Download Newer Antihistamines

Dr. S. Sacchidanand
Professor and H.O.D
Dept. of Dermatology, S.T.D & Leprosy
Victoria Hospital
Bangalore Medical College
Bangalore
Chemical and functional classification of H1 antihistamines
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F. Estelle R. Simons; Advances in H1-Antihistamines: NEJM, 2004: 351:2203-2217
First generation H1 antihistamines
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Competitive inhibitors of histamine action at tissue level
Binding is reversible and displaced by higher levels of
histamine
Additional anticholinergic activity, some possess
antiserotoninergic activity and many of them also inhibit
neuronal uptake of norepinephrine
Also have local anesthetic effect, but carry risk of irritation
and sensitization
Second generation H1
antihistamines
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Antagonists at H1 receptors
Competitive antagonists though some are noncompetitive at
higher doses
High therapeutic index
Poorly lipophilic - do not readily traverse blood brain barrier
Highly selective with little or no anticholinergic activity
Additional antiallergic mechanisms of some, like inhibition of
late phase allergic reaction by acting on leukotrienes or anti
platelet factor activating effect
H1 antihistamines are inverse agonists
not antagonists
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Summary: This review addresses novel concepts of histamine H1-receptor function and attempts to relate
them to the anti-inflammatory effects of H1-antihistamines. Furthermore, the molecular mechanisms
underlying the cardiotoxic effects of H1-antihistamines are discussed.
H1-receptors are G-protein-coupled-receptors (GPCRs), the inactive and active conformations of which
coexist in equilibrium. The degree receptor activation in the absence of histamine is its 'constitutive
activity'. In this two-state model, histamine acts as an agonist by combining with and stabilizing the
activated conformation of the H1-receptor to shift the equilibrium towards the activated state. Drugs
classified previously as antagonists act as either inverse agonists or neutral antagonists. Inverse agonists
combine with and stabilize the inactive conformation of the receptor to shift the equilibrium towards the
inactive state. Thus, they may down-regulate constitutive receptor activity, even in the absence of
histamine. Neutral antagonists combine equally with both conformations of the receptor, do not affect basal
receptor activity but do interfere with agonist binding. All H1-antihistamines examined to
date are inverse agonists. As the term 'H1-receptor antagonists' is obviously
erroneous, we suggest that it be replaced by 'H1-antihistamines'.
The observations that H1-receptors modulate NF-[kappa]B activation and that there are complex
interactions between GPCRs, has allowed us to postulate receptor dependent-mechanisms for some
anti-inflammatory effects of H1-antihistamines, e.g. inhibition of ICAM-1 expression and the effects
of bradykinin.
Finally, the finding that blockade of HERG1 K+ channels is the mechanism by which some H1antihistamines may cause cardiac arrhythmias has allowed the development of preclinical tests to predict
such activity.
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Leurs, R. 1; Church, M. K. 2 1; Taglialatela, M. 3 H1-antihistamines: inverse agonism, anti-inflammatory
actions and cardiac effects. Clinical & Experimental Allergy. 32(4):489-498, April 2002.
Pharmacokinetics: 1st vs 2nd generation
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Simons, F. Estelle R.; Simons, Keith J. Drug Therapy: The Pharmacology And Use Of H(sub 1)-ReceptorAntagonist Drugs. New England Journal of Medicine. 330(23):1663-1670, Jun 9, 1994.
Dosing and frequency
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Simons, F. Estelle R.; Simons, Keith J. Drug Therapy: The Pharmacology And Use Of H(sub 1)-ReceptorAntagonist Drugs. New England Journal of Medicine. 330(23):1663-1670, Jun 9, 1994.
CNS effects
Given that antihistamines are not free of CNS effects, a number
of studies have been carried out to assess the severity or
magnitude of impairment of mental function that these drugs
impose
These studies have focused on :
 measures of sedation (eg. EEG changes, sleep latency,
sleepiness or wakefulness scores)
 effects on psychomotor function (eg. driving, piloting aircraft,
working on an assembly line)
 potential changes in cognitive function (eg. learning, memory,
conceptual knowledge testing, school performance)
Tests Used to Assess Effects of Antihistamines on
Sedation, Psychomotor Function, and Cognitive
Function*
Pitfalls of 1st generation H1 antihistamines
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Diminished alterness, dizziness, tinnitus, disturbed coordination, inability to concentrate, blurred vision and diplopia
impairment to psychomotor performances
impairment of individual’s attention and processing speed
Paradoxically CNS stimulatory effects (eg. convulsions) can
also be seen, especially in children and with overdosage
All these undesirable CNS effects not seen or minimally
observed with 2nd generation H1 antihistamines
Percent daytime ‘sleep-like’ activity. Mean change from
placebo where *p<0.05
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I.Hindmarch, Z. Shamsi, N. Stanley, D. B. Fairweather: A double-blind placebo-controlled investigation of
the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function. Br J Clin
Pharmacol, 48, 200-206
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First-generation H1-antihistamines have been implicated in the
loss of productivity by workers injuries and deaths in aviation
and traffic accidents
Military and civilian pilots are prohibited from using these or
any other potentially sedating medications before or during
flights
Currently, desloratadine, fexofenadine, and loratadine are the
only oral H1-antihistamines for which pilots can receive a
waiver for use from the Federal Aviation Administration
1st generation in children
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Although older, potentially sedating, "first-generation" antihistamines (H1-receptor antagonists) are
commonly used in childhood, their central nervous system (CNS) effects have not been well-documented in
young subjects. We hypothesized that diphenhydramine and hydroxyzine would affect CNS function
adversely in this population. Our objective was to evaluate the effects of these medications on central and
peripheral histamine H1-receptors in children. Fifteen subjects with allergic rhinitis were tested before and
2-2.5 h after administration of diphenhydramine, hydroxyzine, or placebo in a double-blind, single-dose,
three-way crossover study. Impairment of cognitive processing was assessed objectively by the latency of
the P300 event-related potential (P300). Somnolence was assessed subjectively by a visual analog scale.
Peripheral H1-blockade was assessed by suppression of the histamine-induced wheals and flares. At the
central (Cz) and frontal (Fz) electrodes, diphenhydramine and hydroxyzine increased the P300 latency
significantly (P <0.05) compared to baseline. Hydroxyzine increased somnolence, as recorded on the visual
analog scale, significantly compared to baseline (P < 0.05), with a similar trend for diphenhydramine (P =
0.07). Both antihistamines reduced histamine-induced wheals and flares significantly compared to
baseline and compared to placebo. In children, diphenhydramine and hydroxyzine are
effective H1-receptor antagonists, but both these medications cause CNS dysfunction, as
evidenced by increased P300 latency, a measure of cognitive function, and by increased
subjective somnolence.
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Simons, F. Estelle R. 1; Fraser, Terry G. 2; Reggin, James D. 1; Roberts, Janet R. 1; Simons, Keith J. 3
Adverse Central Nervous System Effects of Older Antihistamines in Children. Pediatric Allergy &
Immunology. 7(1):22-27, February 1996.
1st vs 2nd generation in elderly
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Objective: We hypothesized that newer H1-receptor antagonists such as cetirizine and loratadine would cause less central
nervous system dysfunction than the older H1-receptor antagonists diphenhydramine and chlorpheniramine in this
population, as they do in younger subjects.
Methods: We performed a randomized, double-blind, single-dose, placebo-controlled, 5-way crossover study in 15 healthy
elderly subjects (mean age 71 +/- SD 5 years). On study days at least 1 week apart, they received cetirizine 10 mg, loratadine
10 mg, diphenhydramine 50 mg, chlorpheniramine 8 mg, or placebo. Outcome measures, recorded before and 2 to 2.5 hours
after dosing were latency of the P300 event-related potential in which increased latency reflects a decreased rate of cognitive
processing, visual analogue scale for subjective somnolence, and histamine skin tests for measurement of peripheral H1blockade.
Results: The changes in P300 following each treatment yielded variances that were not equal (P > .05), precluding usual
statistical analysis of the means. These variances were ranked: chlorpheniramine > diphenhydramine > loratadine > placebo >
cetirizine. The rank of mean differences in the visual analogue scale increase from pre-dose baseline was: diphenhydramine >
chlorpheniramine > cetirizine > loratadine > placebo. All H1-receptor antagonists suppressed the histamine-induced wheal
and flare significantly compared to baseline.
Conclusion: In the elderly, the new H1-receptor antagonists cetirizine and loratadine are
less likely to cause adverse central nervous system effects than the old H1-antagonists
chlorpheniramine or diphenhydramine, but this requires confirmation using additional
objective tests of central nervous system function.
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Simons, F Estelle R MD, FRCPC *; Fraser, Terry G BSc, Pharm +; Maher, John MB, BCh, MRCP(I), FRCPC
*; Pillay, Neelan MD, MRCP(UK), FRCPC *; Simons, Keith J PhD Central nervous system effects of H1receptor antagonists in the elderly. Annals of Allergy, Asthma, & Immunology. 82(2):157-160, February 1999.
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The second-generation H-antagonist drugs are supplanting
