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Publication Date: June 2003
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THE USE OF LEUKOTRIENE
RECEPTOR ANTAGONISTS TO
TREAT ALLERGIC RHINITIS


Valli Jeanenne, Pharm.D. Candidate



Introduction
Allergic rhinitis (AR) is an IgE-mediated
hypersensitivity reaction of the nasal mucosa to al-
lergens such as animal dander, pollen, dust mites or
mold. Symptoms of AR include sneezing, itching
of the nose and palate prurituss), clear nasal dis-
charge (rhinorrhea), and nasal congestion. Allergic
rhinitis is often associated with itchy, swollen, wa-
tery eyes (allergic conjunctivitis) as well as con-
stant clearing of the throat and snoring.1 Asthma is
a common concomitant disease state with more
than 90 percent of asthma patients reporting at least
one AR symptom and approximately 85 percent of
asthma patients reporting at least four AR symp-
toms.2 Allergic rhinitis may affect people season-
ally or year round depending on the allergen. Com-
plications of untreated AR include ear infections,
sinusitis, recurrent sore throats, cough, headache,
difficulty sleeping, fatigue, irritability, and poor
school performance.3 Approximately 26 percent of
the U.S. population is affected by AR2 and an esti-
mated 80 million people suffer from nasal/ocular
symptoms for more than a week every year.4 Aller-
gic rhinitis sufferers consume over $6 billion in
prescription medications a year.1 One study esti-
mates that AR sufferers miss 3.5 million work days
and more than 2 million school days per year.5 Ac-
cording to a recent Harvard study, AR costs U.S.
employers $5.4 billion annually in sick days and


may be as high as $7.7 billion if loss of productiv-
ity is included in the calculation.6
Pharmacological therapies have included
intranasal cromolyn, oral and topical antihista-
mines, oral and topical decongestants, and oral and
topical corticosteroids. The newest FDA approved
AR agent is montelukast. It is a leukotriene recep-
tor antagonist (LTRA) approved in January 2003
for the treatment of seasonal AR. It is marketed by
Merck as Singulair and was originally approved in
February 1998 for the treatment of asthma.7 A sec-
ond member of the same class of agents whose off-
label uses include treatment of AR is zafirlukast
(Accolate).8 It was approved for the treatment of
asthma in September 1996 and is marketed by As-
traZeneca. Pranlukast (Ultair) is a third LTRA, but
it is not marketed in the U.S. This article will ad-
dress the pharmacology, AR clinical trials, adverse
effects, dosing, and costs of the two LTRAs avail-
able in this country, montelukast and zafirlukast.

Pathogenesis of Allergic Rhinitis
The inflammatory reaction of AR occurs in
two phases denoted as early-phase and late-phase.
Early-phase symptoms occur within minutes of ex-
posure to a sufficient amount of allergen. These
symptoms, such as watery rhinorrhea, sneezing,
itching and the sensation of congestion, are due to
vasodilation, increased vascular permeability,
stimulation of mucus-producing glands and neu-
ronal stimulation. Many mediators are involved in-
cluding histamine, platelet activating factor, pros-
taglandins, cytokines, tryptase, and leukotrienes,
with histamine as a prominent factor in the early-
phase response. Chemotactic factors released dur-
ing the early-phase attract additional inflammatory
mediators to the nasal mucosa, particularly baso-
phils, neutrophils, eosinophils and T lymphocytes.


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Table 1. Pharmacokinetics (PK) of leukotriene receptor antagonists for special populations8'11-13

Population Montelukast Zafirlukast
Children 2-5 y 4 mg tablet is similar to 10 mg tablet in adults No indication for this age group
Children 6-14 y (MTK) 5 mg tablet is similar to 10 mg tablet in adults 10 mg tablet is similar to 20 mg tablet in adults
Children 5-11 y (ZFK)
Adolescents >15 y (MTK) 10 mg tablet is similar to 10 mg tablet in adults 20 mg tablet is similar to 20 mg tablet in adults
Adolescents >12 y (ZFK)
Elderly > 65 y Small decrease in clearance Clearance reduced by 50-60%


