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Selection and Use of Essential Medicines
Review of the role of
Anti Leukotrienes
in the therapy of
Allergic Rhinitis in children
Jan 12th
, 2013
Reviewed by:
Dr Achal Gulati, MS; FIAMS
Director Professor,
Department of ENT & Head and Neck surgery,
Maulana Azad Medical College,
New Delhi. India
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Summary:
Allergic rhinitis (AR) is considered a significant global health challenge. AR is a
major cause of patient visits to physicians in the United States, and commonly
complicating management of other conditions such as asthma and chronic sinusitis.
If AR is left untreated, the individual is at increased risk of missing work, school,
prevalent sleep disruption and diminished day time performance, resulting in
impaired quality of life. The economic burden of allergic rhinitis is substantial, due
to a rising prevalence of AR in both children and adults. The peak onset of AR
occurs primarily in the adolescent years. Research studies estimate prevalence of
AR in children, to be about 10-20%. The current burden of allergic diseases,
estimated by both direct and indirect costs, is approximately $4-10 billion/year in
the United States. The economic burden of AR in Europe is also substantial,
costing 1089 Euros per child/adolescent and 1543 Euros per adult in Europe. In
addition, if asthma is considered a co-morbidity of AR, the costs involved for
disease management, increase manifold.
Treatment goals for AR, is relief of symptoms. Therapeutic options available to
achieve this goal include avoidance measures, oral antihistamines, intranasal
corticosteroids, leukotriene receptor antagonists (LTRA), and allergen
immunotherapy. Daily use of an LTRA, antihistamine or decongestant, or a
combination can be considered instead of, nasal steroids. The newer, second-
generation (i.e. non-sedating) antihistamines are usually preferable to the older
first-generation antihistamines to avoid sedation and other adverse side effects
associated with them. LTRA’s may be preferable to manage AR symptomology,
independently or in combination with intra nasal steroid sprays.
The following molecules in this (LTRAs) group are Monteluakst, Pranlukast and
Zafirlukast. All are readily available for use. Montelukast is indicated in adult and
Page 3 of 70
pediatric patients 6 months of age and older for the prophylaxis and chronic
treatment of asthma, including the prevention of day and night-time symptoms
from AR, the treatment of aspirin-sensitive asthmatic patients, and the prevention
of exercise induced broncho-constriction.
Research studies involving LTRA treatment for AR and associated co-morbidities,
resulted in significantly less symptom severity after the treatment compared to
control. Studies showed a positive correlation between severity of rhinitis, and
effectiveness of LTRA intervention, resulting in improved nasal symptoms and
quality of life (QOL). It was also noted that addition of an Intra Nasal Steroid
Spray (INS) when added to the LTRA, enhanced the efficacy of the management
of both, AR and Asthma. This better enhancement could be achieved by either a
higher dose of LTRA or a lower dose of LTRA in case an INS is added.
Due to LTRAs recent inclusion for AR treatment, there are no current studies
evaluating LTRAs efficacy in children less than 6 years of age. Recent studies
however, have found favorable results using Montelukast is safe for all age groups
during short-term and long-term administration, even at doses substantially higher
than the recommended dose. The safety profile of Montelukast did not change with
long-term use.
Montelukast has the advantage of being able to be administered orally whereas
intranasal steroids may not be practical for small children. This is one of the
aspects that needed to be considered as even though efficacy might be less, the
effectiveness may be more. This is an important point which must be addressed. It
is an important contributing factor (inadequate drug delivery to the tissue/improper
technique of drug delivery, administration/inconvenient method of drug
administration etc.) has been shown to be major contributory factors in the non
efficacy of treatment schedules involving inhalant therapy. This is partly
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responsible in poor control of AR/Asthma in pediatric age group or in fact any age
group.
The treatment modality is a multi-modal therapy ie INS with anti histamine versus
INS with LTRA. So the comparison comes down to the use of anti histamine or
LTRA in combination with the INS. The drawbacks of the use of anti histamine are
more than with LTRA. Considering these two factors, we could say that LTRA
may a better option being safe to use and devoid of harmful side effect and and
should be included in WHO-EML for children to be used as a stand alone or in
augmentation with the INS.
In summary, initiating therapy with Montelukast was associated with better asthma
and AR control and resulted in reduced use of healthcare resources and lower costs
of asthma rescue and allergy medications compared with initiating inhaled
corticosteroid (ICS) therapy or with a placebo. Moreover, a decrease in
prescription rates and costs were observed in the Montelukast cohort for rescue
medications. Even in case of using Montelukast with an INS, it would be
preferable to use Montelukast as the the choice option in management of AR.
Recommendations:
Leukotriene antagonists should be included in the WHO Essential Medicines
List for children.
The recommended molecule is Montelukast in the dose of 5mg once daily
for children aged 6-14 years as Chewable tablets and Oral Granules..
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Aims & Objective:
Review the role of Leukotriene antagonists in the management of childhood
allergic rhinitis.
Introduction:
The first recorded case of allergic rhinitis (catarrhus aestivus) was described by Sir
John Bostock, who presented himself as a case report to the Medical and Surgical
Society of London in 1819. At the dawn of the 20th century, there were only
several thousand members of the U.S. Ragweed Association. One hundred years
later, allergic rhinitis has become the most common allergic or immunologic
disorder in the U.S. population and it now affects an estimated one in seven
Americans. Allergic rhinitis is acknowledged as a significant health challenge on a
global scale. Allergic rhinitis is a major cause of patient visits to physicians in the
United States, commonly complicates management of other
conditions(eg.asthma, chronic sinusitis), and if untreated or undertreated can lead
to considerable morbidity including missed work or school, sleep disruption,
diminished daytime performance, and impaired quality of life The economic
burden of allergic rhinitis is substantial.
A rising prevalence of allergic rhinitis has been found not only in children but also
in adults. The peak in incidence of allergic rhinitis occurs during the young adult
years. Although prevalence declines with age, allergic rhinitis is also an important
health concern in older adults. Incidence of allergic rhinitis is equal in male and
female patients.
Epidemiologic studies have consistently demonstrated that allergic rhinitis
and asthma commonly coexist. Allergic rhinitis is often associated with asthma and
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is a risk factor for developing asthma; in addition, many patients with allergic
rhinitis demonstrate increased bronchial hyper responsiveness to inhalation
challenge with histamine or methacholine1.
Methods:
To review the role of Leukotriene antagonists in the management of childhood
allergic rhinitis, we reviewed the references in pubmed, Cochrane, Medline and
other web portals i.e. Medscape, Google wild search to collate the relevant
information on safety and efficacy of Leucotriene antagonists (Montelukast) in
human subjects.
Note: The following molecules in this Leukotriene Receptor Antagonists (LTRAs)
group: Monteluakst, Pranlukast and Zafirlukast are available. We searched for
LTRA and their utility in AR. We found most of the studies with these LTRAs
were conducted in Asthmatic and we found very few in AR and then in pediatric
patient. Secondly they represent their class effects mostly. However in some of the
articles Montelukast was considered a better molecule as compared to others. We
therefore choose to mention the Montelukast as a reference for our review.
However, it may be mentioned that most of the controlled trials comparing the 3
drugs did not find any significant difference in the action and effects of the 3 drugs
and that is the other reason that we decided to take Montelukast as the prototype
drug in this group
We have explored and evaluated Montelukast and its relevant studies as a
reference to describe tolerability, safety and efficacy and advantages of using
LTRAs in managing AR in children since it was a widely available molecule.
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Prevalence of Allergic Rhinitis (Public health need):
Approximately 20% of the world population suffers from allergic diseases that
cause a substantial health care burden2. Allergic rhinitis is a prevalent yet under-
appreciated inflammatory disorder of nasal mucosa, which is characterized by
pruritus, sneezing, rhinorrhea, and nasal congestion. Allergic rhinitis affects 400
million people worldwide, with high prevalence recorded in industrialized nations,
especially English-speaking ones. Researchers on the International Study of
Asthma and Allergies in Childhood (ISAAC) project investigated the prevalence
and possible causes of atopic diseases, using standardized methods to describe the
prevalence and severity of asthma, rhinitis and eczema with validated
questionnaires in children around the world. The first phase of ISAAC took place
between 1992 and 1998. Prevalence of rhinitis with itchy watery eyes was
estimated to be around 0.8%–14.9% (median 6.9%) in children aged 6-7 years and
1.4%–39.7% (median 13.6%) in those aged 13-14 years. The lowest prevalence
was in parts of Eastern Europe and south and central Asia. The third phase of
ISAAC (at least 5 years later) showed prevalence of rhinitis with itchy watery eyes
in the past year was 1.8%–24.2% in children aged 6-7 years (median 8.5%) and
1.0%–45.0% (median 14.6%) in those aged 13-14 years3.