their predecessors in the treatment of allergic
rhinoconjunctivitis and chronic urticaria
Their use can be justified mainly on the basis of a more
favorable risk-benefit ratio, because they are less toxic to the
central nervous system
Simons, F. Estelle R.; Simons, Keith J. Drug Therapy: The Pharmacology And Use Of H(sub 1)-ReceptorAntagonist Drugs. New England Journal of Medicine. 330(23):1663-1670, Jun 9, 1994.
2nd generation are more revelant
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Histamine is an important chemical mediator of inflammation, vasodilation, increased
vascular permeability, decreased peripheral resistance, airway smooth muscle contraction, and
sensory nerve stimulation causing itching. It also plays a significant role in neurotransmission
and in cardiac function. In allergic rhinoconjunctivitis and urticaria, there is strong evidence
for the role of H1-antihistamine treatment. In asthma, additional dose-response studies,
including higher doses of antihistamines than those used in allergic rhinitis, are needed to
determine the role of antihistamines. In atopic dermatitis, the itch-relieving topical
glucocorticoid-sparing effects of H1-antihistamines also require further documentation.
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The potential benefits of each H1-antihistamine should be weighed
against the potential risks, and second-generation H1-antihistamines
with excellent, well-documented safety records should be used in
preference to older, less safe H1-antihistamines. Second-generation H1antihistamines are more relevant than ever in the treatment of allergic
disorders
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Simons, F. Estelle R. MD, FRCPC * H1-antihistamines: More relevant than ever in the treatment of allergic
disorders. Journal of Allergy & Clinical Immunology. 112(4) Supplement:S42-S52, October 2003.
Fexofenadine, loratadine vs chlorpheniramine
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Methods: In a prospective, randomized, double-blind, parallel-group, multiple-dose study, we gave
fexofenadine 180 mg, loratadine 10 mg, or chlorpheniramine 8 mg to 21 men (7 in each group). Before
dosing and at 1, 3, 6, 9, and 24 hours after the first antihistamine dose as well as at 168, 192, and 216 hours
after the first dose (ie, 12, 36, and 60 hours after the seventh and last consecutive daily H1-antihistamine
dose), we measured fexofenadine, loratadine, or chlorpheniramine concentrations in plasma and in skin
tissue samples obtained through use of punch biopsies, along with suppression of histamine-induced skin
wheals and flares. Loratadine metabolites, including desloratadine and its metabolites, were not measured,
and chlorpheniramine metabolites were not measured.
Results: All 21 participants completed the study. Skin/plasma fexofenadine ratios ranged from 1.2 +/- 0.5 at
1 hour to 110 +/- 74 at 24 hours, and skin fexofenadine concentrations exceeded loratadine and
chlorpheniramine skin concentrations at each test time. This was reflected in significant wheal and flare
suppression by fexofenadine in comparison with loratadine at 3 hours and in comparison with
chlorpheniramine at 6 and 9 hours (wheal) and from 3 to 24 hours and at 192 hours (flare). Compared with
fexofenadine, loratadine significantly suppressed the wheal at 192 hours, and compared with
chlorpheniramine, it significantly suppressed the wheal at 9 hours and the flare at 24 and 192 hours. At no
time did chlorpheniramine suppress the wheal or flare significantly more than fexofenadine or loratadine.
Conclusions: In skin disorders for which H1-antihistamines are
recommended, these results support the use of fexofenadine or
loratadine, and they indicate the need for reexamination of the use of
chlorpheniramine
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Simons, F. Estelle R. MD, FRCPC a; Silver, Norman A. MD, FRCPC a; Gu, Xiaochen PhD b; Simons,
Keith J. PhD a,b Clinical pharmacology of H1-antihistamines in the skin. Journal of Allergy & Clinical
Immunology. 110(5):777-783, November 2002
Fexofenadine vs diphenhydramine
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Objective: We sought to evaluate the extent of fexofenadine and diphenhydramine distribution
into the skin concomitantly with their peripheral H1-receptor antagonist activity.
Methods: In a prospective, randomized, double-blind, parallel-group study, 7 men received
120 mg of fexofenadine, and 7 received 50 mg of diphenhydramine. Before dosing; at 1, 3, 6,
9, and 24 hours after the first dose; and at 168 hours (steady-state), 12 hours after the seventh
and last daily dose, blood samples and skin punch biopsy specimens were obtained, and
epicutaneous tests with histamine phosphate, 1 mg/mL, were performed.
Results: Fexofenadine penetrated the skin to a significantly greater extent than
diphenhydramine at 6, 9, 24, and 168 hours (P <= .05). Maximum skin/plasma ratios of both
the H1-antagonists (41.3 +/- 7.8 for fexofenadine and 8.1 +/- 4.4 for diphenhydramine) were
obtained at 24 hours. Fexofenadine also produced significantly greater suppression of wheals
at 3, 6, and 9 hours and of flares at 3, 6, 9, and 168 hours compared with diphenhydramine (P
<= .05).
Conclusion: In disorders in which the presence and the effects of H1-receptor
antagonists in the skin are clinically relevant, our results support the use of
fexofenadine and indicate the need to re-examine the role of diphenhydramine
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Simons, F. Estelle R. MD, FRCPC a; Silver, Norman A. MD a; Gu, Xiaochen PhD b; Simons, Keith J. PhD
c Skin concentrations of H1-receptor antagonists. Journal of Allergy & Clinical Immunology. 107(3):526530, March 2001
Cetrizine
Chemical name - (±) - [2- [4- [ (4-chlorophenyl)phenylmethyl] -1- piperazinyl]
ethoxy]acetic acid, dihydrochloride
Empirical formula - C21H25C1N2O3·2HCl
Molecular weight - 461.82
Cetrizine
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Cetirizine, a piperazine derivative
Carboxylated metabolite of hydroxyzine
Contains three ionisable structural moieties and exhibits the
differing but pH-dependent partitioning or lipophilicity
characteristics of a zwitterion
Marked affinity for peripheral H1 receptors; penetrates brain
poorly
Minimal sedative and anticholinergic effects in recommended
dosage
At physiological pH
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A very low volume of distribution (0.5 L/kg)
Low serum concentrations
Low affinity for lean tissues such as myocardium - low
potential for cardiac effects
In contrast, skin concentrations of cetirizine have been shown
to be relatively high, contributing to a comparatively prompt
onset and prolonged duration of cutaneous effects
Long recognised usefulness of hydroxyzine for certain allergic
skin conditions could be due in large part to these unusual
pharmacokinetic characteristics of cetirizine
Pharmacokinetics
Absorption
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Time to maximum concentration (T max) - 1 hour following
oral administration of the drug
After multiple doses of cetirizine (10 mg tablets once daily
for 10 days) - a mean peak plasma concentration (C max) of
311 ng/ml
Pharmacokinetics were linear for oral doses ranging from 5
to 60 mg
Food had no effect on the extent of cetirizine exposure but
T max was delayed by 1.7 hours and C max was decreased by
23% in the presence of food
Contd….,
Distribution
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Mean plasma protein binding of cetirizine - 93%
Metabolism
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Cetirizine is metabolized to a limited extent by oxidative Odealkylation to a metabolite with negligible antihistaminic
activity
Elimination
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70% through urine; 10% in the feces
Mean elimination half life - 8.3 hours
Apparent total body clearance - 53 ml/min.
Drug interactions
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With pseudoephedrine, antipyrine, ketoconazole, erythromycin
and azithromycin - No interactions observed
With theophylline (400 mg once daily for 3 days) and
cetirizine (20 mg once daily for 3 days) - a 16% decrease in
the clearance of cetirizine observed
Special conditions
Geriatric Patients
 Following a single 10mg oral dose, elimination half-life
prolonged by 50%, apparent total body clearance lowered by
40%
Renal Impairment
 Mild impairment - pharmacokinetics of cetirizine were similar
as normal volunteers.
 Moderately impaired – 3 fold increase in half-life, 70%
decrease in clearance compared to normal volunteers.
Hepatic Impairment
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50% increase in half-life
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40% decrease in clearance
Pharmacodynamics
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Cetirizine at doses of 5 and 10 mg strongly inhibited
the skin wheal and flare caused by the intradermal
injection of histamine
Onset within 20 minutes in 50% of subjects and
within one hour in 95% of subjects
No tolerance to the antihistaminic (suppression of
wheal and flare response) effects
Late phase recruitment of eosinophils, neutrophils
and basophils, components of the allergic
inflammatory response, was inhibited by cetirizine at
a dose of 20 mg
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Background: Several second-generation antihistamines have documented anti-inflammatory effects which
appear independent of H1-receptor blockade. We investigated the inhibitory effect of cetirizine and its
active enantiomer levocetirizine on eosinophil transendothelial migration (TEM) through monolayers of
normal human dermal microvascular endothelial cells (HMVEC-d) or human lung microvascular
endothelial cells (HMVEC-l).
Methods: HMVEC-d or HMVEC-l were grown to confluence on micropore filters in transwells inserted
into a 24-well tissue culture dish. Eosinophils were isolated by density gradient centrifugation and negative
immunomagnetic selection. Untreated eosinophils or eosinophils pre-incubated (30 min at 37 °C) with a
concentration range of cetirizine or levocetirizine (105 to 109 m) were added to the upper chamber of the
transwell which was incubated for 60 min at 37 °C. Both spontaneous eosinophil TEM and TEM to
