than healthy subjects.
Desloratadine 5mg was administered for 10 days to subjects with normal hepatic function or
moderate dysfunction. Subjects with hepatic dysfunction could experience a 3-fold increase in
exposure (AUC) to desloratadine. These findings are not considered to be clinically relevant.
Neurologic
Treatment should be discontinued in case of nausea or any other neurologic sign (such as
headache or increased headache).
Ophthalmologic
Use with caution in patients with glaucoma and increased intraocular pressure.
Peri-Operative Considerations
If surgery is scheduled, discontinue treatment 24 hours before anaesthesia.
Renal
The safety and efficacy of AERIUS DUAL ACTION 12 HOUR has not been established in
patients with impaired renal function, and there are insufficient data to give adequate dose
recommendations. The combination product is not recommended for use in patients with
impaired renal function (see ACTION AND CLINICAL PHARMACOLOGY).
In a desloratadine single-dose (7.5 mg) pharmacokinetic study, subjects (n=25) with varying
degrees of renal insufficiency (mild, moderate, severe and hemodialysis) had 1.2 to 2.5 fold
increases in desloratadine median AUC with minimal change in 3-hydroxy desloratadine
concentrations. However, these findings are not considered to be clinically relevant.
Special Populations
Pregnant Women: The safe use of AERIUS DUAL ACTION 12 HOUR during pregnancy has
not been established. The use of pseudoephedrine decreases maternal blood flow. The use of
AERIUS DUAL ACTION 12 HOUR is not recommended for pregnant women.
Nursing Women: Desloratadine and pseudoephedrine are both excreted in breast milk,
therefore the use of AERIUS DUAL ACTION 12 HOUR is not recommended for women who
are breast-feeding.
Page 5 of 33
Pediatrics§ (< 12 years of age): AERIUS DUAL ACTION 12 HOUR is not recommended for
use in children below the age of 12 years due to lack of data on safety and efficacy.
Geriatrics§ ( 65 years of age): The number of patients 65 years of age and above treated with
AERIUS DUAL ACTION 12 HOUR were too limited to make any clinically relevant judgement
regarding efficacy or safety of this drug product in this age group. Patients of 65 years or older
are more likely to experience adverse reactions from sympathomimetic medicinal products.
Therefore the combination product should be used with caution in patients above 65 years of age
(See ACTION AND CLINICAL PHARMACOLOGY).
§
CNS stimulations with convulsions or cardiovascular collapse with accompanying hypotension
may be produced by sympathomimetic amines. These effects may be more likely to occur in
children or elderly patients.
Athletes: Athletes should be informed that treatment with pseudoephedrine could lead to
positive doping tests.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
Very rare cases of hypersensitivity reactions including anaphylaxis and rash have been reported
psychomotor hyperactivity, seizures, elevations of liver enzymes, hepatitis and increased
As with other sympathomimetic amines, central nervous system stimulation, muscular weakness,
tightness in the chest and syncope may also be encountered with the use of pseudoephedrine
sulfate.
Page 6 of 33
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events and for approximating rates.
A total of 1248 subjects, 12 years of age and older were randomized in two Phase-3 studies and
received at least one dose of study drug. All subjects were included in the safety evaluation
presented in Table 1, demonstrating adverse events 1%.
Table 1 - Incidence of Adverse Events Reported by
HOUR Extended Release Tablets
1% of Patients Receiving AERIUS DUAL ACTION 12
DL 2.5mg / PSE 120 mg QD
n= 414
(%)
DL, 5mg QD
n= 412
(%)
PSE, 120mg BID
n= 422
(%)
abdominal pain
1
2
1
anorexia
2
0
2
constipation
2
0
1
diarrhea
0
2
1
dyspepsia
1
2
1
nausea
2
1
3
vomiting
General Disorders
0
1
0
back pain
1
1
1
chest pain
0
1
1
fatigue
4
2
2
fever
1
1
0
headache
8
8
9
palpitation
1
0
2
tachycardia
Musculoskeletal System
1
0
1
arthralgia
1
1
1
myalgia
1
2
1
Gastrointestinal
Heart Rate and Rhythm Disorders
Page 7 of 33
Table 1 - Incidence of Adverse Events Reported by
HOUR Extended Release Tablets
1% of Patients Receiving AERIUS DUAL ACTION 12
DL 2.5mg / PSE 120 mg QD
n= 414
(%)
DL, 5mg QD
n= 412
(%)
PSE, 120mg BID
n= 422
(%)
dry mouth
8
2
8
dizziness
3
2
2
psychomotor hyperactivity
Psychiatric
2
1
1
agitation
1
0
1
insomnia
10
3
13
nervousness
1
0
3
sleep disorder
1
0
2
somnolence
Reproductive System
3
4
2
dysmenorrhea
0
1
0
vaginitis
Resistance Mechanism
0
1
0
Infection viral
Respiratory System
2
2
2
coughing
2
1
1
epistaxis
1
1
1
pharyngitis
3
3
3
sinusitis
<1
1
3
upper respiratory tract infection
Urinary System
0
2
2
urinary tract infection
Vision
0
2
1
dry eyes
DL = desloratadine; PSE = pseudoephedrine sulfate
1
1
0
Nervous System
In all clinical studies conducted, AERIUS DUAL ACTION 12 HOUR was safe and well
tolerated. In Phase-3 studies, the overall incidence of adverse events was similar in AERIUS
DUAL ACTION 12 HOUR and pseudoephedrine treatment groups, but was lower in the
desloratadine group. The most common treatment-emergent adverse events of AERIUS DUAL
ACTION 12 HOUR were insomnia, headache and dry mouth.
Page 8 of 33
Less Common Clinical Trial Adverse Drug Reactions (< 1%) with AERIUS DUAL
ACTION 12 HOUR
Cardiovascular: palpitation, premature atrial contractions
Dermatological: pruritus
Gastrointestinal: abdominal pain, gastroenteritis, nausea, stool abnormal
General: aggravated headache, rigors
Hepatobiliary: increased hepatic enzymes
Metabolism and Nutrition: glycosuria, hyperglycemia, thirst
Nervous System: hyperkinesias, hot flashes, confusion
Ophthalmic: blurred vision, dry eyes
Psychiatric: agitation, anxiety, irritability
Renal and Urinary: dysuria, micturition disorder, altered micturition frequency
Respiratory, Thoracic and Mediastinal: epistaxis, nasal irritation, rhinitis, rhinorrhea,
sinusitis, dry throat, hyposmia
Abnormal Hematologic and Clinical Chemistry Findings
None to report.