Hepatic Insufficiency
Renal Insufficiency


CL reduction dependent on loss of hepatic fx CL reduction dependent upon loss of hepatic fx
No clinical affect on PK No clinical affect on PK


MTK=montelukast, ZFK=zafirlukast, CL=clearance


This second wave of mediators is responsible for
the late-phase response hours later, which is charac-
terized primarily by nasal obstruction, but also in-
cludes a sustained perpetuation of the rhinorrhea,
sneezing and itching from the early-phase. The cys-
teinyl leukotrienes LTC4, LTD4 and LTE4, pro-
duced by eosinophils during the late-phase, play a
key role in the perpetuation of nasal symptoms, es-
pecially congestion.9 Many studies have shown in-
creased concentrations of leukotrienes in nasal lav-
ages after allergen challenge.10 Montelukast and
zafirlukast selectively bind to cysteinyl leukotriene
receptors without agonist activity. Blockade of the
cysteinyl leukotriene receptor inhibits both upper
and lower airway inflammation mediated by vari-
ous allergens, thus the drugs may be used for both
asthma and AR.8' 11-13

Pharmacokinetics
The pharmacokinetics profiles for the
LTRAs are not affected by race or gender. Both
zafirlukast and montelukast are administered orally
and have rapid absorption, within 3-4 hours. Both
are highly bound to plasma proteins (>99%) and
have minimal distribution across the blood-brain
barrier. Zafirlukast and montelukast are hepatically
metabolized by the cytochrome P450 2C9 and
3A4/2C9 systems, respectively. At therapeutic con-
centrations, zafirlukast is also an inhibitor of
CYP3A4 and CYP2C9. Montelukast, on the other
hand, is not an inhibitor of CYP450 isoemzymes.
Both drugs are primarily excreted via the biliary
route.8, 11-13
The pharmacokinetics of the LTRAs for
special populations are summarized in Table 1. As
long as smaller doses are administered, the plasma


concentrations profiles of LTRAs in children are
similar to that of healthy young adults. With
healthy young adults as the standard, the pharma-
cokinetics of LTRAs differ in the elderly and pa-
tients with hepatic insufficiency.8' 11-13
The oral bioavailability of a 10 mg montelu-
kast tablet is not affected by food in adults, so it
may be taken without regard to meals. The
bioavailability of 4 mg and 5 mg chewable tablets
in children and adolescents is reduced by 37%
when taken with a meal. In spite of the reduced
bioavailability, there is no reduction in the clinical
efficacy, so it may also be taken without regard to
meals.11 The bioavailability of zafirlukast, on the
other hand, is reduced by approximately 40% when
taken with meals, so it should be taken one hour be-
fore or two hours after a meal.8

Clinical Trials
Donnelly et al. compared zafirlukast to pla-
cebo for relief of acute seasonal AR. In this ran-
domized, double-blind, parallel-group trial, 164
people with documented symptomatic ragweed al-
lergy spent eight hours a day for two consecutive
days in an outdoor park during ragweed season in
Iowa. After 3 hours on the first day, they were ran-
domized to receive a single dose of 10, 20, 40, or
100 mg zafirlukast or placebo. Subjects self-
assessed their symptoms (none, slight, mild, moder-
ate, or severe) hourly at the park and every 2 hours
at home for 2 days. Inhaled 8-agonist use was al-
lowed during the trial for relief of symptomatic
bronchoconstriction. Zafirlukast relieved nasal con-
gestion and rhinorrhea more effectively than pla-
cebo (p<0.05). Sneezing was also reduced
(p<0.05), an unexpected result since sneezing is


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Table 2. Efficacy of leukotriene receptor antagonists in seasonal allergic rhinitis5' 9,13-16