100 ng/mL of human eotaxin in the lower chamber were assessed.
Results: Between 8 and 10% of the eosinophils added to the upper chamber underwent spontaneous TEM
through HMVEC-d or HMVEC-l. The addition of eotaxin to the lower chamber enhanced eosinophil TEM
through HMVEC-d or HMVEC-l monolayers to over 20%, i.e. an enhanced TEM of approximately 100%
in each case. Pre-incubation of eosinophils with cetirizine or levocetirizine dose-dependently inhibited
eosinophil TEM to eotaxin through both HMVEC-d or HMVEC-l with total inhibition of eotaxin-induced
TEM observed at 108 m for HMVEC-d and 107 m for HMVEC-l. Both drugs gave a reduced but
significant inhibition of eosinophil TEM at lower concentrations. No concentration of cetirizine or
levocetirizine had any significant effect on expression of CD11b, CD18 or CD49d by either resting or
eotaxin-stimulated eosinophils. Furthermore, no effect on spontaneous eosinophil TEM, or eosinophil
viability was seen with any concentration of cetirizine or levocetirizine.
Conclusion: Levocetirizine inhibits eotaxin-induced eosinophil TEM through
both dermal and lung microvascular endothelial cells suggesting that, like
cetirizine, levocetirizine has potential anti-inflammatory effects.
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Cetirizine and levocetirizine inhibit eotaxin-induced eosinophil transendothelial migration through human
dermal or lung microvascular endothelial cells: L. Thomson,M. G. Blaylock, D. W. Sexton, A. Campbell,
G. M. Walsh
Indications
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Seasonal allergic rhinitis
Perennial allergic rhinitis
Chronic urticaria
Atopic dermatitis
As a adjuvant in seasonal asthma
Cetrizine and atopic dermatitis
Objective: Our objective was to study the effect of long-term treatment with the H1-receptor
antagonist cetirizine in the prevention of urticaria in young children with atopic dermatitis.
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Methods: In the prospective, double-blind, parallel-group Early Treatment of the Atopic Child
study, 817 children with atopic dermatitis who were 12 to 24 months of age at study entry
were randomized to receive either cetirizine, 0.25 mg/kg, or matching placebo twice daily for
18 months and to be followed up for an additional 6 months, during which time the study
medication code remained unbroken. During both these double-blind phases of the study, for a
total of 24 months, caregivers prospectively recorded all symptoms and events, including
hives, in a diary on a weekly basis when the child was well and on a daily basis when a
symptom or event was observed. The diaries were reviewed and validated with the
investigators at each regularly scheduled study visit.
Results: Acute urticaria occurred in 16.2% of the placebo-treated children and in 5.8% of the
children treated with cetirizine (P < .001). The protective effect of cetirizine disappeared when
treatment was stopped. In the study population as a whole, urticaria episodes were most
commonly associated with intercurrent infection or with food ingestion or direct skin contact.
Conclusion: Acute urticaria is common in toddlers with atopic dermatitis and
can be prevented with cetirizine in this high-risk population
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Simons, F. Estelle R. MD, FRCPC; on behalf of the Early Treatment of the Atopic Child (ETAC) Study
Group * Prevention of acute urticaria in young children with atopic dermatitis. Journal of Allergy &
Clinical Immunology. 107(4):703-706, April 2001.
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Background: In very young children, H1-receptor antagonists have not been adequately studied, although
they are widely used and assumed to be safe.
Objective: Our objective was to test the hypothesis that cetirizine would be as safe as placebo for long-term
use in this population.
Methods: In the prospective, double-blind, parallel-group, 18-month-long Early Treatment of the Atopic
Child (ETAC) study, 817 children with atopic dermatitis who were 12 to 24 months old at study entry were
randomized to receive either cetirizine 0.25 mg/kg or placebo twice daily. Safety was assessed by using the
reports of all adverse events, diary cards, physical examinations, developmental assessments,
electrocardiograms, blood hematology and chemistry tests, and urinalyses.
Results: The population evaluated for safety consisted of 399 children receiving cetirizine and 396 children
receiving placebo. Drop-outs and serious events, including hospitalizations, occurred infrequently and were
less common in the children receiving cetirizine than in those children receiving placebo, although the
differences were not statistically significant. Most reported symptoms and events were mild and were
attributed to intercurrent respiratory or gastrointestinal infections, exacerbations of allergic disorders, or
age-related concerns rather than to medication-related adverse effects. There were no clinically relevant
differences between the groups for neurologic or cardiovascular symptoms or events, growth, behavioral or
developmental assessments, laboratory test results, or electrocardiograms, and no child receiving cetirizine
therapy had prolongation of the QTc interval.
Conclusions: The safety of cetirizine has been confirmed in this prospective study, the
largest and longest randomized, double-blind, placebo-controlled safety investigation of
any H1-antagonist ever conducted in children and the longest prospective safety study of
any H1-antagonist ever conducted in any age group
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Simons, F. Estelle R. MD, FRCPC Prospective, long-term safety evaluation of the H1-receptor antagonist
cetirizine in very young children with atopic dermatitis. Journal of Allergy & Clinical Immunology. 104(2,
Pt. 1):433-440, August 1999.
Dosage and administration
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Adults and Children 12 Years and Older : - initial dose 5 or
10 mg per day with or without food.
Children 6 to 11 Years : - 5 or 10 mg once daily
Children 2 to 5 Years : - 2.5 mg once daily; maximum dose of
5 mg per day
Children 6 months to <2 years: 2.5 mg once daily
Dose Adjustment for renal and hepatic Impairment : - a dose
of 5 mg once daily
Dose Adjustment for Geriatric Patients: dose of 5 mg once
daily recommended
Used with caution in pregnancy, usage not recommended in
breast feeding
Safety of cetrizine in infancy
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Background: H1-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however,
there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date,
no such studies have been conducted in infants.
Objective: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the
safety of the H1-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age
6 to 11 months, inclusive.
Methods: Infants who met the entry criteria for age and had a history of treatment with an H1-antihistamine for an allergic or
other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week.
Results: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD). No differences in all-cause or treatmentrelated adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward
fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No
prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either
baseline values or with values in placebo-treated infants.
Conclusions: We have documented the safety of cetirizine in this short-term investigation, the first
randomized, double-blind, placebo-controlled study of any H1-antihistamine in infants. Additional
prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other
H1-antihistamines are needed in this population
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Simons, F. Estelle R. MD, FRCPC a; Silas, Peter MD b; Portnoy, Jay M. MD c; Catuogno, Joseph PhD d;
Chapman, Douglass MS d; Olufade, Abayomi O.; PharmD, MS d Safety of cetirizine in infants 6 to 11
months of age: A randomized, double-blind, placebo-controlled study. Journal of Allergy & Clinical
Immunology. 111(6):1244-1248, June 2003.
Dosing on body weight and age
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Developmental changes during infancy and childhood can affect drug pharmacokinetics (PK), i.e., absorption,
distribution, metabolism, and renal excretion. This, in turn, influences optimal dosing, efficacy, and safety. To
date, of the 40 H1-antihistamines available worldwide, only 11 have been studied in children using a PK
approach. Here, we provide the pediatricians' perspective on the population PK of levocetirizine, the
pharmacologically active enantiomer of cetirizine, in very young children who received oral cetirizine, and
describe the factors that influence levocetirizine PK in this population. In a prospective, randomized, doubleblind, parallel-group, placebo-controlled study, very young children received oral cetirizine 0.25 mg/kg twice
daily for 18 months. Plasma levocetirizine concentrations were measured in timed, sparse blood samples
collected at steady-state (3, 12 and 18 months after commencement of treatment) for the purpose of
monitoring safety, and levocetirizine population, PK parameters were derived by using non-linear mixed
effects modeling. In 343 children (age 14-46 months, body weight 8.2-20.5 kg), a total of 943 blood samples
were obtained. Compliance with cetirizine dosing was documented. The population PK model used predicted
that with increasing body weight, levocetirizine oral clearance would increase by 0.044 l/h/kg, and
levocetirizine volume of distribution would increase by 0.639 l/kg. Levocetirizine PK were not
influenced by eosinophilia, sensitization to allergens, allergic disease,
gastroenteritis/diarrhea, or concomitant ingestion of other medications. This population
PK model predicts that in very young children, the oral clearance of levocetirizine will be
rapid and will increase as body weight and age increase, therefore, levocetirizine dosing
should be based on body weight and age in this population. Compared with older patients,
on a mg/kg basis, relatively higher doses may be needed, and twice-daily dosing may be
necessary, as previously reported for the related racemic H1-antihistamine cetirizine.