Post-Market Adverse Drug Reactions
Very rare cases of hypersensitivity reactions (including anaphylaxis and rash), tachycardia,
palpitations, psychomotor hyperactivity, seizures, elevation of liver enzymes, hepatitis and
increased bilirubin have been reported during the marketing of desloratadine.
DRUG INTERACTIONS
Overview
Concomitant administration of sympathomimetics and reversible MAO inhibitors are not
recommended.
Caution should be exercised in patients being treated with other
sympathomimetics, including decongestants, anorexogenics or amphetamine-type
psychostimulants, antihypertensive agents, tricyclic antidepressants and other antihistamines.
Caution should be exercised in patients receiving digitalis.
Antacids increase the rate of pseudoephedrine sulfate absorption, kaolin decreases it.
Drug-Drug Interactions
Interaction studies with AERIUS DUAL ACTION 12 HOUR and other medicinal products have
not been conducted, however no clinically relevant interactions were observed in clinical trials
with desloratadine in which azithromycin, erythromycin, ketoconazole, fluoxetine or cimetidine
were co-administered.
Page 9 of 33
Table 2 - Established or Potential Drug-Drug Interactions
<Proper name>
Ref
Effect
Clinical comment
Reversible and
irreversible MAO
inhibitor(s)
T
May cause risk of
vasoconstriction and increased
blood pressure.
n/ap
sympathomimetic
medicines
T
May result in critical
hypertension reactions.
n/ap
Bromocriptine,
cabergoline, lisuride,
pergolide
T
Risk of vasoconstriction and
increase in blood pressure
n/ap
Dihydroergotamine,
ergotamine,
methylergometrine
T
Risk of vasoconstriction and
increase in blood pressure
n/ap
Vasoconstrictors used as
T
Risk of vasoconstriction
nasal decongestant
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical
n/ap
Drug-Food Interactions
Food had no significant effect on the bioavailability (Cmax and AUC) of desloratadine and
pseudoephedrine.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
The administration of AERIUS DUAL ACTION 12 HOUR should be discontinued at least 48
hours before skin tests since antihistamines may prevent or reduce otherwise positive reactions to
dermal reactivity index.
Athletes should be informed that treatment with pseudoephedrine could lead to positive doping
tests.
Drug-Lifestyle Interactions
The interaction with AERIUS DUAL ACTION 12 HOUR and alcohol has not been established,
however in a clinical pharmacology trial, desloratadine taken concomitantly with alcohol did not
potentiate the performance impairing effects of alcohol.
No studies on the effects on the ability to drive and use machines have been performed with
AERIUS DUAL ACTION 12 HOUR. However, in clinical trials that assessed the driving
ability, no impairment occurred in patients receiving desloratadine. However, patients should be
informed that very rarely some people experience drowsiness, which may affect their ability to
drive or use machines.
It is not expected that pseudoephedrine sulfate impairs psychomotor performance.
Page 10 of 33
DOSAGE AND ADMINISTRATION
Dosing Considerations
The duration of the treatment should be kept as short as possible and should not be continued
after the symptoms have disappeared. It is advisable to limit treatment to about 14 days, as
during chronic administration the activity of pseudoephedrine diminishes with time.
Recommended Dose and Dosage Adjustment
Adults and adolescents 12 years of age and over: The recommended dose of AERIUS DUAL
ACTION 12 HOUR is one tablet twice a day, administered approximately 12 hours apart.
After improvement of the congestive condition of the mucosae of the upper airway, treatment
may be maintained with desloratadine alone, if necessary.
Administration
The tablet may be taken with a full glass of water but must be swallowed whole (without
crushing, breaking or chewing it). The tablet may be taken with or without a meal.
OVERDOSAGE
Symptoms of overdose are mostly of a sympathomimetic nature. Symptoms may vary from CNS
depression (sedation, apnoea, diminished mental alertness, cyanosis, coma, cardiovascular
collapse) to CNS stimulation (insomnia, hallucination, tremors, convulsions) with possible fatal
outcome. Other symptoms may include: headache, anxiety, micturition difficulty, muscle
weakness and tenseness, euphoria, excitement, respiratory failure, cardiac arrhythmias,
tachycardia, palpitations, thirst, perspiration, nausea, vomiting, precordial pain, dizziness,
tinnitus, ataxia, blurred vision and hypertension or hypotension. CNS stimulation is particularly
likely in children, as are atropine-like symptoms (dry mouth, fixed and dilated pupils, flushing,
hyperthermia, and gastrointestinal symptoms). Some patients may present a toxic psychosis with
delusions and hallucinations.
Treatment: In the event of overdose, consider standard measures to remove any unabsorbed drug.
Symptomatic and supportive treatment is recommended. Adsorption of active substance
remaining in the stomach may be attempted by administration of active charcoal suspended in
water. Perform gastric lavage with physiologic saline solution, particularly in children. In adults,
tap water can be used. Remove as much as possible of the amount administered before the next
instillation. Desloratadine is not removed by haemodialysis and it is not known if it is eliminated
by peritoneal dialysis. After emergency treatment, continue to monitor the patient medically.
AERIUS (desloratadine) administered at a dose of 45 mg daily (nine times the clinical dose) for
ten days showed no statistically or clinically relevant prolongation of the QTc interval. The
mean changes in QTc were 0.3 msec and 4.3 msec for placebo and desloratadine, respectively
(p=0.09; Lower confidence interval (LCI) = -0.6; Upper confidence interval (UCI) = 8.7).
Page 11 of 33
Treatment of the pseudoephedrine overdosage is symptomatic and supportive. Stimulants
(analeptics) must not be used. Hypertension can be controlled with an alpha-blocking agent and
tachycardia with a beta-blocking agent. Short acting barbituates, diazepam or paraldehyde may
be administered to control seizures. Hyperpyrexia, especially in children, may require treatment
with tepid water sponge baths or hypothermia blanket. Apnoea is treated with respiratory
assistance.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Desloratadine is a non-sedating long acting antihistamine with selective peripheral histamine H1receptor antagonist activity, which has demonstrated antiallergic, antihistaminic and antiinflammatory activity.
Pseudoephedrine sulfate is the synthetic salt of one of the naturally occurring dextrorotatory
diastereomer of ephedrine and classified as an indirect sympathomimetic amine. It provides a
nasal decongestant effect after oral administration due to its vasoconstrictive action and produces
a gradual but sustained decongestant effect, facilitating shrinkage of congested mucosa in upper
respiratory areas.
Pharmacodynamics
After oral administration, desloratadine selectively blocks peripheral histamine H1-receptors as
the drug is effectively excluded from entry into the central nervous system. Receptor binding
data indicate that at a concentration of 2-3 ng/mL, desloratadine shows significant interaction
with the human histamine H1 receptor. Desloratadine inhibited histamine release from human
mast cells in vitro.