But most studies put the figure of the prevalence of allergic rhinitis in children to
about 10% to 20%. In selected other international studies, the prevalence was
reported as follows: Germany (1992; ages 9 to 11), 9.5%; Germany (1994; ages 13
to 16), 22.7%; Italy (1988; ages 9 to 15), 13.1%; Japan (1994; ages 6 to 15),
12.9%; Norway (1994; 7 to 12), 20.6%; Poland (1995; ages 6 to 15), 16.7%;
Sweden (1995; age 7), 13%; UK (1989; age 12), 14.9%; UK (1992; ages 8 to 13),
11.9%; U.S. (1994; age 6), 42%4. In a community-based study in London, the
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minimum prevalence of hay fever (SAR is also termed as Hay fever) in adults
between age 16 and 65 was 16%. Of these, 8% had perennial symptoms, 6% had
both perennial and seasonal symptoms, and 2% had seasonal symptoms5. Estimates
of the prevalence of hay fever vary between 2% and 15% depending on the
diagnostic criteria chosen, method of investigation, and the age groups studied.
Worldwide the prevalence of hay fever in school-age children appears to be lower
in European countries than in America. The prevalence of diagnosed hay fever
among patients consulting general practitioners is reported to be 11 per 1000 in
Denmark, 19.7 per 1000 in England and Wales, and 86 per 1000 in Australia6.
Allergic Rhinitis and Asthma may be a spectrum of the same disease based on the
surmise of “One airway, one disease”. So it will not be wrong to say that the
burden of Allergic Rhinitis is a subset of the total burden of the disease complex of
Allergic Rhinitis and asthma.
The economic burden of the disease:
The current burden of allergic diseases, estimated by both direct and indirect costs,
is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10
billion dollars/year in the U.S. and to an average annual cost of 1089 Euros per
child/adolescent and 1543 Euros per adult in Europe7. If we consider Asthma as a
co-morbidity of Allergic Rhinitis, the costs involved in the disease complex grow
manifold. A few global facts and figures for two common allergic diseases:
asthma and rhinitis are as follows 8.
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* Direct costs: Expenditure on medications and health care provision
** Indirect costs: Cost to society from loss of work, social support, loss of taxation
income, home modifications, lower productivity at work, etc
Thus it may be comfortable to say that the global costs involved in the
management of Asthma may be curtailed to a great amount if we can manage to
bring a lowering of the Allergic Rhinitis burden of the disease complex
Management of Allergic Rhinitis:
The treatment goal for allergic rhinitis is relief of symptoms. Atopy has a genetic
component involved. Thus the management of such individuals would be a control
of symptoms or managing the disease prophylectically. These atopic individuals
can only be provided either symptomatic or prophylactic treatment for their
symptoms in addition to the specific measures as immunotherapy, allergen
avoidance etc.
Therapeutic options available to achieve this goal include avoidance measures, oral
antihistamines, intranasal corticosteroids, leukotriene receptor antagonists, and
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allergen immunotherapy (see Figure). Other therapies that may be useful in select
patients include decongestants and oral corticosteroids. If the patient’s symptoms
persist despite appropriate treatment, referral to an allergollogist should be
considered. As mentioned earlier, allergic rhinitis and asthma appear to represent a
combined airway inflammatory disease and, therefore, treatment of asthma is also
an important consideration in patients with allergic rhinitis9. Most cases of allergic
rhinitis respond to pharmacotherapy. Patients with intermittent symptoms are often
treated adequately with oral antihistamines, decongestants, or both as needed.
Regular use of an intranasal steroid spray may be more appropriate for patients
with chronic symptoms. Daily use of a leukotriene receptor antagonist,
antihistamine or decongestant, or a combination can be considered instead of or in
addition to nasal steroids. The newer, second-generation (ie. Non-sedating)
antihistamines are usually preferable to the older first-generation antihistamines to
avoid sedation and other adverse effects associated with them. Leukotriene
receptor antagonists may be preferable to manage the allergic rhinitis symptom
either alone or in combination with intra nasal steroid sprays. Ocular antihistamine
drops (for eye symptoms), intranasal antihistamine sprays, intranasal cromolyn,
intranasal anti cholinergic sprays, and short courses of oral corticosteroids
(reserved for severe, acute episodes only) may also provide relief10.
ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines give a
recommended algorithm to manage Allergic rhinitis:
Page 11 of 70
ARIA recommendations:
Page 12 of 70
A simplified, stepwise algorithm for the treatment of allergic rhinitis. Note:
Treatments can be used individually or in any combination9.
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Drugs Available for management of Allergic Rhinitis:
Glossary of Rhinitis Medications:
Name and
Also known as
Generic name
Mechanism of
action
Side effects Comments
Oral H-1
antihistamines
H-1 blockers
2nd
generation
Cetrizine
Ebastine
Fexofenadine
Loratadine
Mizolastine
Acrivastine
Azelastine
Mequizatine
New Products
Desloratadine
Levocetrizine
Rupatadine
-Blockage of
H-1 receptor
–Some anti
allergic activity
–New
generation
drug can be
used once daily
–No
development of
tachyphylaxis
2nd
generation
–no sedation
for most
drugs
–No anti
cholinergic
effects
– No
cardiotoxocit
y
– Acrivastine
has sedative
effects
– Oral
Azelastine
may induce
sedation and
a bitter taste
-First line therapy
except in
moderate/severe
persistent allergic
rhinitis
-2nd
generation oral H-
1 blockers are
preferred for their
favorable
efficacy/safety ratio
and pharmacokinetics;
first generation
molecules are no
longer recommended
because of their
unfavorable
safety/efficacy ratio.
– Rapidly effective
(less than 1hr)on nasal
and ocular symptoms –
moderately effective on
nasal congestion
– Cardiotoxic drugs
(Astemizole,
Terfenadine) are no
longer marketed in
most countries
Page 14 of 70
Local H-1
antihistamines
(intranasal,
intraocular)
Azelastine
Levocabastine
Olopatadine
-Blockage of
H-1 receptor
– Some anti
allergic activity
for Azelastine
-Minor local
side effects
– Azelastine:
bitter taste in
some patients
Rapidly effective (less
than 30 min) on nasal
or ocular symptoms
Intranasal
glucocortico-
steroids
Beclomethason
e dipropionate
Budesonide
Ciclosenide
Flunisolide
Fluticasone
propionate
Mometasone
furoate
Triamcinolone
acetonide
-Potently
reduce nasal
inflammation
– Reduce nasal
hyperreactivity
Minor local
side effects
– Wide
margin for
systemic side
effects –
growth
concerns with
Beclomethas
one
dipropionate
(BDP) only
– In young
children
consider the
combination
of intranasal
and inhaled
drugs
The most effective
pharmacologic
treatment of allergic
rhinitis; first line
treatment for
moderate/severe
persistent allergic
rhinitis. It may be
reiterated that the best
control in AR is
achieved by a multi
modal delivery in a
combination of INS
and LTRA which are
preferable over anti
histamines
– Effective on nasal
congestion
–Effective on smell
– Effect observed after
6 -12 hrs but maximal
effect after a few days
– Patient should be
advised on the proper
method of
administering
intranasal
Glucocorticosteroids,
including the
importance of directing
the spray laterally
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rather than medially
(toward the septum) in
the nose.
Oral/IM gluco
corticosteroids
Dexamethason
e
Hydrocortisone
Methylprednis
olone
Prednisolone
Prednisone
Triamcinolone
Betamethasone
Deflazacort
-Potently
reduce nasal
inflammation
– Reduce nasal
hyperreactivity
-Systemic
side effects
common in
particular for
IM drugs
–Depot
injections
may cause
local tissue
atrohy
When possible
intranasal
glucocorticosteroids
should replace oral or
IM drugs
Local
cromones
(intranasal,
intraocular)
Cromoglycate
Nedocromil
-Mechanism of
action poorly
known
- Minor local
side effects
-Intraocular cromones
are very effective
– intranasal cromones
are less effective and
their effect is short
lasting
–overall excellent
safety
Oral
decongestants
Ephidrine
Phenylephrine
Phenyl
propanolamine
Pseudoephedri
ne
Oral H-1
antihistamine
decongestant
combination
Sympathomim
etic drug
– Relieve
symptoms of
nasal
congestion
Hypertension
– Palpitation
Restlessness
– Agitation
–Tremor
– Insomnia
– Headache
– Dry
mucous
membranes
Use oral decongestants
with caution in patients
with heart disease oral
H-1 antihistamine
decongestant
combination products
may be more effective
than either product
alone but side effects
are combined
Page 16 of 70
– Urinary
retention
Exacerbation
of glaucoma/
thyrotoxicosi
s
Intranasal
decongestants
Oxymetazoline
Others
Sympathomim
etic drugs
– Relieve
symptoms of
nasal
congestion
- Same side
effects as oral
decongestants
but less
intense
–Rhinitis
medicamento
sa is a
rebound
phenomenon
occurring
with
prolonged use
(over 10days)
Act more rapidly and
more effectively than
oral decongestants
limit duration of
treatment to less than
10 days to avoid
rhinitis medicamentosa
Intra nasal
anticholinergic
s
Ipratropium Anticholinergic
s block almost
exclusively
rhinorrhea
Minor local
side effects
almost no
systemic
anticholinergi
c activity
Effective in allergic
and non allergic
patients with
rhinorrhea. (Note:
Rhinorrhoea due to
other non allergic
causes like tumors,
polyps etc would not
be responsive to any
medical treatment.