Reference Design Duration Treatment N Results


Donnelly et al.
200213

Flowers et al.
199015

Philip et al.
200210


Lis et al.
2001'8



Meltzer et al.
200016



Wilson et al.
200119


Pullerits et al.
199917

Wilson et al.
200120

Wilson et al.
200121

Wilson et al.
200122


Wilson et al.
200023


R, DB, PC, PG


2 days


DB, PC, C not specified


R, DB, PC, PG



R, DB, PC, PG




R, DB, PC, PG




R, SB, PC, C



R, DB, PC, PG


R, SB, PC, DD,
C


R, SB, PC, C


R, SB, PC, DD,
C



R, SB, PC, PG


ZFK 10, 20, 40, 100mg
PBO


MTK 10mg
PBO


MTK 10mg
2 weeks LTD 10mg
PBO
MTK 10mg + LTD 10mg
2 weeks MTK 10mg
2 weeks
LTD 10mg
PBO
MTK 10mg + LTD 10mg
MTK 10mg
2 weeks MTK 20mg
LTD 10mg
PBO
FXD 120mg
MTK 10mg
2 weeks
LTD 10mg
PBO
ZFK 40mg
7 weeks BCM 400mcg
PBO
MTK 10mg
2 weeks Inhaled BDS 400mcg +
intranasal BDS 200mcg
MTK 10mg + CTZ 10mg
2 weeks MTS 200mcg
PBO
MTK 10mg + CTZ 10mg
2 weeks Inhaled BDS 400mcg +
intranasal BDS 200mcg

CTZ 10mg + MTK 10mg
4 weeks CTZ 10mg + MTS 200mcg
CTZ 10mg + PBO


ZFK > PBO


MTK = PBO


LTD = MTK > PBO


1302


MTK + LTD = monotherapy with
907
either agent > PBO



MTK + LTD > monotherapy with
either agent = PBO



37 FXD = MTK + LTD > PBO


BCM > ZFK = PBO


BDS > MTK > PBO


22 MTS = MTK + CTZ > PBO



21 BDS = MTK + CTZ > PBO



CTZ = CTZ + MTK = CTZ + MTS
38P
> PBO


N=number of patients, R=randomized, DB=double-blind, PC=placebo-controlled, PG=parallel-group, ZFK=zafirlukast, PBO=placebo, C=crossover,
MTK=montelukast, LTD=loratadine, SB=single-blind, FXD=fexofenadine, BCM=beclomethasone, DD=double-dummy, BDS=budesonide, CTZ= cetirizine


thought to be histamine-mediated. The 20 and 40
mg doses relieved symptoms more consistently
than either the 10 or 100 mg doses. Overall, there
was greater symptom relief on the second day.14
Flowers et al. compared montelukast to pla-
cebo in a double-blind, placebo-controlled cross-
over antigen-challenge study of 12 participants with
documented symptomatic ragweed and grass pollen
allergies. A solution of ragweed or mixed grass pol-
len extract was delivered intranasally to the sub-
jects. There was no clinical difference between


rhcrmlinte


montelukast and placebo in relief of rhinorrhea, na-
sal congestion, throat irritation or sneezing.15
Philip et al. examined the daily administra-
tion of montelukast 10 mg, loratadine 10 mg, and
placebo for relief of seasonal AR. In spring 2000,
1302 people were evaluated in a randomized, dou-
ble-blind, parallel-group study at 50 study centers
in the U.S. and Canada. Subjects rated and recorded
their daytime and nighttime symptoms. Both nasal
symptoms (nasal congestion, rhinorrhea, nasal pru-
ritus and sneezing) and ocular symptoms (tearing,


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I I I I I I I I i i







Table 3. Adverse effects of leukotriene receptor antagonists compared to placebo8'11-13,19
Adverse Effect Montelukast vs. Placebo Zafirlukast vs. Placebo