Simons, F. Estelle R.; on behalf of the ETAC Study Group Population pharmacokinetics of levocetirizine in
very young children: the pediatricians' perspective. Pediatric Allergy & Immunology. 16(2):97-103, March
2005.
Single dosing optimal

Background: The pharmacokinetics and pharmacodynamics of medications may differ between children
and adults, necessitating different dose regimens for different age groups. Levocetirizine, the active
enantiomer of cetirizine, is used in the treatment of allergic rhinitis and chronic urticaria in Europe. Its
pharmacokinetics and pharmacodynamics have not yet been studied prospectively in school-age children.
Objectives: This study was performed to investigate levocetirizine pharmacokinetic disposition and
pharmacodynamics in relation to skin reactivity to histamine in children aged 6 to 11 years.
Methods: Blood samples were obtained at predose baseline and at defined intervals up to and including 28
hours after a 5-mg levocetirizine dose. Concurrently, epicutaneous tests with histamine phosphate, 1
mg/mL, were performed. Wheals and flares were traced at 10 minutes, and the areas were measured with a
computerized digitizing system
Results: In children aged 8.6 +/- 0.4 years (+/- SEM), the peak levocetirizine concentration was 450 +/- 37
ng/mL, and the time at which peak concentrations occurred was 1.2 +/- 0.2 hours. The terminal elimination
half-life was 5.7 +/- 0.2 hours, the oral clearance was 0.82 +/- 0.05 mL/min/kg, and the volume of
distribution was 0.4 +/- 0.02 L/kg. Compared with predose areas, the wheals and flares produced by
histamine phosphate were significantly decreased from 1 to 28 hours, inclusive (P < .05). Mean maximum
inhibition of wheals and flares occurred from 2 to 10 hours (97% +/- 1%) and from 2 to 24 hours (93% +/1%), respectively
Conclusions: Levocetirizine had an onset of action within 1 hour and provided significant peripheral
antihistaminic activity for 28 hours after a single dose. Once-daily dosing may be optimal in children
aged 6 to 11 years, as it is in adults