CysLT
antagonist
Antileukotriene
s
Montelukast
Pranlukast
Zafirlukast
Block CysLT
receptor
Excellent
tolerance
Effective on rhinitis
and asthma
Effective on all
symptoms of rhinitis
Page 17 of 70
and on ocular
symptoms
Reference: 1 International Primary Care Airways Group (IPAG) Handbook
available at www.globalfamilydoctor.com
2. Allergic rhinitis and its impact on Asthma (ARIA) 2007 documents and
resources.
Pharmacology of LTRA
The following molecules in this (LTRAs) group: Monteluakst, Pranlukast and
Zafirlukast are available. We have explored and evaluated Montelukast and it
relevant studies as a reference to describe tolerability, safety and efficacy and
advantages of using LTRAs in managing AR in children.
General Information on Montelukast11:
Nomenclature
International Non-proprietary Name: Montelukast Sodium
British Approved Name: Montelukast
British Approved Name, modified: Montelukast Sodium
U.S. Adopted Name: Montelukast Sodium
ChemicalName:[R-(E)]-1-[[[1-[3-[2-(7-Chloro-2- uinolinyl)ethenyl]phenyl]-3-[2-
(1-hydroxy-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopropane acetic acid
sodium salt
Page 18 of 70
Montelukast sodium is a selective and orally active leukotriene receptor antagonist
that specifically inhibits the cysteinyl leukotriene CysLT1 receptor. Montelukast
sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-
quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1
methylethyl)phenyl]propyl]thio]methyl]cyclopropaneaceticacid, monosodium salt.
The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18.
Montelukast sodium is a hygroscopic, optically active, and white to off-white
powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and
practically insoluble in acetonitrile.
Montelukast is indicated in adult and pediatric patients 6 months of age and older
for the prophylaxis and chronic treatment of asthma, including the prevention of
day- and nighttime symptoms, the treatment of aspirin-sensitive asthmatic patients,
and the prevention of exercise induced bronchoconstriction.
Montelukast is indicated for the relief of daytime and nighttime symptoms of
allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of
age and older, and perennial allergic rhinitis in adults and pediatric patients 6
months of age and older). (Refer to ARIA guidelines).
Availability
Active ingredient: Montelukast Sodium
Forms and strength available: Tablet; oral: 10 mg, 5 mg, and 4 mg Oral Granules:
4 mg
Commonly used brand names: Montelukast, Montair, Romilast etc.
Page 19 of 70
The product is available as:
Oral granules form, 4mgm: 4-mg oral granules contains 4.2 mg montelukast
sodium, which is equivalent to 4 mg of montelukast. The oral granule formulation
contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, and
magnesium stearate.
Oral chewable tablet form, 5 mgm: 5-mg chewable MONTELUKAST tablet
contains 5.2 mg montelukast sodium, respectively, which are equivalent to 5 mg of
Montelukast.. Chewable tablets contain the following inactive ingredients:
mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide,
croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate.
Oral tablets, 10mgm: 10-mg film-coated MONTELUKAST tablet contains 10.4
mg montelukast sodium, which is equivalent to 10mg of montelukast, and the
following inactive ingredients: microcrystalline cellulose, lactose monohydrate,
croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The
film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose,
titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax.
DOSAGE AND ADMINISTRATION11
:
Patients with both asthma and allergic rhinitis should take only one tablet daily in
the evening.
Pediatric Patients 6 to 14 Years of Age with Asthma and/or Allergic Rhinitis
The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet
daily.
Pediatric Patients 2 to 5 Years of Age with Asthma and/or Allergic Rhinitis
Page 20 of 70
The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet
daily or one packet of 4-mg oral granules daily
Pediatric Patients 6 Months to 2 Years of Age with Asthma or Perennial Allergic
Rhinitis
The dosage for pediatric patients 6 months to 2 years of age is one packet of 4-mg
oral granules daily.
Administration of oral granules11
:
Montelukast oral granules can be administered either directly in the mouth, mixed
with a spoonful of cold or room temperature soft food (e.g., applesauce), or
dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or
breast milk. The packet should not be opened until ready to use. After opening the
packet, the full dose of Montelukast oral granules must be administered
immediately (within 15 minutes). If mixed with food, or dissolved in baby formula
or breast milk, Montelukast oral granules must not be stored for future use.
Montelukast oral granules are not intended to be dissolved in any liquid other than
baby formula or breast milk for administration. However, liquids may be taken
subsequent to administration.
General Recommendations for intake 11
:
Montelukast tablets, chewable tablets, and oral granules can be taken with or
without food.
No dosage adjustment is necessary for pediatric patients, for the elderly, for
patients with renal insufficiency, or mild-to-moderate hepatic impairment, or for
patients of either gender.
Page 21 of 70
PEDIATRIC USE11
:
Montelukast has been studied in pediatric patients 6 months to 14 years of age (see
Dosage and Administration). Safety and effectiveness in pediatric patients younger
than 6 months of age have not been studied. Studies have shown that SINGULAIR
does not affect the growth rate of pediatric patients.
CLINICAL PHARMACOLOGY11
Mechanism of Action11
The cysteinyl leukotrienes (LTC4, LTD4, LTE4), are potent inflammatory
eicosanoids released from various cells including mast cells and eosinophils. These
important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors.
The CysLT type-1 (CysLT1) receptor is found in the human airway (including
airway smooth muscle cells and airway macrophages) and on other pro-
inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs
have been correlated with the pathophysiology of asthma and allergic rhinitis. In
asthma, leukotriene-mediated effects include a number of airway actions, including
bronchoconstriction, mucous secretion, increased vascular permeability, and
eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal
mucosa after allergen exposure during both early- and late-phase reactions and are
associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs
has been shown to increase nasal airway resistance and symptoms of nasal
obstruction.
Montelukast is a potent, orally active compound that significantly improves
parameters of asthmatic inflammation. Based on biochemical and pharmacological
bioassays, it binds with high affinity and selectivity to the CysLT1 receptor (in
Page 22 of 70
preference to other pharmacologically important airway receptors such as the
-adrenergic receptor). Montelukast potently inhibits
physiologic actions of LTC4, LTD4, and LTE4 at the CysLT1 receptor without
any agonist activity.
Pharmacokinetics11
Absorption11
:
Montelukast is rapidly and nearly completely absorbed following oral
administration. For the 10-mg film-coated tablet, the mean peak plasma
concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in
the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and
Cmax are not influenced by a standard meal.
For the 5-mg chewable tablet, the Cmax is achieved 2 hours after administration in
adults in the fasted state. The mean oral bioavailability is 73%. Food does not have
a clinically important influence with chronic administration.
For the 4-mg chewable tablet, Cmax is achieved 2 hours after administration in
pediatric patients 2 to 5 years of age in the fasted state.
The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet
when administered to adults in the fasted state. The co-administration of
applesauce or a standard meal with the oral granule formulation did not have a
clinically meaningful effect on the pharmacokinetics of Montelukast as determined
by AUC (1225.7 vs 1223.1 ng.hr/mL with and without applesauce, respectively,
and 1191.8 vs 1148.5 ng.hr/mL with and without a standard meal, respectively).
Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable
tablet, 5-mg chewable tablet, and 10-mg film-coated tablet were administered
without regard to the timing of food ingestion. The safety of Montelukast was also
Page 23 of 70
demonstrated in a clinical study in which the 4-mg oral granules were administered
without regard to the timing of food ingestion.
Distribution11
:
Montelukast is more than 99% bound to plasma proteins. The steady-state volume
of distribution of Montelukast averages 8 to 11 liters. Studies in rats with radio
labeled Montelukast indicate minimal distribution across the blood-brain barrier. In
addition, concentrations of radio labeled material at 24 hours post dose were
minimal in all other tissues.