Pseudoephedrine sulfate is a sympathomimetic agent with mostly -adrenergic activity. It has
an indirect sympathomimetic effect due primarily to the release of adrenergic mediators from the
post-ganglionic nerve endings. Oral administration of pseudoephedrine at the recommended
dose can cause other sympathomimetic effects, such as increased blood pressure, tachycardia or
manifestations of central nervous system excitation.
Pharmacokinetics
Absorption: In a single dose pharmacokinetic study with AERIUS DUAL ACTION 12 HOUR,
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. For pseudoephedrine, the mean Tmax occurred at 6-7 hours post dose
and mean peak plasma concentrations (Cmax and AUC) of approximately 263 ng/ml and
4,588 ng•hr/ml, respectively, were observed. Food had no effect on the bioavailability (Cmax and
AUC) of desloratadine or pseudoephedrine.
Page 12 of 33
Following oral administrations of AERIUS DUAL ACTION 12 HOUR 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. Similar values of
DSL and PSE for AUC and Cmax between the 0-12 hour and 12-24 hour intervals indicates a
lack of diurnal variation.
In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability
(Cmax and AUC) of desloratadine.
Distribution: Desloratadine is moderately bound, 83% to 87%, to plasma proteins. Protein
binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired
renal function.
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 cannot 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. In pharmacokinetic
and clinical trials in subjects between 2 and 70 years of age, 6 % of the subjects were poor
metabolizers of desloratadine and reached a higher desloratadine concentration (poor metabolizer
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). In this data, no difference in
prevalence of poor metabolizers was noted across age groups, but the frequency was higher in
Blacks (18%) compared to Caucasians (2%) or Hispanics (2%). 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. The desloratadine
exposure (AUC) associated with the poor 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 poor metabolizers was
31.9 (14-74) ng•hr/mL and 116 (72-210) ng•hr/mL, respectively. The corresponding values for
adult normal and poor metabolizers were 33.5 (8.7-99) ng•hr/mL and 139 (82-393) ng•hr/mL,
respectively. In adults characterized as poor 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
Page 13 of 33
children. The safety profile of adult and pediatric poor metabolizers of desloratadine was not
different from that of the general population.
Following administration of desloratadine 5mg for 28 days, the approximate two-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
AERIUS (5 mg to 20 mg) for 14 days.
Excretion A human mass balance study documented a recovery of approximately 87% of the
14
C-desloratadine dose, which was equally distributed in urine and feces as metabolic products.
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. The
active substance and its metabolite are excreted in urine; 55-75% of the administered dose is
excreted unchanged.
Special Populations and Conditions
Pediatrics: AERIUS DUAL ACTION 12 HOUR Extended Release Tablets are not an
appropriate dosage form for use in pediatric patients below 12 years of age.
Geriatrics: The number of patients (n=10) 65 years of age and above treated with AERIUS
DUAL ACTION 12 HOUR 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 AERIUS® (desloratadine) 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.
Gender:
No clinically significant gender-related differences were observed in the
pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine or pseudoephedrine
following administration of AERIUS DUAL ACTION 12 HOUR Extended Release Tablets.
Female subjects treated for 14 days with AERIUS® Tablets had 10% and 3% higher
desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3hydroxydesloratadine 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.
Page 14 of 33
Race: No studies have been conducted to evaluate the effect of race on the pharmacokinetics of
AERIUS DUAL ACTION 12 HOUR Extended Release Tablets. Following 14 days of treatment
with AERIUS® 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.
Hepatic Insufficiency: No studies with AERIUS DUAL ACTION 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 ChildPugh 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.
AERIUS DUAL ACTION 12 HOUR Extended Release Tablets is not recommended in patients
with severe hepatic impairment (see WARNINGS AND PRECAUTIONS).
Renal Insufficiency: No studies with AERIUS DUAL ACTION 12 HOUR 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.
Page 15 of 33
AERIUS DUAL ACTION 12 HOUR Extended Release Tablets is not recommended in patients
with severe renal impairment (see WARNINGS AND PRECAUTIONS).
STORAGE AND STABILITY
Temperature and Moisture
Store between 15 and 30°C.
Protect from excessive moisture.
Protect from light.
Others
Keep in a safe place out of the reach of children.
SPECIAL HANDLING INSTRUCTIONS
Keep blister package in the outer carton.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Dosage Form
Extended release tablet for oral administration.
Composition
Blue and white bilayer oval tablet with “D12” branded to the blue layer.
Medicinal Ingredients: 2.5 mg desloratadine in the blue immediate-release layer and 120 mg
pseudoephedrine sulfate, USP in the white extended-release layer which is released slowly.
Non medicinal ingredients (in alphabetical order): citric acid anhydrous, corn starch, edetate
disodium, FD&C Blue No. 2 aluminum lake dye, hypromellose, povidone, magnesium stearate,
microcrystalline cellulose, silicon dioxide and stearic acid
Packaging:
AERIUS DUAL ACTION 12 HOUR is supplied in unit dose blisters comprised of laminate
blister film and foil lidding. The blister is packaged in a folding carton.
Available in packs of 2 (physician sample), 4, 7, 10, 14, 20 and 30 tablets.
Page 16 of 33
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance (1 of 2)
Proper name:
desloratadine
Chemical name:
8-chloro-6, 11-dihydro-11-(4-piperidinylidene)-5H-benzo-[5,6] cyclohepta
[1, 2-b]pyridine
Molecular formula:
C19H19CIN2
Molecular mass:
310.8
Structural formula:
Cl
N
N
H
Physicochemical properties:
Physical Form:
white to off-white powder
Solubility:
ethanol
methylene chloride
methanol
octanol
0.1N HCl
DMSO
water
pH 7.4 phosphate buffer
0.1N NaOH
0.1mg/mL (very slightly soluble)
1.5 mg/mL (slightly soluble)
<0.1 mg/mL (practically insoluble)
pKa Values:
pyridine functional group
piperidine functional group
4.2
9.7
Page 17 of 33
Partition Coefficient:
Melting Point:
log KO/W
n-octanol/0.1N HCl
-2.27
-1.44
0.342
1.02
0.944
Form I
156.0 to 157.5 C
Drug Substance (2 of 2)
Proper name:
pseudoephedrine sulfate
Chemical name:
benzenemethanol, - [1-(methylamino) ethyl]-, S-(R*, R*)]-, sulfate (2:1)
(salt)
Molecular formula:
(C10H15NO)2 H2SO4
Molecular mass:
428.54
Structural formula:
Physicochemical properties: Pseudoephedrine sulfate is a colourless hygroscopic crystal or
white, hygroscopic crystalline powder, practically odourless, with
a bitter taste. It is very soluble in alcohol and sparingly soluble in
ether.