Headache 18.4% 18.1% 9.9% 9.0%
Nausea <1% <1% 2.6% 2.2%
Diarrhea 3.1% 3.1% 2.3% 1.8%
Abdominal pain 2.9% 2.5% 1.6% 1.2%
Dyspepsia 2.1% 1.1% 1.3% 1.2%
Rash 1.6% 1.2% <1% <1%
Cough 2.7% 2.4% <1% <1%
Fever 1.5% 0.9% 1.6% 1.1%


ocular pruritus, redness and puffiness) were as-
sessed during a 3- to 5-day placebo run-in period
followed by a two-week double-blind treatment pe-
riod. Montelukast provided significant relief com-
pared to placebo (p<0.001), as did loratadine
(p<0.001 for daytime symptoms, p<0.003 for night-
time symptoms). A statistical comparison between
montelukast and loratadine was not incorporated
into this study. However, according to the authors,
mean changes from baseline numerically favored
montelukast over loratadine for the night-time
symptoms score (difficulty going to sleep, night-
time awakenings, congestion upon awakening);
while daytime nasal, eye, and daily composite
scores numerically favored loratadine."10
The Montelukast Study Group published a
randomized, placebo-controlled comparison of
combination therapy with montelukast and
loratadine vs. monotherapy with each agent. Sub-
jects were randomized into 5 treatment groups and
received montelukast 10 mg, montelukast 20 mg,
loratadine 10 mg, montelukast 10 mg + loratadine
10 mg, or placebo. The study consisted of 453 sub-
jects participating in a 1-week placebo run-in pe-
riod followed by a 2-week treatment period. Nei-
ther montelukast nor loratadine monotherapy was
rated significantly more effective than placebo at
relieving daytime nasal symptoms. Combination
treatment gave better results than monotherapy
with either agent. 16
Pullerits et al. published the results of a ran-
domized, double-blind, placebo-controlled, paral-
lel-group trial comparing zafirlukast 20 mg bid, in-
tranasal beclomethasone 200 mcg bid, and placebo.
Thirty-two patients with documented seasonal grass


pollen AR participated in this 50-day study. Pa-
tients began using their randomly assigned treat-
ment three weeks prior to the beginning of grass
pollen season and continued throughout the grass
pollen season. Symptoms of sneezing, rhinorrhea,
nasal itch, and blockage were rated and recorded
daily by each subject. There was no significant dif-
ference between zafirlukast and placebo. However,
subjects consistently rated the beclomethasone
treatment superior to both zafirlukast and placebo
on daily symptom relief. In addition, six weeks af-
ter the study began, nasal biopsies were evaluated
for eosinophil cationic protein (labeled with mouse
antihuman EG2 antibody) as a marker of activated
eosinophils. The beclomethasone treatment group
showed a significantly smaller increase in EG2-
positive cells than did the placebo group. The in-
crease in EG2-positive cells was not significantly
different between the placebo and the zafirlukast
groups.17 The results of these and other pertinent
studies are summarized in Table 2.

Adverse Effects
Montelukast's adverse effects have been
studied in over 2900 adults and children age six and
over for periods of up to two years.19 Likewise, the
adverse effects of zafirlukast have been evaluated
in more than 4000 adults and children age 12 and
over for periods ranging from 13 weeks to more
than a year.13 The adverse effect profile of LTRAs
is similar to that of a placebo (Table 3), with head-
ache being the most commonly reported adverse
reaction.19 Asymptomatic elevations in hepatic en-
zymes have been reported in 1.5%-1.8% of adults
using zafirlukast during post-marketing studies.


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Table 4. Leukotriene receptor antagonists dosages for various populations8' 11
Population Montelukast Zafirlukast
Adults and adolescents 10 mg qd (adolescents > 15 y) 20 mg qd (adolescents > 12 y)
Adolescents and children 6-14 y 5mg qd Contraindicated for < 12 y
Children 2-5 y 4mg qd Contraindicated
Children and infants < 2 y Contraindicated Contraindicated
Elderly No dosing adjustment needed No dosing adjustment needed
Patients with renal impairment No dosing adjustment needed No dosing adjustment needed
Patients with hepatic impairment Use with caution Use with caution
Pregnant women No dosing adjustment needed No dosing adjustment needed
Lactating women Contraindicated Contraindicated