Metabolism11
:
Montelukast is extensively metabolized. In studies with therapeutic doses, plasma
concentrations of metabolites of Montelukast are undetectable at steady state in
adults and pediatric patients.
In vitro studies using human liver microsomes indicate that cytochrome P450 3A4
and 2C9 are involved in the metabolism of Montelukast. Based on further in vitro
results in human liver microsomes, therapeutic plasma concentrations of
Montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
Elimination11
:
The plasma clearance of Montelukast averages 45 mL/min in healthy adults.
Following an oral dose of radio labeled Montelukast, 86% of the radioactivity was
recovered in 5-day fecal collections and less than 0.2% was recovered in urine.
Coupled with estimates of Montelukast oral bioavailability, this indicates
Montelukast and its metabolites are excreted almost exclusively via the bile.
In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5
hours in healthy young adults. The pharmacokinetics of Montelukast is nearly
linear for oral doses up to 50 mg. No difference in pharmacokinetics was noted
Page 24 of 70
between dosing in the morning or in the evening. During once-daily dosing with 10
mg Montelukast, there is little accumulation of the parent drug in plasma (~14%) .
Undesirable effects (refer: SPC.SGA-5mg.12.UK.3624.II-070-WS-007; Date of revision of text Dec-2012)
Montelukast has been evaluated in clinical studies as follows:
• 10 mg film-coated tablets in approximately 4,000 adult patients 15 years of age
and older, and
• 5 mg chewable tablets in approximately 1,750 paediatric patients 6 to 14 years of
age.
The following drug-related adverse reactions in clinical studies were reported
commonly (≥1/100 to <1/10) in patients treated with montelukast and at a greater
incidence than in patients treated with placebo:
Body System Class Adult Patients 15
years and older
(two 12-week studies;
n=795)
Paediatric Patients 6 to
14 years
old
(one 8-week study;
n=201)
(two 56-week studies;
n=615)
Nervous system
disorders
headache headache
Gastro-intestinal
disorders
abdominal pain
With prolonged treatment in clinical trials with a limited number of patients for up
to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of
age, the safety profile did not change.
Page 25 of 70
Post-marketing Experience
Adverse reactions reported in post-marketing use are listed, by System Organ
Class and specific Adverse Experience Term, in the table below. Frequency
Categories were estimated based on relevant clinical trials.
System Organ
Class Adverse Experience Term
Frequency
Category
Infections and
infestations upper respiratory infection†
Very
Common
Blood and
lymphatic system
disorders
increased bleeding tendency Rare
Immune system
disorder hypersensitivity reactions including
anaphylaxis
Uncommon
hepatic eosinophilic infiltration Very Rare
Psychiatric
disorders dream abnormalities including nightmares,
insomnia, somnambulism, irritability, anxiety,
restlessness, agitation including aggressive
behaviour or hostility, depression
Uncommon
tremor Rare
hallucinations, disorientation, suicidal
thinking and behaviour (suicidality)
Very Rare
Nervous system
disorder dizziness, drowsiness
paraesthesia/hypoesthesia, seizure
Uncommon
Cardiac disorders palpitations Rare
Respiratory,
thoracic and
mediastinal
disorders
epistaxis
Uncommon
Churg-Strauss Syndrome (CSS) (see section
4.4)
Very Rare
Gastrointestinal
disorders diarrhoea‡, nausea‡, vomiting‡ Common
dry mouth, dyspepsia Uncommon
Hepatobiliary
disorders elevated levels of serum transaminases (ALT,
AST)
Common
Page 26 of 70
Hepatitis (including cholestatic,
hepatocellular, and mixed-pattern liver
injury).
Very Rare
Skin and
subcutaneous
tissue disorders
rash‡ Common
bruising, urticaria, pruritus Uncommon
angiooedema Rare
erythema nodosum, erythema multiforme
Very Rare
Musculoskeletal,
connective tissue
and bone
disorders
arthralgia, myalgia including muscle
cramps
Uncommon
General disorders
and
administration site
conditions
pyrexia‡
asthenia/fatigue, malaise, oedema
Common
Uncommon
*Frequency Category: Defined for each Adverse Experience Term by the
incidence reported in the clinical trials
data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon
(≥1/1000 to <1/100), Rare (≥1/10,000 to
<1/1000), Very Rare (<1/10,000).
†This adverse experience, reported as Very Common in the patients who
received montelukast, was also reported
as Very Common in the patients who received placebo in clinical trials.
‡This adverse experience, reported as Common in the patients who received
montelukast, was also reported as
Common in the patients who received placebo in clinical trials.
Page 27 of 70
Overdose (refer: SPC.SGA-5mg.12.UK.3624.II-070-WS-007; Date of revision of text Dec-2012)
No specific information is available on the treatment of overdose with montelukast.
In chronic asthma studies, montelukast has been administered at doses up to 200
mg/day to patients for 22 weeks and in short-term studies, up to 900 mg/day to
patients for approximately one week without clinically important adverse
experiences.
There have been reports of acute overdose in post-marketing experience and
clinical studies with montelukast.
These include reports in adults and children with a dose as high as 1000 mg
(approximately 61 mg/kg in a 42 month old child). The clinical and laboratory
findings observed were consistent with the safety profile in adults and paediatric
patients. There were no adverse experiences in the majority of overdose reports.
The most frequently occurring adverse experiences were consistent with the safety
profile of montelukast and included abdominal pain, somnolence, thirst, headache,
vomiting, and psychomotor hyperactivity.
It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis
ANIMAL TOXICOLOGY11
Acute Toxicity
No mortality occurred following a single oral administration of montelukast
sodium at doses up to 5000 mg/kg, in mice and rats, (15,000 mg/m2 and 29,500
mg/m2 in mice and rats, respectively) the maximum dose tested (oral LD50 >5000
mg/kg). This dose is equivalent to 25,000 times the recommended daily adult
human dose*. (* Based on an adult patient weight of 50 kg)
Page 28 of 70
Chronic Toxicity
The toxic potential of montelukast sodium was evaluated in a series of repeated
dose toxicity studies of up to 53 weeks in monkeys and rats and up to 14 weeks in
infant monkeys and in mice. Montelukast sodium was well tolerated at doses
which provide a wide margin of safety based on total dose administered. The no
effect level for all toxicological parameters in any of the species tested was at least
125 times the recommended human dose*. There were no findings that would
preclude administration at the therapeutic dosage level for both adults and pediatric
patients. (* Based on an adult patient weight of 50 kg).
Carcinogenicity
Montelukast sodium was not carcinogenic when administered at oral doses of up to
200 mg/kg/day in a 106-week study in rats, or at oral doses of up to 100 mg/kg/day
in a 92-week study in mice. These doses are equivalent to 1000 times and 500
times the recommended adult human dose*.(* Based on an adult patient weight of 50 kg).
Mutagenesis
Montelukast sodium was found to be neither genotoxic nor mutagenic.
Montelukast sodium was negative in the in vitro microbial mutagenesis assay and
the V-79 mammalian cell mutagenesis assays, with and without metabolic
activation. There was no evidence of genotoxicity in the in vitro alkaline elution
assay in rat hepatocytes and the in vitro chromosomal aberration assays in Chinese
hamster ovary cells, with or without a microsomal enzyme activation system.
Similarly, there was no induction of chromosomal aberrations in bone marrow
cells of male or female mice after the administration of oral doses of up to 1200
mg/kg (3600 mg/m2) (6000 times the recommended daily adult dose*).
(* Based on an adult patient weight of 50 kg).
Page 29 of 70
Reproduction
Fertility and reproductive performance were not affected in studies with male rats
given oral doses of up to 800 mg/kg/day or with female rats given doses of up to
100 mg/kg/day. These dosages provide margins of 4000-fold and 500-fold,
respectively, above the recommended adult human dose*. (* Based on an adult patient
weight of 50 kg).
Development
In developmental toxicity studies, there were no treatment related adverse effects
at doses up to 400 mg/kg/day in rats and up to 100 mg/kg/day in rabbits. Fetal
exposure of montelukast sodium in rats and rabbits does occur and significant
concentrations of drug were observed in milk of lactating rats.
REGULATORY STATUS:
Montelukast (Montelukast) was covered by U.S. Patent No. 5,565,473 which
expired on August 3, 2012. The same day, the FDA approved several generic
versions of Montelukast.
The U.S. Food and Drug Administration today approved the first generic versions
of Montelukast (montelukast sodium) for use in adults and children to control
asthma symptoms and to help relieve symptoms of indoor and outdoor allergies.