Page 18 of 33
CLINICAL TRIALS
The clinical efficacy and safety of AERIUS DUAL ACTION 12 HOUR 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 AERIUS DUAL ACTION 12 HOUR Extended Release Tablets. In the two trials
patients were randomized to receive AERIUS DUAL ACTION 12 HOUR Extended Release
Tablets twice daily, AERIUS® 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 AERIUS DUAL ACTION 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 AERIUS DUAL ACTION 12 HOUR Extended Release Tablets, as
measured by nasal stuffiness/congestion, was significantly greater than desloratadine alone over
the 2-week treatment period. Clinical trial summary is presented in Table 3. Primary efficacy
variable results are shown in Tables 4 and 5.
Table 3 - Summary of Efficacy and Safety Studies using AERIUS DUAL ACTION 12 HOUR in patients with
Seasonal Allergic Rhinitis
Study #
Trial design
Dosage, route of
administration and
duration
P00355
Randomized, parallelgroup, Multicenter,
double-blind, activecontrolled study
Subjects received
AERIUS D-12 HOUR
BID, DL 5.0 mg QD or
PSE 120 mg BID orally
for 15 days.
598
Randomized, parallelgroup, Multicenter,
double-blind, activecontrolled study
Subjects received
AERIUS D-12 HOUR
BID, DL 5.0 mg QD or
PSE 120 mg BID orally
for 15 days.
650
P00362
Study subjects
(n=number)
Mean age
(Range)
12 - 76
Gender
224 Males
374 Females
12 - 78
221 Males
429 Females
Page 19 of 33
Study results
Table 4 - Primary Endpoint Results of study P00355: Changes in Symptoms in a 2-week Clinical Trial in
Patients with Seasonal Allergic Rhinitis
Treatment Group (n)
Mean Baseline*
Change (% change) from
Baseline**
AERIUS DUAL ACTION
12 HOUR comparison to
components *** (p-value)
Total Symptom Score (Excluding Nasal Congestion)
AERIUS DUAL
ACTION 12 HOUR
Extended Release
Tablets BID (199)
14.18
-6.54 (-46.0)
-
Desloratadine Tablet
5 mg QD
(197)
14.82
-5.09 (-33.5)
P <0.001
Pseudoephedrine Tablet
120 mg BID
(197)
14.06
-5.07 (-35.9)
P <0.001
Nasal Stuffiness/Congestion
AERIUS DUAL
ACTION 12 HOUR
Extended Release
Tablets BID (199)
2.47
-0.93 (-37.4)
-
5 mg QD
(197)
2.50
-0.66 (-26.7)
P <0.001
2.46
-0.75 (-31.2)
P = 0.006
120 mg BID
(197)
*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 43 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.
Page 20 of 33
Table 5 - Primary Endpoint Results of study P00362: 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)
AERIUS DUAL ACTION
12 HOUR comparison to
components *** (p-value)
Total Symptom Score (Excluding Nasal Congestion)
AERIUS DUAL
ACTION 12 HOUR
Extended Release
Tablets BID (213)
15.19
-6.65 (-43.0)
-
5 mg QD
(212)
14.66
-5.35 (-36.1)
P = 0.001
120 mg BID
(221)
14.86
-5.28 (-35.4)
P <0.001
Nasal Stuffiness/Congestion
AERIUS DUAL
ACTION 12 HOUR
Extended Release
Tablets BID (214)
2.55
-0.92 (-36.0)
-
5 mg QD
(213)
2.56
-0.73 (-28.9)
P = 0.005
2.56
-0.83 (-31.8)
P = 0.167
120 mg BID
(221)
*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 43 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 if 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.
AERIUS DUAL ACTION 12 HOUR significantly relieved rhinorrhea, nasal
stuffiness/congestion, nasal itching and sneezing, itching/burning eyes, tearing/watering eyes,
redness of the eyes, and itching of the ears or palate to a greater extent than either component
alone. DL and PSE each improved nasal stuffiness/congestion to a similar degree (no
statistically significant difference). Additionally, rhinitis symptoms were reduced as early as
after the first day’s dosing and the effects of the dose were maintained over the 12-hour dosing
period.
There were no significant differences in the efficacy of AERIUS DUAL ACTION 12 HOUR
Extended Release Tablets across subgroups of patients defined by gender, age, or race.
Page 21 of 33
DETAILED PHARMACOLOGY
Pre clinical studies of desloratadine in combination with pseudoephedrine sulfate have not been
conducted. However, non-clinical data with desloratadine reveal no special hazard for humans
based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and
toxicity to reproduction. The lack of carcinogenic potential was demonstrated in studies
conducted with desloratadine and loratadine.
Preclinical Pharmacology
In addition to antihistaminic activity, desloratadine has demonstrated antiallergic and antiinflammatory activity in a number of in vitro (mainly conducted on cells of human origin) and in
vivo studies. These studies have shown that desloratadine inhibits the broad cascade of events
that initiate and propagate allergic inflammation, including:
the release of proinflammatory cytokines including IL-4, IL-6, IL-8 and IL-13,
the release of important proinflammatory chemokines such as RANTES (Regulated upon
Activation, Normal T-cell Expressed and Secreted),
superoxide anion production by activated polymorphonuclear neutrophils,
eosinophil adhesion and chemotaxis,
the expression of the adhesion molecules such as P-selectin,
IgE-dependent release of histamine, prostaglandin (PGD2) and leukotriene (LTC4)
the acute allergic bronchoconstrictor response and allergic cough.
Desloratadine exhibits excellent receptor specificity for histamine H1-receptors. This selectivity
together with a limited entry to the CNS accounts for the little or no sedation liability observed in
clinical studies. Although antimuscarinic activity is significant from in vitro studies, this activity
does not seem to be relevant in vivo where anticholinergic effects are only seen at very high
doses, well in excess of the antihistamine dose.
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.
Reports of serious cardiac arrhythmias with the use of some antihistamines prompted a careful
and extensive evaluation of the cardiovascular safety of desloratadine. Years of clinical
experience with loratadine, and indirectly with desloratadine, indicates that desloratadine has not
been associated with ventricular arrhythmias. Studies with desloratadine in rats, guinea pigs and
monkeys, at multiples of the clinical dose, have confirmed there is no effect on important
components of the ECG such as PR interval, QRS interval or QTc interval. Further studies on
cardiac K+ channels, including the important HERG channel, have shown no effect at 1
micromolar desloratadine concentration, which is well in excess of therapeutic plasma levels.