Simons, F. Estelle R. MD, FRCPC a; Simons, Keith J. PhD a,b Levocetirizine: Pharmacokinetics and
pharmacodynamics in children age 6 to 11 years. Journal of Allergy & Clinical Immunology. 116(2):355361, August 2005.
Adverse experience Cetirizine (n=2034) Placebo (n=1612)
Somnolence
13.7
6.3
Fatigue
5.9
2.6
Dry mouth
5.0
2.3
Pharyngitis
2.0
1.9
Dizziness
2.0
1.2
Adverse Experiences Reported in Patients Aged 12 Years and Older in PlaceboControlled United States Cetirizine Trials (Maximum Dose of 10 mg) at Rates of
2% or Greater (Percent Incidence)
Adverse event
Cetrizine 10 mg
(n=2111)
Placebo
(n=1912)
Somnolence
10.1%
5.4%
Headache
7.0%
7.9%
Dry mouth
2.8%
0.7%
Fatigue
2.1%
1.0%
Most frequently reported adverse events (>2% incidence)
reported in clinical placebo-controlled trials of 10 mg
Cetrizine daily
Other side effects


(infrequent)
Skin : acne, alopecia, angioedema, bullous eruption,
dermatitis, dry skin, eczema, erythematous rash, furunculosis,
hyperkeratosis, hypertrichosis, increased sweating,
maculopapular rash, photosensitivity reaction.
Central and Peripheral Nervous Systems: abnormal
coordination, ataxia, confusion, dysphonia, hyperesthesia,
hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine,
myelitis.
Precautions
Activities Requiring Mental Alertness:

In clinical trials, the occurrence of somnolence has been reported in some
patients

Concurrent use of cetirizine with alcohol or other CNS depressants should
be avoided
Pregnancy Category B:

There are no adequate and well-controlled studies in pregnant women

Cetirizine should be used in pregnancy only if clearly needed
Nursing Mothers:

Cetirizine has been reported to be excreted in human breast milk

Use of cetirizine in nursing mothers is not recommended.
Paediatric patients
 The safety and effectiveness of cetirizine in pediatric patients under the
age of 6 months have not been established.
Overdosage



Somnolence, restlessness and irritability followed by
drowsiness
Treatment should be symptomatic or supportive
Cetirizine is not effectively removed by dialysis
Fexofenadine
Chemical name - (±)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1piperidinyl]-butyl]-a, a-dimethyl benzeneacetic acid hydrochloride
Empirical formula - C32H39NO4.HCl
Molecular weight - 538.13
Fexofenadine







Piperidine chemical class
Active metabolite of terfenadine, free from arrhythmogenic
potential
Selective peripheral H1 receptor antagonist activity
No anticholinergic or alpha1 adrenergic blocking effects
observed
Undergoes minimal biotransformation in the body
No sedative or other central nervous system effects observed
Does not cross the blood-brain barrier
Pharmacokinetics
Absorption
 Mean time to maximum plasma concentration - 2.6 hours
post-dose
 After administration of a single 60 mg capsule - mean
maximum plasma concentration is 131 ng/mL
 Pharmacokinetics are linear for oral doses up to a total daily
dose of 240 mg
 Co-administration of 180 mg fexofenadine hydrochloride
tablet with a high fat meal decreases Cmax of fexofenadine
by 20%
Contd….,
Distribution
 60% to 70% bound to plasma proteins, primarily albumin and
alpha1-acid glycoprotein
Metabolism
 Approximately 5% of the total dose-eliminated by hepatic
metabolism
Elimination
 Elimination half life - 14.4 hours
 Recovery of approximately 80% and 11% of the fexofenadine
hydrochloride dose in the feces and urine, respectively
 Absolute bioavailability - has not been established
Pharmacodynamics



Wheal and Flare - drug exhibits an antihistamine effect by 1
hour, achieves maximum effect at 2 to 3 hours, and an effect
is still seen at 12 hours
No evidence of tolerance to these effects after 28 days of
dosing
Greater than 49% inhibition of wheal area, and 74% inhibition
of flare area were maintained for 8 hours following the 30 and
60 mg dose
Effects on QTc




Fexofenadine hydrochloride does not prolong QTc
In subjects with chronic idiopathic urticaria, there were no
clinically relevant differences for any ECG intervals, including
QTc, between those treated with fexofenadine hydrochloride
180 mg once daily (n = 163) and those treated with placebo (n
= 91) for 4 weeks
No effect was observed on calcium channel current, delayed
K+ channel current, or action potential duration in myocytes
However not entirely safe in patients with long QTc,
bradycardia and hypokalemia
Advantages


Two 4-week multicenter, randomized, double-blind,
placebo-controlled clinical trials compared four
different doses of fexofenadine hydrochloride tablet
(20, 60, 120, and 240 mg twice daily) to placebo in
subjects aged 12 to 70 years with chronic idiopathic
urticaria (n=726)
Efficacy was demonstrated by a significant reduction
in mean pruritus scores (MPS), mean number of
wheals (MNW), and mean total symptom scores
Contd….,



Symptom reduction was greater and efficacy was
maintained over the entire 4-week treatment period
with fexofenadine hydrochloride doses of ≥60 mg
twice daily
No additional benefit of the 120 or 240 mg
fexofenadine hydrochloride twice daily dose was seen
No significant differences in the effect across
subgroups of subjects defined by gender, age, weight,
and race
Contd….,