Apotex Inc., Aurobindo Pharma, Endo Pharmaceuticals, Glenmark Generics,
Kudco Ireland Inc., Mylan Inc., Roxane Laboratories, Sandoz Inc., Teva
Pharmaceuticals Inc., and Torrent Pharmaceuticals have gained FDA approval for
generic montelukast tablets.
Page 30 of 70
Apotex, Aurobindo, Endo, Kudco, Mylan, Roxane, Sandoz, Teva, and Torrent
have received approval for chewable tablets. Teva has received approval for the
oral granule form. (Ref: FDA News Release: For Immediate Release: Aug. 3,
2012; Media Inquiries: Sandy Walsh, 301-796-4669, [email protected]
“FDA approves first generic versions of Montelukast to treat asthma, allergies”)
The presence of the above companies is distributed among various countries and
the web search revealed that Momtelukast is available in China, Indinesia,
Hongkong , India, Malaysia, Philipines, Singapore, Thailand, Taiwan, Vietnam,
US and Europe .
Whilst patent protection for the Montelukast molecule expired in Canada in
October 2011, protection extends to August 2012 in the US. In Europe, many
Supplementary Protection Certificate SPCs protecting the Montelukast molecule
were granted with expiries in August 2012. However, Merck successfully
complied with the agreed paediatric investigation plan (PIP) and successfully
applied for 6 month extensions to the terms of several SPCs, giving a potential
expiry of February 2013 in some of western Europe’s largest markets, namely
France, Germany and the UK, as well as in many of the region’s smaller markets.
Due to later authorisation of the product in Australia, the s70 extension on the
molecule patent in this jurisdiction extends to April 2013. Patent family
US17493193A claims crystalline Montelukast sodium and processes for its
preparation. (Ref: GenericsWeb - January 2012; News letter 'INNsight')
Page 31 of 70
Safety and efficacy
Search methods for identification of Data:
An online database search for articles published from 1950 to present was
conducted. The relevant articles were studied and summarized in combination with
other resources.
Electronic searches
1. Cochrane library
2. Pubmed
Searching other resources: multiple sources were used wherever possible to
validate the data. ARIA Guideline available on ARIA website and the flow charts
for selecting the included articles.
Inclusion criteria:
• English language articles
• Human subjects
• Types of studies:
1. Systematic reviews
2. Randomized controlled trials which subjects were assigned to treatment or
control group (placebo-controlled or different drug) on the basis of random
allocation.
3. Reviews
4. Observational studies
• Types of participant: Children between 0-14 years old
Page 32 of 70
• Types of interventions: the treatment group received Montelukast at any dose for
any duration at any time
Exclusion Criteria:
• Non English language articles
• Animal studies
• Studies not targeting pediatric population
•Studies including pediatric populations, but pediatric specific data not reported
separately
• Studies without clear specification of intervention or dose
• Individual case reports
Description of the included studies:
Efficacy:
A number of studies were conducted to generate evidences on Montelukast use in
controlling allergic airway diseases. Some of the relevant evidences available are
as follows:
To assess the effectiveness of anti-leukotrienes prophylactic treatment on the
course of seasonal allergic rhinitis, a study which enrolled 48 patients aged 6–12
years were done in Italy12
. From those 28 patients with already diagnosed seasonal
allergic rhinitis conducted main group who received the Montelukast once per day
and 20 patients without any previous treatment consist the second control group.
The symptom severity scores and its correlation to quality of life questionnaire
were assessed in both groups. The most frequent symptom was nasal secretion, but
Page 33 of 70
the most serious or disturbing symptom, that affects quality of life was nasal
obstruction. The results showed that in main group all nasal symptom scores
(sneezing, nose blows, nasal obstruction, interference with daily living, and
symptom comparison with the previous year) has significantly less symptom
severity after the treatment compared to control. All subscales of PRQLQ
(Pediatric Rhino-conjunctivitis Quality of Life Questionnaire) indicated higher
scores for group main group. The quality of life scores depend on treatment
duration; the longer the treatment period, the higher the QOL (Quality of Life)
score12
.
The result showed correlation between severity of rhinitis and quality of life and
effectiveness of using anti-leukotrienes in treatment for improvement of nasal
symptom scores as well as quality of life of patients with seasonal rhinitis12
.
However it was noted in the study there was not much difference between the
treatment groups in the primary outcome while there was some difference in
secondary outcomes from there been some minor differences
The study noted that the dosing schedule for Montelukast was once daily evening
time. And the onset of action is approx 3-6 hrs after ingestion. The impact of
addition of Montelukast on PNTS was observed. Secondly the mean percent
change in decreased turbinate swelling was significantly greater in the Montelukast
group. This also strengthens the importance of using Montelukast in controlling
AR symptom and underlying inflammation as well.
Another study was conducted to compare the effectiveness of Montelukast
combined with Loratadine once daily to Loratadine alone for a 2-week treatment
course of allergic rhinitis in a randomized, double-blind placebo controlled trial
which enrolled 115 children, 6-15 years old13
. The patients were randomly
assigned to receive Montelukast and Loratadine (treatment group) or placebo and
Page 34 of 70
Loratadine (control group). The primary outcome was the mean percent change of
the total daytime nasal symptom scores (PDTS) and secondary outcomes were the
mean percent changes of the nighttime nasal, daytime eye and composite symptom
scores (PNTS, PES, PCS), as well as the nasal secretion, turbinate swelling and
nasal congestion scores (PNSS, PTSS, PNCS). There were no significant
differences in the PDTS of the 2 groups. The change in the night time nasal
congestion score (PNTS-congestion) was higher in the treatment group, but not
statistically significant (p = 0.077). Only the mean percent change in decreased
turbinate swelling was significantly greater in the Montelukast and Loratadine
group than the Loratadine alone group (-22 +/- 7 vs. -1 +/- 5, p less than 0.05).
A randomized, placebo-controlled study was conducted to compare Montelukast
plus Loratadine and Loratadine alone with respect to efficacy in the treatment of
allergic rhinitis in 115 children ages 6-15 yr13
. Patients received Loratadine 5 or 10
mg depending on weight and Montelukast 5 mg (n=56) or Loratadine plus placebo
(n=59) at bedtime for 2 wk. Patients completed daily rhinitis diary cards. The
primary outcome was mean percent change in total daytime nasal symptom scores
(PDTS). Secondary outcomes were mean percent change in nighttime nasal
symptoms scores (PNTS), daytime eye symptoms scores (PES), composite
symptoms scores (PCS), nasal secretion (PNSS), turbinate swelling (PTSS), and
nasal congestion scores (PNCS). The combination group had significant
improvement in turbinate swelling compared to the Loratadine group. The
combination group also had greater improvements in PNTS, PDTS, PES, and PCS
than the Loratadine group, but the differences were not significant. The authors
conclude that Montelukast plus Loratadine had a significant effect on nasal
congestion but not on other symptoms in children with allergic rhinitis13
.
Leukotriene receptor antagonists (LTRAs) were recently added to the method of
treating allergic rhinitis (AR). However, in children under 6 yr old, there has been
Page 35 of 70
no study about its efficacy in treating AR. To compare the clinical efficacy of
Montelukast, Cetirizine and placebo in the treatment of children from 2 to 6 yr old
with perennial allergic rhinitis (PAR), to see if there are any significant
differences14
. Sixty children were selected and treated with Montelukast, or
Cetirizine, or placebo once daily14
. The efficacy of the three agents was compared
with the Pediatric Rhino conjunctivitis Quality of Life Questionnaire (PRQLQ)
and Total Symptom Score (TSS) by diary. In addition, Serum IgE, serum
eosinophil cationic protein (ECP), blood eosinophil counts, nasal airway resistance
(NAR) and eosinophil percentage in nasal smears were also examined. The results
revealed that both Montelukast and Cetirizine were significantly efficacious
compared with placebo in NAR, eosinophil percentage in nasal smears, PRQLQ,
TSS and all symptom items except nasal itching, throat itching and tearing. For
nasal itching, only Cetirizine was significantly efficacious. On the other hand, for
night sleep quality, Montelukast was significantly superior to Cetirizine14
.
A randomized, double-blind, placebo-controlled, parallel-group study was
performed to compare the effects of oral Montelukast 4 mg once daily at bedtime
(n=20; 11 M, 9 F, mean age 4.49 yr) with those of oral Cetirizine 5 mg once daily
at bedtime (n=20; 12 M, 8 F mean age 4.53 yr) for 12 wk in 40 children (age 2-6
yr) with perennial allergic rhinitis; 20 children received placebo14
. After 12 wk of
therapy, total symptoms scores had decreased significantly in the Montelukast and
Cetirizine groups (both P<0.001); however, total symptoms scores were lower in
the Cetirizine group than in the Montelukast group (P less than 0.05 between
groups). Nasal itching decreased to a greater degree in the Cetirizine group than in
the Montelukast group, while the quality of night sleep improved more in the
Montelukast group than in the Cetirizine group. Pediatric Rhino conjunctivitis
Quality of Life Questionnaire scores improved significantly in the Montelukast and
Cetirizine groups over 12 wk of therapy (P=0.028 and P<0.001, respectively).