Page 22 of 33
Pharmacokinetics
In laboratory animals and humans, desloratadine was extensively absorbed (> 90%) following
oral administration. In laboratory animals, accurate exposure estimates to desloratadine were
only obtained at low doses since duration (0-24 hr) of plasma sampling did not allow for an
accurate determination of AUC (0- ). In rats and monkeys, CL/F values for desloratadine
decreased with duration of dosing; however in humans, single dose and multiple dose CL/F
values were the same. The cause for the changes in CL/F in rats and monkeys is unknown. In
all species, exposure to desloratadine was greater following desloratadine administration than
following an equal dose (mg/kg or mg) of loratadine.
The low amounts of desloratadine recovered in urine and feces indicate that, in laboratory
animals and humans (normal metabolizers), desloratadine is metabolically cleared from plasma.
In vivo and in vitro metabolic profiles for desloratadine, loratadine and their metabolites were
obtained in laboratory animals and humans. The metabolic pathways for desloratadine were the
same within each species following 14C-desloratadine and 14C-loratadine administration. The
primary pathways for desloratadine metabolism involved hydroxylation at either the 3-, 5-, or 6positions. All desloratadine metabolites identified in human plasma and excreta following
desloratadine and loratadine administration were also observed in profiles from at least one of
the preclinical species.
The major (>5%) human metabolites of desloratadine were present in all species (mouse, rat,
rabbit, monkey) after exposure to desloratadine and loratadine. In laboratory animals,
hydroxylation was primarily at the 5- and 6-position while in humans hydroxylation occurred
primarily at the 3-position.
Human Pharmacodynamics
Wheal and Flare: Desloratadine 5mg 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.
Effects on QTc: In clinical trials for AERIUS DUAL ACTION 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 AERIUS DUAL ACTION 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 AERIUS DUAL ACTION 12 HOUR
Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of
3.2 bpm in patients receiving desloratadine alone.
Cardiovascular Pharmacodynamics: To confirm the cardiovascular safety of AERIUS
(desloratadine), a study to evaluate the electrocardiographic effects of desloratadine in subjects
(n=24) treated with 45 mg desloratadine (nine times the clinical dose) once daily for 10 days was
Page 23 of 33
conducted. The primary endpoint of this study was the difference between Baseline (Day -1)
maximum ventricular rate, PR, QRS, QT and QTc intervals and the corresponding Day 10
maximum ECG parameters. At 9-fold the proposed clinical dose, there was no statistically or
clinically relevant prolongation of the QTc interval. The mean changes in QTc were 0.3 msec
and 4.3 msec for placebo and desloratadine, respectively (p=0.09; Lower confidence interval
(LCI) = -0.6; Upper confidence interval (UCI) = 8.7). It should be noted that in a separate rising,
multiple dose study in which up to 20 mg of AERIUS was administered daily for 14 days, no
statistically or clinically relevant cardiovascular effects were observed.
Psychomotor Pharmacodynamics: Drowsiness and somnolence, which affect psychomotor
performance, have been reported with first generation antihistamines. The co-administration of
alcohol with such products has resulted in further impairment of psychomotor performance.
In the previously mentioned clinical study, which utilized a 45 mg dose of AERIUS, there were
no reports of somnolence. In a separate randomized, single-dose, double-blind, placebocontrolled, 4-way crossover study, 25 healthy volunteers were treated with desloratadine 7.5
mg/juice, desloratadine 7.5 mg/alcohol in juice, placebo tablet/alcohol in juice and placebo
tablet/juice. No significant differences were found in the psychomotor test results between
desloratadine and placebo groups, whether given alone or with alcohol. In a study with AERIUS
(desloratadine) no effects on the ability to drive and use machines have been observed. In a
separate study in normal volunteers administered a single dose of 5mg of desloratadine, no
effects on standard measures of flight performance were observed.
Human Pharmacokinetics
Protein Binding: The in vitro protein binding of desloratadine to human plasma protein was
determined by ultrafiltration and ranges between 82.8% to 87.2% over the concentration range of
5 to 400 ng/mL. For this degree of protein binding (free fraction 13%), interactions involving
displacement are not known to be clinically important.
Effect of Food: In a single dose crossover trial using AERIUS DUAL ACTION 12 HOUR,
there was no significant effect of food on the disposition of DL or PSE.
In another study, grapefruit juice had no effect on the disposition of desloratadine.
Drug-Drug Interactions: No drug interaction studies have been conducted with AERIUS
DUAL ACTION 12 HOUR. Two randomized, two-way crossover, third-party blind, multiple
dose (10 days), placebo-controlled studies characterized the effect of CYP3A4 inhibitors
ketoconazole (N=24) and erythromycin (N=24) on the pharmacokinetics and cardiovascular
safety of AERIUS (desloratadine 5 mg).
A third study (N=90) with similar design, except comparing parallel groups, investigated the
effect of azithromycin, an azilide antibiotic that also inhibits CYP3A4, on the pharmacokinetics
and cardiovascular pharmacodynamics of AERIUS (desloratadine 5 mg).
Page 24 of 33
Two additional randomized, multiple dose, parallel group studies investigated the effect of
cimetidine (N=36) and fluoxetine (N=54) on the pharmacokinetics and cardiovascular
pharmacodynamics of AERIUS (desloratadine 5 mg).
Ketoconazole co-administered 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 increased Cmax and AUC values for
desloratadine by 24% and 14%, respectively. The increases were 43% and 40%, respectively,
for 3-hydroxy desloratadine. Azithromycin co-administered 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. Throughout these studies, there was no
evidence of change in the safety profile of desloratadine, therefore the increases in plasma
concentrations are not considered to be clinically relevant. Ketoconazole induced a small
increase in the plasma desloratadine concentrations compared with those reported for loratadine.
These data suggest that desloratadine has a reduced potential for interacting with inhibitors of
CYP3A4. The similarity of the erythromycin concentrations from this study to previous studies
suggests that desloratadine is unlikely to inhibit the metabolism of substrates of CYP3A4, which
comprise at least 50% of drugs currently marketed. Fluoxetine co-administered 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 for 3-hydroxy desloratadine were increased by 17%
and 13% respectively. Cimetidine co-administered with desloratadine increased Cmax and AUC
values by 12% and 19% respectively and the Cmax and AUC of 3-hydroxy desloratadine were
reduced by 11.2% and 2.8% respectively.
Serial ECG measurements showed no statistically significant or clinically relevant changes in
QTc intervals.