Summary: It is clear that as a starting point an H1-antihistamine for the 21st
century should be effective, but non-sedative and non-cardiotoxic. In addition it is
desirable that an oral H1-antihistamine should be rapidly absorbed so that it can be
distributed to the target organ sites, be readily bioavailable, and have a half-life
sufficient to enable once daily dosing and to have clinical effect throughout a 24-h
dosing interval. The effect of the drug should be maintained with repeated dosing.
To give confidence in drug administration it should require no dosage adjustment in
renally or hepatically impaired individuals and have no significant drug
interactions, especially in view of past experience with drugs such as ketoconazole
and macrolide antibiotics that may modify hepatic metabolism. In addition to these
considerations there is a desire for a designer molecule that has activity over and
beyond H1-receptor blockade, thus providing an oral therapy with a broader 'antiinflammatory' activity. Such activity may underlie the improved benefit in quality
of life that is evident with some antihistamines over others. As we enter the 21st
century there are a number of oral H1-antihistamines that fulfil the
majority of these requirements, with fexofenadine, out of those most
widely used, appearing to come closest to the desired profile.

Howarth, PH The choice of an H1-antihistamine for the 21st century. Clinical & Experimental Allergy
Reviews. 2(1):18-25, May 2002.
Indications


Chronic idiopathic urticaria
Seasonal allergic rhinitis
Dosage and administration
Chronic Idiopathic Urticaria
 Adults and Children 12 Years and Older - 60 mg twice daily or
180 mg once daily with water
A dose of 60 mg once daily is recommended as the starting
dose in patients with decreased renal function
 Children 6 to 11 Years -30 mg twice daily with water
Adverse experience
Fexofenadine 60 mg
Twice Daily
(n=191)
Placebo
(n=183)
Dyspepsia
4.7%
4.4%
Myalgia
2.6%
2.2%
Back Pain
2.1%
1.1%
Dizziness
2.1%
1.1%
Pain in extremity
2.1%
0.0%
Adverse experiences reported in subjects 12 years of age and older
in placebo-controlled chronic idiopathic urticaria studies
Twice-daily dosing with fexofenadine hydrochloride in studies in the United States and
Canada at rates of greater than 2%
Adverse experience
Fexofenadine 180 mg
Once Daily
(n=167)
Placebo
(n=92)
Headache
4.8%
3.3%
Nasopharyngitis
2.4%
2.2%
Upper respiratory tract
infection
2.4%
2.2%
Once daily dosing with fexofenadine hydrochloride in a
study in the United States at rates of greater than 2%
Side effects with incidences less than 1%








Insomnia
Nervousness
Sleep disorders
Paranoia
Rash
Urticaria
Pruritus
Hypersensitivity reactions - angioedema, chest tightness,
dyspnea, flushing and systemic anaphylaxis
Drug interactions
Drug Interaction with Erythromycin and Ketoconazole

Co- administration of fexofenadine hydrochloride with either ketoconazole
or erythromycin lead to increased plasma concentrations of fexofenadine

Fexofenadine has no effect on the pharmacokinetics of either erythromycin
or ketoconazole

No differences in adverse events or QTc interval observed when
fexofenadine hydrochloride administered in combination with either
erythromycin or ketoconazole

Ketoconazole or erythromycin co-administration enhances fexofenadine
gastrointestinal absorption - due to transport - related effects, such as pglycoprotein

Ketoconazole decreases fexofenadine gastrointestinal secretion

Erythromycin may also decrease biliary excretion
Contd….,
Drug interaction with antacids
 Administration of 120 mg of fexofenadine hydrochloride
within 15 minutes of an aluminium and magnesium containing
antacid decreases fexofenadine Cmax by 43%
 Should not be taken closely in time with aluminum and
magnesium containing antacids
Contd….,
Interaction with fruit juices
 Fruit juices such as grapefruit, orange and apple may reduce
the bioavailability and exposure of fexofenadine
 The size of wheal and flare were significantly larger when
administered with either grapefruit or orange juices compared
to water.
 Bioavailability of fexofenadine was reduced by 36%
 Therefore, to maximize the effects of fexofenadine should be
taken with water
PRECAUTIONS
Pregnancy
 Category C. There was no evidence of teratogenicity in
experiments on rats.( Nonteratogenic Effects-Dose-related
decreases in pup weight gain and survival were observed in
rats )
 There are no adequate and well controlled studies in pregnant
women; should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus
Nursing Mothers
 There are no adequate and well-controlled studies in women
during lactation. Caution should be exercised when
administered to a nursing woman
Contd….,
Pediatric Use
 The safety and effectiveness - in pediatric patients under 6
years of age have not been established
Geriatric Use
 This drug is known to be substantially excreted by the kidney,
and the risk of toxic reactions to this drug may be greater in
patients with impaired renal function
 Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection
Overdosage




Dizziness, drowsiness, and dry mouth have been reported.
Consider standard measures to remove any unabsorbed drug
Symptomatic and supportive treatment is recommended
Following administration of terfenadine, hemodialysis did
not effectively remove fexofenadine, the major active
metabolite of terfenadine, from blood (up to 1.7% removed)
Loratadine
Chemical name- ethyl4-(8-chloro-5,6-dihydro-11Hbenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1- piperidinecarboxylate
Empirical formula - C22H23ClN2O2
Molecular weight - 382.89
Loratadine






Piperidine chemical class
Long-acting tricyclic antihistamine
Selective peripheral histamine H1-receptor antagonistic
activity
Antihistaminic effect begin within 1 to 3 hours, reaching a
maximum at 8 to 12 hours, and lasting in excess of 24 hours
No evidence of tolerance to this effect after 28 days of dosing
Neither loratadine nor its metabolites readily cross the bloodbrain barrier
Pharmacokinetics
Absorption
 Following oral administration of 10 mg tablets- maximum
concentration (Tmax) of 1.3 hours for loratadine and 2.5 hours
for its major active metabolite, descarboethoxyloratadine.
With food
 Increased the systemic bioavailability of loratadine and
descarboethoxyloratadine by approximately 40% and 15%,
respectively
 Time to peak plasma concentration (Tmax) of loratadine and
descarboethoxyloratadine delayed by 1 hour
 Peak plasma concentrations (C max) not affected by food
Contd….,
Metabolism
 Loratadine is metabolized to descarboethoxyloratadine
predominantly by cytochrome P450 3A4 (CYP3A4) and, to a
lesser extent, by cytochrome P450 2D6 (CYP2D6)
 In the presence of a CYP3A4 inhibitor ketoconazole,
loratadine is metabolized to descarboethoxyloratadine
predominantly by CYP2D6
 Concurrent administration of loratadine with either
ketoconazole, erythromycin (both CYP3A4 inhibitors), or
cimetidine (CYP2D6 and CYP3A4 inhibitor) - substantially
increases plasma concentrations of loratadine
Contd….,
Elimination
 Approximately 80% of the total loratadine dose administered;
equally distributed between urine and feces in the form of
metabolic products within 10 days
 The mean elimination half-lives in normal adult subjects (n =
54) were 8.4 hours (range = 3 to 20 hours) for loratadine and
28 hours (range = 8.8 to 92 hours) for
descarboethoxyloratadine
 Loratadine and descarboethoxyloratadine reach steady-state in
most patients by approximately the fifth dosing day
Contd….,
Special conditions
Pediatric