Page 36 of 70
There were no significant changes in levels of serum IgE, serum eosinophil
cationic protein, or blood eosinophil counts over 12 wk of therapy with
Montelukast or Cetirizine. Nasal airway resistance values decreased significantly
in the Montelukast and Cetirizine groups after 8 (P=0.007 and P=0.026,
respectively) and 12 wk of therapy (P=0.007 and P=0.013, respectively). Similarly,
the number of eosinophils in nasal smears decreased significantly in the
Montelukast and Cetirizine groups over 12 wk of therapy (P=0.045 and P=0.004,
respectively). Two children in the Cetirizine group experienced mild Cetirizine-
induced sedation. The authors conclude that both Montelukast and Cetirizine are
effective for the treatment of perennial allergic rhinitis in children14
.
It was noted that Cetrizine has associated side effect of sedation, which is not
associated with Montelukast. Also, the Quality of night sleep was better in
Montelukast group as compared to cetrizine.Considering therapeutic index
(Efficacy and Side effect ratio) profile, Montelukast would be the preferred choice.
Another study was carried out to investigate the role of treatment with Montelukast
on symptoms, eNO levels, and peripheral eosinophil counts of children with
seasonal allergic rhinitis during pollen season15
. METHODS: A randomized,
double-blind, parallel-group study performed between April and June 2005 in 57
children aged 7 to 14 years with seasonal allergic rhinitis was performed. The
study comprised a 1-week screening period, a 1-week run-in period, and a 2-week
treatment period with once daily Montelukast, 5 mg, or matching placebo.
RESULTS: No significant difference at baseline was found in symptom scores,
eNO levels, and blood eosinophil counts between the treatment and placebo groups.
After 2 weeks of Montelukast treatment, improvements from the baseline in the
daytime nasal, composite, and daytime eye symptoms scores were significantly
greater in the Montelukast group compared with the placebo group (P < .001, P
Page 37 of 70
< .001, and P < .01, respectively). A significant decrease was also found in
eosinophil counts (P < .001) in the Montelukast group compared with the placebo
group after treatment. Montelukast treatment did not produce a significant effect
on eNO levels compared with placebo (P = .96). The study results concluded that
Montelukast treatment provided significant improvement in symptoms and
peripheral eosinophil counts of school-age children with seasonal allergic rhinitis;
however, it did not show a significant effect on eNO levels15
but the article did
suggest that Montelukast would be a better option.
A study to determine the impact of rhinitis on sufferers' sleep and daily routine
with using nasal sprays or Montelukast drug were done wherein the authors
retrospectively investigated symptom severity and the potential efficacy of
treatment with Montelukast or corticosteroids among 20 children (age 3-15 yr)
with rhino sinusitis and seasonal or perennial allergic rhinitis16
. A total of 10 of the
children received oral Montelukast, while the other 10 received corticosteroids in a
nasal spray formulation. A greater proportion of children with perennial rhinitis
(with or without seasonal allergic rhinitis) than of children with only seasonal
allergic rhinitis indicated that their symptoms interfered with their sleep patterns
and other activities of daily living. Also, a greater proportion of patients with
perennial rhinitis than of patients with seasonal rhinitis would agree to use
Montelukast if symptom control would be improved with this agent. The authors
concluded that children with perennial rhinitis experience substantial disruptions of
their sleep patterns and activities of daily living16
.
Page 38 of 70
Safety and Tolerability:
Montelukast is a potent leukotriene-receptor antagonist administered once daily
that provides clinical benefit in the treatment of asthma and allergic rhinitis in
children and adults. Because of its wide use as a pediatric controller, there is a need
for a further review of the safety and tolerability of Montelukast in children. To
evaluate and establish the safety and tolerability of Montelukast in pediatric
patients, various studies conducted and their results were found favorable. We have
included some of the studies mentioned underneath:
Montelukast is a leukotriene receptor antagonist administered orally once daily for
treatment of chronic asthma in adults and children. A comprehensive analysis of
safety data from double-blind, randomized, placebo-controlled trials with
Montelukast was conducted. A pooled analysis of safety data from 11 multicentre,
randomized, controlled Montelukast Phase IIb and III trials and five long-term
extension studies was performed17
. A total of 3386 adult patients (aged 15-85
years) and 336 paediatric patients (aged 6-14 years) were enrolled in the trials;
2031 adults received Montelukast for up to 4.1 years, and 257 children received
Montelukast for up to 1.8 years. Summary statistics comparing incidences of
adverse events among treatment groups were calculated. The overall incidence of
clinical and laboratory adverse events among Montelukast-treated patients, both
adult and paediatric, was similar to that among patients receiving placebo. There
were no clinically relevant differences in individual adverse events, including
infectious upper respiratory conditions and transaminase elevations, between
Montelukast and placebo groups. Discontinuations due to adverse events occurred
with similar frequencies during placebo, Montelukast and inhaled Beclomethasone
therapy. No dose-related adverse effects of Montelukast were observed in adults
Page 39 of 70
treated with dosages as high as 200 mg per day (20 times the recommended dose)
for 5 months. This tolerability profile Montelukast observed in clinical trials has
been generally reflected in the post-marketing safety experience seen to date.
These data indicate a tolerability profile for Montelukast similar to placebo during
both short-term and long-term administration, even at doses substantially higher
than the recommended clinical dose of 10 mg once daily for adults and 5 mg once
daily for children aged 6-14 years17
. But we could not find more studies on this
issue in our referenced material
A meta-analysis of 11 multicenter, randomized, placebo-controlled studies and 5
extension studies was performed to determine the safety of Montelukast in patients
age 6 yr or older17
. Ten of the 11 double-blind studies were Phase IIb/III trials in
3386 adults aged 15-85; the other study was a Phase III trial in 336 children aged
6-14 yr. Of the 5 extension studies, 4 were in adults where Montelukast exposure
lasted up to 4.1 yr; the other study was in children where Montelukast exposure
lasted up to 1.8 yr. Overall, 2031 adults and 257 children received Montelukast.
Dosages ranged from 2-200 mg per day. One of the double-blind studies and 2 of
the extension studies used inhaled Beclomethasone as an active comparator agent.
The percentage of patients discontinuing the double-blind and extension studies
because of clinical adverse events was similar among the Montelukast, placebo,
and Beclomethasone groups. Most of these discontinuations were due to asthma-
related events. The overall incidence of clinical and laboratory adverse events was
similar among the Montelukast, placebo, and Beclomethasone groups. Individual
adverse events, including upper respiratory conditions and elevated transaminase
levels, occurred in a similar proportion of patients in the Montelukast and placebo
groups. One patient treated with Montelukast in an adult extension study
discontinued due to an elevated aspartate aminotransferase level. Two patients
treated with Montelukast in the pediatric Phase III trial discontinued due to an
Page 40 of 70
elevated alanine aminotransferase level in 1 and a decreased neutrophil count in
the other. Four patients treated with Montelukast in the pediatric extension study
discontinued due to an elevated alanine aminotransferase level in 1, a decreased
neutrophil count in 1, an elevated bilirubin level in 1, and a decreased neutrophil
count in 1 patient with a history of cyclic neutropenia. There were 30 pregnancies
during the 11 clinical studies (6 placebo, 20 Montelukast, 4 Beclomethasone). The
outcome in these 30 was 13 healthy infants born (3, 9, and 1), 16 abortions (3, 10,
3,) and 1 lost to follow up (Montelukast). Three of 10 aborted Montelukast
pregnancies were spontaneous (no details). There were no increases in treatment
discontinuations or in clinical or laboratory adverse events among patients treated
with doses of Montelukast of up to 200 mg/day. The authors concluded that
Montelukast is safe for all age groups during short-term and long-term
administration, even at doses substantially higher than the recommended dose17
.
There is a recent Cochrane review (May 2012) which clearly states that inhaled
corticosteroids is the preferred treatment (over Montelukast) for treatment of
asthma. This definitively meets all the speculation on Montelukast in the treatment
of asthma. This review states that Montelukast is an effective treatment option for
mild persistent asthma. But as mentioned, most of the study was on adult
population while we are reviewing Montelukast in Pediatric age group. Moreover
if we refer to PRACTALL consensus for pediatric asthma management, which
highlights phenotypes in pediatric asthma, then it says that Montelukast is an
alternative first line treatment for mild asthma and preferred treatment in viral
induced wheeze in pediatric patient. One point needs to be emphasized: AR and
Asthma are a part of the same airway. The ARIA guidelines surmises proposes and
says "One airway, one disease" as the basis of the iteopathogenisis of both the
entities. The etiopathogenesis in both the conditions is essentially the same ie.