Mean changes in QTc were 5.4 msec and 2.3 msec for
ketoconazole/desloratadine and desloratadine/placebo, respectively (p=0.14; LCI = -7.3; UCI=
11). Mean changes in QTc were 9.8 msec and 7.8 msec for erythromycin/desloratadine and
desloratadine/placebo, respectively (p=0.53; LCI = -8.4; UCI = 4.5). Mean changes in QTc were
-4.2 msec and -6.3 msec for desloratadine/Azithromycin and desloratadine/placebo, respectively
(p = 0.61).
MICROBIOLOGY
Not applicable.
TOXICOLOGY
Non-clinical toxicology studies of desloratadine in combination with pseudoephedrine sulfate
have not been conducted. Since animals and humans are exposed to desloratadine through
metabolism of loratadine, studies conducted with loratadine/pseudoephedrine also support the
nonclinical drug safety profile of desloratadine/pseudoephedrine.
Page 25 of 33
Loratadine/Pseudoephedrine Acute toxicity
In acute and single-dose studies, loratadine/ pseudoephedrine sulfate tablets exhibited a low
order of toxicity. Acute oral LD50 values ranged from approximately 600 mg/kg in mice to
about 2000 mg/kg in rats. Cynomolgus monkeys tolerated single doses up to 240 mg/kg.
Loratadine/pseudoephedrine sulfate tablets were no more toxic than either their individual
components, and observed effects were generally related to the pseudoephedrine component.
Loratadine/Pseudoephedrine Repeat dose toxicity
Loratadine/pseudoephedrine sulfate tablets were administered orally for 3 months to rats and
monkeys. Loratadine/pseudoephedrine tablets were well tolerated in rats at doses up to 200
mg/kg/day, which is 40 times the proposed maximum clinical dose. In monkeys, daily doses up
to 50 mg/kg/day were also well tolerated. Severe toxicity was observed in monkeys at a dose of
125 mg/kg/day and was attributed to the effects of the pseudoephedrine component.
Desloratadine - Acute Toxicity
The acute oral (gavage) and intraperitoneal toxicity of desloratadine was evaluated in six week
old Sprague-Dawley rats and CD-1 mice. Estimated oral and intraperitoneal LD50 values in both
rats and mice were significant multiples of a human dose of 5.0 mg desloratadine/day. Oral LD50
values were 3530 and
5490 times the daily human dose in mice and rats respectively.
Intraperitoneal LD50 values were 460 and 680 times a daily human dose in mice and rats,
respectively.
In an oral (gavage) rising-dose tolerance study in young adult cynomolgus monkeys, emesis was
observed at doses
23.5 and
93.75 mg/kg in males and females, respectively. Emesis
occurred approximately 15 minutes after and/or up to three hours post dose. The maximum dose
that did not produce emesis in male monkeys (11.75 mg/kg) still represents an 118-fold multiple
of the human dose (0.10 mg desloratadine/kg/day), and an 92-fold monkey-to-human systemic
exposure multiple compared to an arithmetic mean Cmax value of 4.0 ng/mL in humans
following a 5.0 mg/day dose of desloratadine.
Desloratadine - Repeated-Dose Toxicity
Two-week, one-month and three-month desloratadine studies were conducted in rats at doses of
up to 240 mg/kg for an initial pilot two-week study, up to 8 mg/kg for the second two-week
study and up to 120 mg/kg for one- and three-months. Desloratadine systemic exposure at 60
mg/kg is similar to that achieved with a 120 mg/kg dose of loratadine. The no-effect level for
the three-month study was
3 mg/kg (low-dose) but less than 30 mg/kg. Mortality was
observed in the 30, 60 and 120 mg/kg dose groups and in the comparative control (120 mg
loratadine/kg) dose group in the three-month study. Fecal changes were observed and were
considered related to the anticholinergic effect of this class of compounds. Clinical pathology
changes occurred at desloratadine doses 30 mg/kg (systemic exposure multiple of at least 458
times). The findings associated with target organs/tissues consisted mainly of vacuolation
corresponding to phospholipidosis. Phospholipidosis is a common finding of amphiphilic
compounds like desloratadine and loratadine. Centrilobular hepatocyte hypertrophy occurred at
Page 26 of 33
desloratadine doses of 30 mg/kg and at 120 mg/kg of loratadine. There was no evidence of
phospholipidosis at the 3 mg/kg dose.
Renal tubular cell necrosis and/or renal tubular dilatation were observed at desloratadine doses
60 mg/kg (systemic exposure multiple of at least 605 times) or at a loratadine dose of
120 mg/kg (desloratadine systemic exposure multiple of at least 663 times).
Renal tubular casts were seen in males given either 60 mg/kg of desloratadine or 120 mg/kg of
loratadine. Myofiber degeneration, muscle fibrosis and/or mononuclear infiltrates in muscle
occurred at desloratadine doses of 60 mg/kg and at 120 mg/kg of loratadine. Luminal cellular
debris was seen in the seminiferous tubules of the testes at a desloratadine dose of 60 mg/kg and
at 120 mg/kg dose of loratadine.
Hypospermatogenesis occurred in the testes of one or more males given 120 mg loratadine/kg or
desloratadine doses 30 mg/kg. Luminal cellular debris was present in the epididymides of the
loratadine-dosed males and in the desloratadine-dosed males at doses 30 mg/kg. Oligospermia
was also seen in the epididymides of one male given 30 mg/kg of desloratadine, in one male
given 60 mg/kg of desloratadine, and in some males given 120 mg/kg of desloratadine or
loratadine. However, there were no testicular changes observed in the one-month study at doses
up to 120 mg/kg. Furthermore, these testicular-related changes were consistent with those
previously observed with loratadine at doses as low as 2 mg loratadine/kg in rats but with a
loratadine no effect dose of 1 mg loratadine/kg for similar findings after one year of dosing. This
effect on rat testes has been reported with other antihistamines. With loratadine and
desloratadine, this effect is only observed in rats. In the three-month study, granulosa cell
necrosis was seen in the ovaries of many females given 120 mg/kg of desloratadine and in some
females given 120 mg/kg of loratadine. Uterine immaturity occurred in some females given 60
mg/kg of desloratadine and in many females given 120 mg/kg of desloratadine or loratadine.
A seven-day, a two-week, two one-month and a three-month study were conducted in monkeys
with desloratadine. Desloratadine doses of up to 12 mg/kg (systemic exposure multiple of at
least 182 times) were well tolerated for up to three-months of dosing and was the no-effect dose
in the one-month studies. Doses 36 mg/kg (systemic exposure multiple of at least 842 times)
in the repeat one-month study caused emesis.