There have been rare cases of hyperbilirubinemia
or jaundice associated with zafirlukast. It is recom-
mended that liver function enzymes be taken im-
mediately should a patient on an LTRA develop
symptoms of hepatic dysfunction. If enzymes are
elevated, the LTRA should be discontinued.8
Churg-Strauss syndrome, a systemic eosi-
nophilic vasculitis, has been associated with both
LTRAs. It is very rare and in most, but not all
cases, it is associated with a reduction in oral corti-
costeroid therapy. Symptoms of Churg-Strauss in-
clude eosinophilia, inflammation of blood vessels,
especially in the lungs, leading to worsening pul-
monary symptoms. It occurs more often in women
than in men. A causal relationship between LTRAs
and this syndrome has not been established.8' 13

Dosing
Montelukast is available as a 10 mg film-
covered tablet and 4 mg and 5 mg chewable
cherry-flavored tablets. Zafirlukast is available as a
10 mg and 20 mg tablet. Dosages are listed in Ta-
ble 4. Both LTRAs are Pregnancy Category B.8 11

Drug Interactions
Zafirlukast increases the AUC (63%) and
half-life (36%) of S-warfarin, resulting in a 35%
increase in prothrombin time. Co-administration of
zafirlukast (40 mg/day) and aspirin (650 mg qid)
can cause a 45% increase in zafirlukast's concen-
tration. Zafirlukast's inhibition of CYP 3A4 and
2C9 has the potential to increase the concentrations
and risk of toxicity of drugs metabolized by one or
both of these isoenzymes. No significant effect on
oral contraceptives has been observed.8' 13
Montelukast has no clinically significant


interactions with theophylline, fexofenadine, oral
contraceptives, digoxin or warfarin. Phenobarbital
can decrease montelukast AUC by approximately
40%. Because montelukast is metabolized via CYP
3A4 and 2C9, there is a potential for interactions
with other drugs that are enzyme inhibitors
(ketoconazole, erythromycin) or enzyme inducers
(carbamazepine, phenobarbital, phenytoin).11' 12

Cost
As of March 2003 a survey of three phar-
macies in the Gainesville, FL area revealed a dif-
ference of over $22 and $41 in quoted zafirlukast
and montelukast prices, respectively (Table 5).

Summary
Montelukast and zafirlukast have been used
for the treatment of seasonal AR. However, only
montelukast has recently received FDA approval
for such indication. Leukotrienes play a key role in
perpetuation of AR symptoms, especially nasal
congestion. The pharmacology of LTRAs, block-
ade of the cysteinyl leukotriene receptor resulting
in inhibition of one pathway of airway inflamma-
tion, supports their indication for the treatment of
AR. However, clinical trials have provided incon-
sistent results comparing LTRAs to placebo for im-
provement of AR.

References
1. Becker, Jack MD. Allergic Rhinitis. EMedicine. May 22,
2002. Available from: URL: mhp \ \ \\ medicinen.
com/PED/topci2560.htm.
2. American College of Allergy, Asthma & Immunology.
Press Release: Nov. 19, 2001. Available from: URL:
http://www.medem.com/MedLB/article.
3. American College of Allergy, Asthma & Immunology.


Pha ma oteVolme 8, ssu 9 une200


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Volume 18, Issue 9 June 2003








Table 5. Retail cost of a 30-day supply of LTRAs in Gainesville, FL area pharmacies

LTRA Pharmacy #1 Pharmacy #2 Pharmacy #3

Zafirlukast 10mg, #60 $74.46 $85.65 $96.19
Zafirlukast 20mg, #60 $74.46 $85.65 $96.19
Montelukast 4mg, #30 $89.88 $102.95 116.19
Montelukast 5mg, #30 $89.88 $102.95 $116.29
Montelukast 10mg, #30 $83.46 $102.95 $125.09