The pharmacokinetic profile of loratadine in children similar to that of
adults
Geriatric

AUC and peak plasma levels (Cmax) of both loratadine and
descarboethoxyloratadine were approximately 50% greater than those
observed in studies of younger subjects
Renal Impairment

AUC and Cmax increased by approximately 73% for loratadine and by
120% for descarboethoxyloratadine

Mean elimination half-lives of loratadine (7.6 hours) and
descarboethoxyloratadine (23.9 hours) were not substantially different

Hemodialysis does not have an effect on the pharmacokinetics of
loratadine or descarboethoxyloratadine in subjects with chronic renal
impairment
Contd….,
Hepatic Impairment
 AUC and Cmax of loratadine were double while the
pharmacokinetic profile of descarboethoxyloratadine was
not substantially different
 Elimination half-lives for loratadine and
descarboethoxyloratadine were 24 hours and 37 hours,
respectively, and increased with increasing severity of liver
disease
Indications


Chronic idiopathic urticaria
Seasonal allergic rhinitis
Dosage and administration




Adults and children 6 years of age and over: 20 mg once daily
Children 2 to 5 years of age: 5 mg once daily
In adults and children 6 years of age and over with liver failure or
renal insufficiency - starting dose should be 10 mg every other
day
In children 2 to 5 years of age with liver failure or renal
insufficiency- starting dose should be 5 mg every other day
Adverse
experience
Loratadine
10 mg qd
(n=1926)
Placebo
(n=2545)
Clemastine
I mg bd
(n=536)
Terfenadine
60 mg bd
(n=684)
Headache
12
11
8
8
Somnolence
8
6
22
9
Fatigue
4
3
10
2
Dry mouth
3
2
4
3
Reported adverse events with an incidence of more than 2% in placebo Controlled Chronic Urticaria clinical trials in patients 12 years of age and
older
Drug interactions


Loratadine co-administered with therapeutic doses of
erythromycin, cimetidine, and ketoconazole - increased
plasma concentrations (AUC 0-24 hrs) of loratadine and/or
descarboethoxyloratadine observed
There were no clinically relevant changes in the safety
profile of loratadine, as assessed by electrocardiographic
parameters, clinical laboratory tests, vital signs, and adverse
events
Precautions
Pregnancy Category B

No evidence of animal teratogenicity in studies performed in rats and
rabbits

No adequate and well-controlled studies in pregnant women

Loratadine should be used during pregnancy only if clearly needed
Nursing Mothers

Loratadine and its metabolite, descarboethoxyloratadine, pass easily into
breast milk

A decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother
Pediatric Use

The safety and effectiveness in pediatric patients under 6 years of age have
not been established
Overdosage




In adults, somnolence, tachycardia, and headache have been
reported with overdoses greater than 10 mg
Extrapyramidal signs and palpitations have been reported in
children with overdoses of greater than 10 mg
Treatment of overdosage - emesis followed by the
administration of activated charcoal to absorb any remaining
drug
Loratadine is not eliminated by hemodialysis
Comparision of cetrizine,
fexofenadine and loratadine
Pharmacokinetics and pharmacodynamics of 2nd
generation antihistamines

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Pharmacokinetics
Cetrizine
Fexofenadine
Loratadine
Onset
of
action
Tmax
hrs
Protein
binding
%
P450 metabolism
Food effect on
absorption
Rapid
1
93
;50% excreted
unchanged
delayed 60%
2.6
60-70
;95% excreted
unchanged
-
1.32.5
97
Rapid
Rapid
;3A4,2D6
Delayed 1hr
Contd…
Elimination
Half life (hrs)
Metabolism
Excretion
Cetrizine
8.3
Minimal
metabolism
Excreted
unchanged in
urine
Fexofenadine
14.4
Excreted
unchanged
80% in feces,
12% in urine
Loratidine
8-11
Active
metabolite descarboethoxyl
oratidine
Negligible
urinary
excretion
Comparison of half life in special populations
Population
Cetrizine
12a
Elderly
Fexofenadine
Desloratadine Loratadine
-
42a
17a
18c
15c
4b
Children
5 – 7b, c
Infants
3b
-
-
-
Liver disease
14a
16c
-
-
Renal failure
19a
19c
24a
8c




a - increased/prolonged as compared with healthy adults
b - decreased/shortened as compared with healthy adults
c - similar as compared with healthy adults
Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Recommended daily oral dosage of 2nd generation
antihistamines
Drug
Adults
Children
Elderly
Renal
impairment
Hepatic
impairment
Cetrizine
5-10 mg
6-11yr: 5-10
mg
0.5-5yr: 2.55 mg
5-10 mg
5 mg
5 mg
Fexofenadine
180 mg
6-11yr: 30
mg bd
180 mg
60 mg
180 mg
Loratadine
10 mg
>6yr: 10mg
Not stated in 10 mg q
product
48hrs
labelling
Desloratadine
5 mg
>12yr: 5 mg
5 mg

10 mg q 48hrs
5 mg q 48hrs 5 mg q 48hrs
Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Inflammatory responses affected by 2nd generation
Contd….,
Contd….,
Contd….,

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005


Newer antihistamines additionally have proven to
exert important anti-inflammatory effects
independent of their histamine-blocking actions,
including:
Downregulation of mediator release, intracellular
adhesion molecule expression, superoxide
generation, chemotaxis, cytokine expression
Upregulation of neutrophil and epithelial cell
immunoreactivity, number and function of [beta]adrenergic receptors


Hayashi S, Hashimoto S. Anti-inflammatory actions of new antihistamines. Clin
Exp Allergy 1999; 29: 1593-6
Walsh GM. The clinical relevance of the anti-inflammatory properties of
antihistamines. Allergy 2000; 55 Suppl. 60: 53-61
Suppression of wheal and flare response asssesed by
cutaneous testing
Contd….,

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005



On average, suppression of wheal and flare
reactions following dermal antigen challenge
tends to be greater following cetirizine
treatment than following other antihistamines.
Rank order of suppressive activity among
available antihistamines
cetirizine > fexofenadine > loratadine
Cetirizine is by far the most potent H1
antagonist

Juhlin L. A comparison of the pharmacodynamics of H1-receptor antagonists as
assessed by the induced wheal-and-flare model. Allergy 1995; 50: 24-30
Comparison of adverse event profile (%)