In the three-month study, the high dose of 18 mg/kg of desloratadine was increased to 24 mg/kg
and the loratadine dose was increased from 22 mg/kg to 72 mg/kg on Day 36. Clinical signs,
including few or no feces, extended abdomen, hunched posture and/or lethargy, at the 18/24
mg/kg of desloratadine (systemic exposure multiple of at least 953 times) and 22/72 mg/kg of
loratadine (desloratadine systemic exposure multiple of at least 1147 times) doses were attributed
to the anticholinergic effects of this class of compounds. Decreases in serum cholesterol and
alkaline phosphatase were noted in the 18/24 mg/kg desloratadine group and in the 22/72 mg/kg
loratadine group. Evaluation of histopathologic findings from the desloratadine 18/24 mg/kg
dose group suggests that this dose produces phospholipidosis similar to that produced by the
22/72 mg/kg loratadine dose. There was no evidence of phospholipidosis following
desloratadine doses of 6 mg/kg. There were no testicular changes observed in monkeys dosed
Page 27 of 33
for three months at doses up to 18/24 mg desloratadine/kg or 22/72 mg loratadine/kg. In this
three-month study, the only effects observed at the 12 mg/kg dose of desloratadine were
vacuolation in the salivary glands and lungs. A dose of 6 mg/kg (systemic exposure multiple 204
times) was the no-effect dose.
The toxicity studies demonstrate adequate exposure multiples at the no-effect levels and ensure
an acceptable safety profile for desloratadine.
Teratogenicity, Mutagenicity and Carcinogenicity
Since animals and humans are exposed to desloratadine through metabolism of loratadine,
carcinogenicity studies conducted with desloratadine and loratadine/pseudoephedrine assessed
the teratogenic, mutagenic and carcinogenic risk of desloratadine/pseudoephedrine.
Loradatadine carcinogencity
Studies in mice and rats demonstrated that carcinogenicity findings were not considered relevant
to humans taking recommended therapeutic doses of either loratadine or desloratadine. The
carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a
desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at
doses up to 25 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were
approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly
higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in
males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of
loratadine. The estimated desloratadine and desloratadine metabolite exposures in rats given 10
mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily
oral dose.
Desloratadine carcinogenicity
In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day
desloratadine, respectively, did not show significant increases in the incidence of any tumors.
The estimated desloratadine and metabolite exposures in mice at these doses were 12 and 27
times, respectively, the AUC in humans at the recommended daily oral dose.
Desloratadine mutagenicity
In mutagenicity studies with desloratadine, there was no evidence of mutagenic potential in a
reverse point mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity
assay) or in two assays for chromosomal aberrations (human peripheral blood lymphocyte
clastogenicity assay and mouse bone marrow micronucleus assay).
Desloratadine genotoxicity
In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a
reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay)
or in two assays for chromosomal aberrations (human peripheral blood lymphocyte
clastogenicity assay and mouse bone marrow micronucleus assay). There was no effect on
female fertility in rats at doses up to 24 mg/kg/day (estimated desloratadine and desloratadine
Page 28 of 33
metabolite exposures were approximately 130 times the AUC in humans at the recommended
daily oral dose.)
Likewise, pseudoephedrine sulfate is not considered to be carcinogenic, mutagenic or
teratogenic.
Desloratadine Reproductive Toxicology
Desloratadine was not teratogenic in animal studies. There was no effect on female fertility at
doses up to 24 mg/kg/day which produced systemic exposure levels in female rats which were at
least 506 times those in humans given the highest recommended clinical dose of desloratadine.
In a separate study, decreased fertility in male rats was shown by lower female conception rates
associated with decreases in sperm numbers and motility and histopathologic testicular changes,
which occurred at an oral dose of desloratadine of 12 mg/kg (systemic exposure approximately
175 times higher than in humans given the maximum recommended dose of desloratadine).
Although there was no overall effect on mean sperm motility or concentration, a few rats given
desloratadine at a dose of 3 mg/kg/day appeared to have testicular findings consistent with those
observed previously with loratadine, which had a no effect dose of 1 mg/kg/day for similar
findings after one year of administration. There was no effect on fertility at 3 mg/kg/day, which
produced plasma levels (AUC) in rats that were 34 times higher than in humans receiving the
maximum clinical dose of desloratadine. This effect on rat testes has been reported with other
antihistamines but as with desloratadine and loratadine, this effect is not observed in other
laboratory animal species and appears to be unique to the rat.
Loratadine/pseudoephedrine teratogencity
Loratadine/pseudoephedrine sulfate tablets were not teratogenic when administered orally to rats
and rabbits during the period of organogenesis. The course of pregnancy of embryo/fetal
viability of rats was not affected at doses up to 150 mg/kg/day (30 times the proposed clinical
dose). Loratadine/pseudoephedrine sulfate tablets did not directly affect the embryo/fetal
viability or offspring development of rabbits at doses up to 120 mg/kg/day.
Page 29 of 33
REFERENCES
1.
Data on File: SCH 00483: Efficacy and safety of desloratadine (SCH 34117) +
pseudoephedrine, BID, versus its components in the treatment of subjects with seasonal
allergic rhinitis (study report for Protocol No. P00355). Kenilworth (NJ): ScheringPlough Research Institute; 2000 Jun.
2.
Data on File: SCH 00483: Efficacy and safety of desloratadine (SCH 34117) +
pseudoephedrine, BID, versus its components in the treatment of subjects with seasonal
allergic rhinitis (study report for Protocol No. P00362). Kenilworth (NJ): ScheringPlough Research Institute; 2000 Jun.
3.
Data on File: SCH 00483: The multiple-dose and steady-state pharmacokinetics of DL D12 (study report for Protocol No. P02041). Kenilworth (NJ): Schering-Plough Research
Institute; 2002 Nov.
4.
Data on File: SCH 00483: Influence of food on the oral bioavailability of DL D 12
administered to healthy subjects: a two-way crossover study (study report for Protocol
No. P00440). Kenilworth (NJ): Schering-Plough Research Institute; 2000 Apr.
5.
Data on File: SCH 00483: Bioequivalence of DL and pseudoephedrine following singledose administration of DL D-12, DL 2.5 mg and pseudoephedrine 120 mg tablet (study
report for Protocol No. P00446). Kenilworth (NJ): Schering-Plough Research Institute;
2000 Apr.
6.
Data on File: SCH 00483: The bioavailability of pseudoephedrine from controlled-release
(12-hour) formulations: a four-way crossover study (study report for Protocol No.
P02043). Kenilworth (NJ): Schering-Plough Research Institute; 2004 Apr.
7.
AERIUS and AERIUS KIDSTM Product Monograph; Date of Revision: October 13,
2006: Schering Canada Inc.