Medical Library: Rhinitis. Mar 2000. Available from:
URL: http://www.medem.com/MedLB/article.
4. Allergic Rhinitis: A Pharmacy Perspective. PowerX-Pak
C.E. 2000. Alert Marketing. Nov 2000. Available from:
URL: hup % %\ .powerpak.com/CE/Allergic/lesson.cfm
5. Virant FS. Allergic rhinitis. Immunol Allergy Clin North
Am. 2000;20:265-282.
6. Montminy J. Allergic rhinitis costs employers billions a
year. Harvard Medical School Office of Public Affairs.
Press: Oct. 16, 2001. Available from: URL: http://
www.hmw.harvard.edu/news/releases/1016kessler.html.
7. FDA approves Singulair for seasonal allergic rhinitis.
Merck Newsroom. Produce News Press Release. Jan 2,
2003. Available from: URL: http://www.merck.com/
newsroom/press releases/010203.html.
8. Zafirlukast Drug Monograph. Clinical Pharmacology
Online 2003. Gold Standard Multimedia. Available from:
URL: mhp \%\\ .cpip.gsm.com.
9. Nathan RA, MD. Pharmacotherapy for allergic rhinitis: a
critical review of leukotriene receptor antagonists com-
pared with other treatments. Annals of Allergy, Asthma,
& Immunology 2003;90:182-189.
10. Philip G, Malmstrom K, et al. Montelukast for treating
seasonal allergic rhinitis: a randomized, double-blind,
placebo-controlled trial performed in the spring. Clin Exp
Allergy 2002;32:1020-1028.
11. Montelukast Drug Monograph. Clinical Pharmacology
Online 2003. Gold Standard Multimedia. Available from:
URL: mhp \%\\ .cpip.gsm.com.
12. Montelukast Drug Monograph. PDRElectronic Library
2002-2003. Thomson-Medical Economics. Available
from: http://pdrel.thomson.hc.com.
13. Zafirlukast Drug Monograph. PDRElectronic Library
2002-2003. Thomson-Medical Economics. Available
from: URL: http//pdrel.thomsonhc.com.
14. Donnelly A, Glass M, et al. The leukotriene D4-receptor
antagonist, ICI 204, 219, relieves symptoms of acute sea-
sonal allergic rhinitis. American Journal of Respiratory &
Critical Care Medicine 1995;151:1734-1739.
15. Flowers BK, Proud D, et al. The effect of a leukotriene
antagonist on the early response to antigen. Otolaryngol-
ogy-Head and Neck Surgery 1990;102 (3):219-224.
16. Meltzer EO, Malmstrom K, et al. Concomitant montelu-
kast and loratadine as treatment for seasonal allergic
rhinitis: a randomized, placebo-controlled clinical trial. J
Allergy Clin Immunol. 2000:105:917-922.
17. Pullerits T, Ana R, et al. Randomized placebo-controlled
study comparing a leukotriene receptor antagonist and a
nasal glucocorticoid in seasonal allergic rhinitis. Am J


Respir Crit Care Med. 1999; 159:1814-1818.
18. Lis K, Malmstrom K, et al. Treatment of fall allergic
rhinitis with montelukast alone or in combination with
loratadine in a multicenter, double-blind, randomized,
placebo-controlled study [abstract]. J Allergy Clin Immu-
nol 2001;107 (pt 2):S158. Abstract 520.
19. Wilson AM, Orr LC, et al. A comparison of once daily
fexofenadine (FEX) alone or the combination of monte-
lukast plus loratadine (ML + LT) on symptoms and nasal
peak flow in seasonal allergic rhinitis (SAR) [abstract]. J
Allergy Clin Immunol 2001:107 (2 pt 2): abstract 1022.
20. Wilson M, Dempsey OJ, et al. A comparison of topical
budesonide and oral montelukast in seasonal allergic
rhinitis and asthma. Clin Exp Allergy 2001;31:616-24.
21. Wilson AM, Orr LC, et al. Effects of monotherapy with
intranasal corticosteroid or combined oral antihistamine
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rhinitis. Clin Exp Allergy 2001;31:61-68.
22. Wilson AM, Simms EJ, et al. Effects of topical corticos-
teroid and combined mediator blockade on domiciliary
and laboratory measurements of nasal function in sea-
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2001;87:344-349.
23. Wilson A, Dempsey OJ, et al. Evaluation of treatment
response in patients with seasonal allergic rhinitis using
domiciliary nasal peak inspiratory flow. Clin Exp Allergy
2000;30:833-838.


The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


Pha rma Note Volume 18, Issue 9 June 2003


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