Clarinex® (desloratadine) tablets: package insert. Kenilworth (NJ): Schering Corporation, 2003
Allegra® (fexofenadine hydrochloride) capsules and tablets: package insert. Kansas City (MO):
Aventis Pharmaceuticals Inc., 2003
Claritin® (loratadine) tablets, syrup, and rapidly-disintegrating tablets: package insert. Kenilworth
(NJ): Schering Corporation, 2000
Zyrtec® (cetirizine hydrochloride) tablets and syrup: package insert. New York: Pfizer Inc., 2002
Eight most commonly reported events for loratadine in first month of
treatment and corresponding incidence densities for acrivastine,
cetirizine, and fexofenadine
Incidence density of events related to sedation in the first
month of treatment for four antihistamines
Potential adverse CNS effects of 2nd generation
Contd….,
Contd….,

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Incidence densities and number of reports of
sedation with four antihistamines
Studies that have evaluated CNS effects of secondgeneration antihistamines suggest that CNS effects
of:
Fexofenadine and loratadine

resemble those of placebo
Desloratadine
 generally similar to placebo
Cetirizine
 demonstrate mixed results, with no difference from placebo
shown in some studies
 modest although statistically significant deterioration in
psychomotor test results and cognitive abilities identified in
others
 Cetirizine sometimes is categorised as low or mildly sedating.

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Serious adverse events reported with 2nd generation
antihistamines in case reports

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Cardiac side effects
Cetirizine, desloratadine and fexofenadine are not likely to
produce important cardiac effects
None of Loratadine blocks IKr, but only at concentrations
unlikely to be attained clinically
The antihistamines may be entirely free of cardiac risks in
predisposed patients, but, if acute cardiac events do occur in
response to use of available second-generation antihistamines,
they are extremely rare




Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Pregnancy
Testing in several animal species has led to relegation to US
FDA
 Cetirizine and loratadine- Pregnancy Category B
 Fexofenadine and desloratadine- Pregnancy Category C
These designations, signify no evidence of teratogenicity but
possible fetotoxicity at varying multiples of the recommended
daily human dose
All of these agents carry the FDA-mandated caution that they
should be used in pregnancy only if clearly needed

F. Horak, U. P. Stubner; Comparative Tolerability of Second Generation Antihistamines: Drug safety
1999 May; 20(5): 385-401
Lactation



Fexofenadine and loratadine - compatible with
breast feeding
Cetirizine -not been evaluated in lactating
women( based on studies in dogs, appreciable
concentrations in milk may occur). For this
reason, use of cetirizine in nursing mothers is
not recommended
F. Horak, U. P. Stubner; Comparative Tolerability of Second Generation Antihistamines: Drug safety
1999 May; 20(5): 385-401
Clinically important drug interactions
The potential of second-generation antihistamines to cause
interactions with drugs metabolised by hepatic cytochrome
P450 (CYP) enzymes has been studied in considerable detail
The results of these studies suggest that newer secondgeneration antihistamines, including loratadine, which weakly
inhibits CYP2C19 and CYP2D6, in therapeutic concentrations
are unlikely to affect the pharmacokinetics of most coadministered drugs
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Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Summary of English-language, randomised clinical
trials evaluating the efficacy of 2nd generation
antihistamines in patients with Chronic Urticaria
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Antihistamines are clearly helpful in the treatment of chronic
urticaria
Cetrizine, fexofenadine and loratadine superior to placebo in
management
Cetrizine scores over fexofenadine in relative efficacy
Tharp MD. Cetirizine: a new therapeutic alternative for chronic urticaria. Cutis 1996; 58: 94-8
Ring J, Hein R, Gauger A, et al. Once-daily desloratadine improves the signs and symptoms of
chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J
Dermatol 2001; 40: 72-6
Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of
chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000; 84: 517-22
Handa S, Dogra S, Kumar B. Comparative efficacy of cetirizine and fexofenadine in the
treatment of chronic idiopathic urticaria. J Dermatolog Treat 2004; 15: 55-7
To summarize….
Antihistamines, and particularly 2nd generation, are a mainstay for the
treatment of chronic urticaria
2nd generation score over the 1st generation due to:
- Safer adverse effect profile
- Absence or minimal undesirable CNS effects
- Less interaction with other co-administered agents
- Additional antiallergic mechanisms
2nd antihistamines generally to be preferred over more sedating firstgeneration antihistamines, when indicated
Recommended for people who drive or must perform other tasks requiring
high psychomotor skills such as aircraft personnel
Although the risk of sedation was low, fexofenadine and loratadine may be
more appropriate for people working in safety critical jobs.
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Ronald D Mann, Gillian L Pearce, Nicholas Dunn, Saad Shakir; Sedation with "non-sedating"
antihistamines: four prescription-event monitoring studies in general practice: BMJ
2000;320:1184-1187 ( 29 April )
Studies that have evaluated CNS effects of secondgeneration antihistamines suggest that CNS effects
of:
Fexofenadine and loratadine
 Resemble those of placebo
Desloratadine
 Generally similar to placebo
Cetirizine
 Demonstrate mixed results, with no difference from placebo
shown in some studies
 Modest although statistically significant deterioration in
psychomotor test results and cognitive abilities identified in
others
 Cetirizine sometimes is categorised as low - or mildly
sedating.
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Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Data presently are inadequate to identify
a superior agent among available second generation antihistamines

Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005
Cetrizine
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On average, suppression of wheal and flare reactions following
dermal antigen challenge tends to be greater following cetirizine
treatment
Cetirizine is effective for treatment of: nasal
polyposis,pollinosis, atopic dermatitis in young children &
adults, minimal persistent inflammation/mite allergy,acute
urticaria/angioedema, cholinergic urticaria, solar urticaria,
eosinophilic cellulitis & itching associated with burn wounds
Cetirizine was at least 3.5 times more likely to result in reports
of sedation than other second-generation antihistamines
Fexofenadine
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Fexofenadine has proven effective for treatment of pruritus
associated with atopic dermatitis in adults
Effective in treatment of chronic urticaria
Fexofenadine proved ineffective as a possible means to
increase total motile sperm counts in infertile men with
elevated numbers of testicular mast cells
To date, fexofenadine is the only second-generation
antihistamine proven to facilitate substantial cost savings
upon mandated formulary use by a large healthcare service
provider
Loratadine
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Loratadine is effective for nonallergic rhinitis with
eosinophilia
Desloratadine markedly inhibits reactions in cold -induced
urticaria
Loratadine blocks IKr, but only at concentrations unlikely
to be attained clinically
Cetrizine, desloratadine and fexofenadine are not likely to
produce important cardiac effects
To conclude….
Substantial clinical evidence supports
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Usefulness of second-generation antihistamines for treatment of allergic
rhinitis, chronic urticaria and possibly other allergic disorders
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The safety of available antihistamines in this group, and serious adverse
effects have occurred only rarely
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Judicious selection and use of these drugs facilitates patient care that
generally is cost effective
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Golightly, Larry K 1; Greos, Leon S 2 Second-Generation Antihistamines: Actions and Efficacy in
the Management of Allergic Disorders. Drugs. 65(3):341-384, 2005