8.
CLARITIN ALLERGY & SINUS Product Monograph; Date of Preparation: December
10, 2004: Schering Canada Inc.
Page 30 of 33
PART III: CONSUMER
INFORMATION
AERIUS® DUAL ACTION 12 HOUR™
2.5 mg desloratadine &
120 mg pseudoephedrine sulfate / tablet
This leaflet is part III of a three-part “Product
Monograph" published when AERIUS DUAL
ACTION 12 HOUR was approved for sale in
Canada and is designed specifically for
Consumers. This leaflet is a summary and will not
tell you everything about AERIUS DUAL
ACTION 12 HOUR. Contact your doctor or
pharmacist if you have any questions about the
drug.
ABOUT THIS MEDICATION
What the medication is used for:
AERIUS DUAL ACTION 12 HOUR provides:
$ Relief from symptoms of seasonal allergies
(trees, grass, pollen and ragweed). Symptoms
include: runny, stuffy & itchy nose; sneezing;
itchy, burning, watery red eyes; itching of the
ears & palate.
$ Relief from nasal congestion.
Take AERIUS DUAL ACTION 12 HOUR if you
desire the decongestant relief of pseudoephedrine
in addition to the allergy relief provided by
desloratadine.
What it does:
AERIUS DUAL ACTION 12 HOUR contains:
a long-acting antihistamine - it blocks the action
of histamine and relieves allergy symptoms.
Histamine is a chemical released by the
immune system – the body’s defence against
invading substances – when the body is affected
by substances to which it is allergic (allergens).
a nasal decongestant – it relieves nasal
stuffiness by constricting the blood vessel in the
lining of the nose.
Symptom relief begins on the first day of treatment
with AERIUS DUAL ACTION 12 HOUR and
lasts for 12 hours after each dose.
When it should not be used:
AERIUS DUAL ACTION 12 HOUR should not
be used:
if you are allergic to desloratadine, loratadine or
to any of the other product ingredients (See
What the non-medicinal ingredients are).
If you have experienced side effects with oral
decongestants in the past
If you are taking a MAO inhibitor or stopped
taking one less than two weeks ago
If you have heart disease
If you have thyroid disease
If you have a form of glaucoma which causes
rapid increase in eye pressure
If you have urinary retention
If you have severe hypertension
AERIUS DUAL ACTION 12 HOUR is not
recommended if you are pregnant or nursing.
What the medicinal ingredient is:
Desloratadine
Pseudoephedrine sulfate
What the important non-medicinal ingredients are:
Citric acid anhydrous, corn starch, edetate
disodium, dye (FD&C Blue No. 2 Aluminum
Lake), hypromellose, povidone, magnesium
stearate, microcrystalline cellulose, silicon dioxide,
stearic acid
What dosage forms it comes in:
Bi-layer tablets – containing desloratadine for
immediate
release
in
one
layer
and
pseudoephedrine sulfate for extended release in the
other layer.
$ Tell your doctor if you have severe liver or kidney
disease
BEFORE you use AERIUS DUAL ACTION 12
HOUR talk to your doctor or pharmacist if:
you have heart disease or a heart
condition
you have a stomach condition
you have problems with your prostate or
urinating
you have diabetes
Use as directed on the label.
Use with caution if you are aged 65 or older.
Do not use with other over the counter
antihistamines and decongestants.
Discontinue use 24 hours prior to surgery.
Do not use 48 hours prior to skin test
Of interest to athletes: Treatment with
pseudoephedrine could lead to positive doping
tests.
Page 31 of 33
INTERACTIONS WITH THIS MEDICATION
Drugs that may interact with AERIUS DUAL
ACTION 12 HOUR include:
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect
If you are taking any medication, it is important to
ask your physician or pharmacist before taking
AERIUS DUAL ACTION 12 HOUR.
PROPER USE OF THIS MEDICATION
Usual dose:
Adults and adolescents 12 years of age and
over: one tablet twice a day, every 12 hours.
May be taken with or without food.
Do not crush, break or chew the tablet.
Swallow whole with water.
Limit treatment to 14 days.
Overdose:
Contact your Poison Control Centre, physician or
pharmacist as soon as possible.
Missed Dose:
If you miss taking your dose on time, do not worry:
take your dose when you remember. Do not
exceed more than one dose in 12 hours.
SIDE EFFECTS AND WHAT TO DO ABOUT
THEM
Along with its desired effects, AERIUS DUAL
ACTION 12 HOUR may cause undesirable effects.
Side effects that may occur include insomnia,
headache and dry mouth.
Rarely, you may experience allergic reactions to
the medication, which may appear as a rash or
difficulty in breathing. Very rarely, the following
side effects may occur: abnormally fast heart rate
or heart palpitations, restlessness with increased
body movement, seizures and liver dysfunctions,
such as hepatitis (inflammation of the liver) which may be recognized by jaundice (yellowing
of the skin).
Talk with your
doctor or
pharmacist
Only
if
severe
Rare
Allergic reaction
(rash, difficulty
in breathing)
Rare
Fast heart rate
or heart
palpitations
Rare
Restlessness
with increased
body movement
Rare
Seizures
Rare
Liver
dysfunction - i.e.
inflammation of
the liver
(appearance of
jaundice yellowing of the
skin)
In all
cases
Stop taking
drug and
call your
doctor or
pharmacist
This is not a complete list of side effects. For any
unexpected effects while taking AERIUS DUAL
ACTION 12 HOUR, contact your doctor or
pharmacist.
HOW TO STORE IT
Store between 15 and 30oC.
Protect from excessive moisture
Protect from light.
Keep blister package in outer carton.
Page 32 of 33
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions
associated with the use of health products to the
Canada Vigilance Program by one of the following
3 ways:
1.
Report online at
www.healthcanada.gc.ca/medeffect
2.
Call toll-free at 1-866-234-2345
3.
Complete a Canada Vigilance Reporting
Form and:
-
Fax toll-free to 1-866-678-6789, or
Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701C
Ottawa, ON K1A 0K9
Postage paid labels, Canada Vigilance Reporting
Form and the adverse reaction reporting guidelines
are available on the MedEffect™ Canada Web site
at www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to
the management of side effects, contact your
health professional. The Canada Vigilance
Program does not provide medical advice.
MORE INFORMATION
This document plus the full product monograph,
prepared for health professionals can be found by
contacting the sponsor, Schering-Plough Canada
Inc., at:
1-800-463-5442
This leaflet was prepared by Schering-Plough
Canada Inc
Last revised: June 3, 2009
Page 33 of 33

AERIUS® AERIUS KIDS®

Transcription

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