Inflammation and it is this that forms the basis of the use of INS to treat the
Page 41 of 70
inflammation. This, when augmented with the use of LTRA's improves the
outcome of the treatment modalities.
To summarize safety and tolerability data for Montelukast from previously
reported as well as from unpublished placebo-controlled, double-blind, pediatric
studies and their active-controlled open-label extension/extended studies. These
studies evaluated 2,751 pediatric patients 6 months to 14 years of age with
persistent asthma, intermittent asthma associated with upper respiratory infection,
or allergic rhinitis18
. These patients were enrolled in seven randomized, placebo-
controlled, double-blind registration and post-registration studies and three active-
controlled open-label extension/extended studies conducted by Merck Research
Laboratories between 1995 and 2004. Montelukast was well tolerated in all studies.
Clinical and laboratory adverse experiences for patients treated with Montelukast
were generally mild and transient. The most frequent clinical adverse events for all
treatments (placebo, Montelukast, active control/usual care) in virtually all studies
were upper respiratory infection, worsening asthma, pharyngitis, and fever. The
clinical and laboratory safety profile for Montelukast was similar to that observed
for placebo or active control/usual care therapies. The safety profile of
Montelukast did not change with long-term use18
.
One review describes recent studies in children that evaluated long-term outcomes
of controller asthma medications. The literature is replete with studies
demonstrating the immediate profound effects of inhaled corticosteroids on
symptom control, reduction in morbidity and mortality rates, improvement in lung
function, bronchial hyper responsiveness, and inflammatory markers. Recent
evidence supports that even this most effective class of medication does not alter
the progression of recurrent wheeze to asthma, and that its effects on decline in
lung function are limited. The lack of evidence supporting the superiority of lower
dose inhaled corticosteroids combined with a long-acting beta-agonist over a full
Page 42 of 70
dose inhaled corticosteroid with respect to long-term efficacy measures and growth
effects suggests that monotherapy with acceptable inhaled corticosteroid dose is
the preferred treatment in children with mild to moderate persistent asthma.
Montelukast has been shown to significantly reduce asthma exacerbations and
lower use of supplemental inhaled corticosteroids compared with placebo. There is
mounting evidence that the currently available medications for childhood asthma
have a substantial impact on multiple dimensions of asthma control. No drug in our
current armamentarium, however, has been found to neither alter the natural
progression of childhood asthma nor halt progressive airway damage in the more
susceptible children.
In this review, the authors discuss the results of recent studies of the long-term
effects of inhaled corticosteroids, long-acting b-agonists, and leukotriene receptor
antagonists on the disease course of asthma in children. Several studies of inhaled
corticosteroids (Childhood Asthma Management Program [CAMP], inhaled
Steroid Treatment As Regular Therapy in early asthma [START], and Prevention
of Early Asthma in Kids [PEAK]) showed that these agents do not alter the natural
course of asthma. For example, in CAMP, Budesonide improved lung function to a
greater extent than did placebo while children received Budesonide; but
measurements obtained for asthma control and bronchial hyper responsiveness in
the Budesonide group after treatment discontinuation were similar to those
obtained for the placebo group. In the START study, initiating treatment with
Budesonide in children who had asthma for less than 2 yr improved lung function
test results, but lung function worsened later. In PEAK, children at risk of
developing asthma received Fluticasone or placebo for 2 yr. During the 3rd year,
when study drugs were discontinued, there was no difference between the
Fluticasone group and the placebo group with respect to the proportion of children
with active wheezing. One particularly important study, the Pediatric Asthma
Page 43 of 70
Controller Trial (PACT)19
, compared treatment regimens with Fluticasone 100 mcg
twice daily, Fluticasone 100 mcg-Salmeterol 50 mcg in the morning and
Salmeterol 50 mcg in the evening, and Montelukast 5 mg in the evening. In this
study, the proportion of asthma control days over 48 wk was 64.2% with
Fluticasone, 59.6% with Fluticasone-Salmeterol, and 52.5% with Montelukast.
Improvement on the Asthma Control Questionnaire score did not differ between
the Fluticasone and Fluticasone-Salmeterol groups. Therefore, the PACT study did
not support the use of Fluticasone-Salmeterol as a particularly appropriate
corticosteroid-sparing regimen for children. Several studies have demonstrated that
treatment with Montelukast can decrease the risk and frequency of asthma
exacerbations and that Montelukast can control asthma symptoms to the same
degree as inhaled corticosteroids. In the 12-month Montelukast Study of Asthma in
Children, children received Montelukast or Fluticasone. In this study, the
proportion of rescue-free days increased from 64% to 84% with Montelukast and
from 64% to 86.7% with Fluticasone. In a placebo-controlled study over 12 mo,
children who received Montelukast 4-5 mg/day orally had a 31.9% decrease in
asthma exacerbations in comparison with children who received placebo. In a 12-
mo study of intermittent Montelukast or placebo treatment, Montelukast recipients
had 163 unscheduled healthcare resource uses for asthma, while placebo recipients
had 228 such uses20
This study had a placebo as a comparator and the study has
focused on the safety and tolerability of a molecule. To address the objective ie
Safety profile, placebo could be a good comparator but only if patient enrolled in
the placebo arm remain asymptomatic during the study period.
To examine the use, effectiveness, and tolerability of Montelukast in clinical
practice for treating asthma and to explore prognostic factors that could predict a
favorable response to the drug. There was a retrospective, cross-sectional,
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observational study of clinical outcomes seen in patients prescribed Montelukast
for asthma that used routinely collected clinical information21
. Data were collected
on all consenting patients who had been prescribed Montelukast for asthma
irrespective of the continuation or duration of treatment. Independent observers,
treating physicians, and patients assessed certain outcomes after the initiation of
Montelukast, including the general asthma response and changes in activity-related
symptoms. Fifty-six centers in the United Kingdom (20 primary care and 36
secondary care) participated21
. The analysis was based on 1351 eligible patients for
whom essential data were available. Eight hundred thirty patients (66.4%; 95% CI,
63.8% to 69.0%) were recorded as having shown an improvement in their asthma
control, and 103 (8.2%; 95% CI, 6.8% to 9.9%) experienced a dramatic
improvement. The greatest proportion of patients responding was seen in those
with mild to moderate asthma. Montelukast was well tolerated; no new adverse
events were recorded. The study results concluded that Montelukast is an effective,
well-tolerated treatment for asthma in routine practice. The overall response rate
and tolerability seen in this survey are similar to those reported in randomized
clinical trials21
.
This retrospective, observational, cross-sectional survey was conducted in the
United Kingdom to evaluate the use, effectiveness, and tolerability of Montelukast
in patients treated for asthma in routine clinical practice; possible predictive factors
for a favorable response were also studied. A total of 1351 patients (597 M, 743 F,
age 1-88 yr, mean age 35 yr) seen at 56 centers were included. Information was
obtained by questionnaires tailored for patients, prescribing physicians, and
independent observers (respiratory nurse trainers who answered questions based on
patient records). Patients taking Montelukast at the time of the survey had been
taking it for a median of 15 mo (range, <1-38 mo), and patients who had
discontinued Montelukast had taken it for a median of 3 mo (range, <1-36 mo).
Page 45 of 70
Independent observer assessments showed overall improvement in asthma for
66.4% of patients, with 8.2% of patients having very good or dramatic
improvement. Asthma was much improved or dramatically improved in a larger
proportion of children (41.3%) than adults (33.5%). Similar results were found
with physician assessments. Among 211 patients who also had rhinitis and had a
response recorded, 54.5% had improvements in rhinitis. Overall asthma responses
to Montelukast were reported by 292 patients, and the results were similar to those
from independent observers and physicians. Among 199 patients who were still
taking Montelukast, 69.8% reported that their asthma was much better. Prognostic
factors that were significantly associated with a response to Montelukast were age,
sex, other asthma treatment at the start of Montelukast, activity-induced asthma,
and sleep disturbance; only activity-induced asthma remained significant
(P=0.002) in a forward inclusion model. Montelukast was well tolerated, with
records showing drug-related adverse events in 137 patients (9.3%). There was
only one serious adverse event (diarrhea) that was possibly related to Montelukast.
The authors concluded that Montelukast is effective and well tolerated as asthma
therapy in routine clinical practice21
.
Another 2-period, 14-wk, randomized, prospective, parallel group study was
conducted to determine the effectiveness, reliability, and tolerability of
Montelukast therapy and to compare the effects of Montelukast therapy with those
of inhaled corticosteroid therapy in 63 children (36 M, 27 F, age 8-14 yr) with mild,
persistent asthma22
. Patients were randomized to 1 of 3 groups: group 1,
Montelukast 5-mg chewable tablet administered once daily in the evening; group 2,
inhaled Budesonide 400 mcg b.i.d.; and group 3, Montelukast plus Budesonide
combination therapy. The mean duration of asthma ranged from 26.9 month to
28.4 mo. Fifty-seven patients completed the study: 1 patient from group 3
discontinued because of an asthma attack; 2 patients in group 2 discontinued
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because of pneumonia; and 3 were lost to follow-up. Treatment with Montelukast
resulted in improvements in airway obstruction, asthma exacerbations, daily
symptom scores, nocturnal awakenings, total daily B-agonist therapy, and urinary
leukotriene E4 levels. The FEV-1 values increased with treatment when compared
to the baseline values. Patients in all 3 groups had significant improvements in
morning PEF measurements. Monthly as-needed treatment with beta-agonists
decreased significantly among patients in all 3 groups. Improvements in exercise
capacity were observed among patients in all 3 groups. The authors concluded that
Montelukast may be an effective treatment option for pediatric patients with mild,
persistent asthma22
.
Another open, prospective, multicenter, non-comparative, Pediatric Montelukast
Study Group was conducted in 881 patients (573 M, 308 F, age 6-14 yr, mean age
11.83 yr) with persistent asthma to evaluate the tolerability and efficacy of
treatment with oral Montelukast 5 mg-tablet once daily for 30 days23
. With
Montelukast, the daytime total asthma score decreased from 9.55 to 3.59. The
number of nocturnal awakenings decreased from 1.54 to 0.43. At the completion of
the study, physicians rated Montelukast tolerability: 46% as excellent; 28% as very
good; 20% as good; 6% as fair; and none as poor. The authors concluded that
Montelukast therapy is well tolerated and effective in pediatric patients with
persistent asthma23
.
A 3-month, multicenter, open-label, controlled, extension study was performed to
evaluate the safety and tolerability of oral granular Montelukast 4 mg once daily in
113 children 6-31 mo of age with asthma or asthma-like symptoms who needed
controller therapy based on Global Initiative for Asthma (GINA) guidelines24
.
Patients had completed a 6-wk, randomized, double-blind, placebo-controlled
study and received oral granular Montelukast 4 mg once daily (n=175) or placebo
(n=81). The extension study started after patients were off active treatment for a
Page 47 of 70
minimum of 2 month. When children who received Montelukast were compared
with children who received usual care (inhaled controller therapy with Cromolyn,
Nedocromil, or corticosteroids) there were no differences regarding clinical or
laboratory adverse experiences, patients exceeding the predefined limits of change
for laboratory tests, or change in postexposure transaminase levels relative to
baseline. The authors conclude that in asthmatic children 6-31 mo of age, oral
granular Montelukast 4 mg once daily is generally well tolerated over a 3-mo
period. It is stated that these results are consistent with Montelukast safety data that
has been previously reported for adults and other pediatric patients24
.
A multicenter, randomized, double-blind, placebo-controlled, parallel-group study
was conducted to determine the safety and tolerability of oral granular Montelukast
(sprinkles) in children aged less than or equal to 6 month to less than 2 yr who
required controller therapy and to evaluate the effects of Montelukast on the use of
b-agonists in those at risk of developing persistent asthma25
. Children were
randomized to receive once-daily Montelukast 4 mg with applesauce in the
evening for 6 wk (n=175) or matching placebo (n=81). Montelukast and placebo
had similar safety and tolerability. There were fewer episodes of worsening asthma
in the Montelukast group than in the placebo group (18.9% vs 22.2%). The number
of days without b- agonist use was greater in the subgroup of patients at risk of
developing persistent asthma than in the placebo group. Montelukast was also
superior to placebo in a subgroup of patients with atopic dermatitis, allergic rhinitis,
or a family history of asthma. The authors concluded that oral granular
Montelukast 4 mg for 6 wk is safe and tolerable in children aged >=6 mo to <2 yr
with asthma25
.
Further, the results of a national prescription event monitoring (PEM) study of
Montelukast in 15,612 patients who had prescriptions filled between February
1998 and December 1998 in England were reported. Age was not recorded for
Page 48 of 70
2125 patients; however, for the remaining 13,487 patients, the mean age was 48 yr.
The most frequent indications for the use of Montelukast were asthma (55%) and
chronic obstructive airway disease (3%); indications were unspecified in 39% of
the patients. Treatment was effective in 64% (7826/12,248) of the patients for
whom an opinion on effectiveness was given. Six months after initiating therapy,
56.2% (8114/14,433) of the patients were still receiving Montelukast. Events with
the highest incidence density in the 1st month of Montelukast treatment (ID-1 per
1000 patient-mo of treatment) were respiratory tract infections (17.5), improved
condition (16.2), headache/migraine (13.7), nausea/vomiting (7.1), nonsurgical
admissions (6.2), noncompliance (5.6), and malaise/lassitude (5.5). Specifically,
the events with the highest ID-1 in children aged <6 yr (n=107) were
headache/migraine and respiratory tract infection, followed by abnormal behavior
and dizziness. In children aged 6-14 yr (n=1258), the event with the highest ID-1
was headache/migraine, followed by nausea/vomiting and abdominal pain. General
practitioners reported 250 drug-related adverse events in 191 (1.2%) patients. Of
the 250 adverse events, 62 were reported to the Committee on Safety of Medicines.
The most frequently reported adverse event was headache (n=35), which was also
the most frequent reason for discontinuing medication (n=211). There were 11
reports of serious suspected adverse events, including Churg-Strauss syndrome (3
reports), angioedema (3 cases), allergy (2 cases), facial edema (2 cases), and
anaphylaxis (1 case). Adverse events that were possibly related to Montelukast
included insomnia (36 cases), abnormal dreams (8 cases), dizziness (29 cases),
palpitations (9 cases), worsened eczema (8 cases), flu-like symptoms (7 cases),
depression (5 cases), drug interaction (3 cases), and allergy (2 cases). The authors
note that there were 5 reports of improved eczema or urticaria that were possibly
related to the use of Montelukast. Among the 53 women who reported pregnancies,
38 had been exposed to Montelukast in the 1st trimester. Pregnancy outcomes
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included 21 live births, 2 stillborns, 7 spontaneous abortions, 4 therapeutic
terminations, and 4 unknown outcomes. No fetal malformations were recorded.
There were 305 deaths including 21 deaths due to asthma, 84 due to chronic
obstructive airways disease, 3 due to status asthmaticus, 1 due to multiorgan failure,
1 due to hepatic failure, and 1 due to an unspecified hepatic disease. None of the
deaths were attributed to Montelukast. The authors concluded that Montelukast is
well tolerated in this cohort of patients26
.
The tolerability of a medication, especially in children with asthma, is linked to a
number of key factors. These include clinical effectiveness, adverse effects,
frequency of drug regimen, ease and route of administration, and taste.
Montelukast is unusual in that, in most countries, a license for children aged ≥6
years was granted at the same time as the adult license. This is related to a variety
of evidence, which includes pharmacological and adult studies suggesting the
specificity and safety of the drug at many times the licensed dose, and a tolerability
profile similar to that with placebo or inhaled corticosteroids in both adult and
paediatric studies. The most common adverse effects in paediatric studies were
headache, asthma and upper respiratory tract infection at rates not statistically
significantly different from those with placebo. Up to July 1999, more than 2
million patients worldwide have received Montelukast, of whom nearly 220 000
have received the paediatric formulation. In the UK, one prescribing database
suggests that, of children who commenced Montelukast therapy, less than 25%
discontinued the drug. This implies that Montelukast is effective and well tolerated
in most children. Adverse effect monitoring by regulatory bodies has revealed little
that would not be expected on the basis of the results of clinical trials. Montelukast
has been associated with Churg-Strauss syndrome in a very small number of adults.
In most, the syndrome was associated with corticosteroid withdrawal, which may
have unmasked the condition. Churg-Strauss syndrome has not been reported in
Page 50 of 70
children. Its clinical effectiveness, lack of major adverse effects, oral route of
administration, palatability and the once-daily regimen combine to make
Montelukast a generally well tolerated medication in children27
.
An open-label, extension study was performed to examine the safety of therapy
with Montelukast 4-mg chewable tablets once daily at bedtime (n=288) or
inhaled/nebulized corticosteroids or Cromolyn sodium (usual care (UC); n=119)
for 26-409 days in children (age 2-5 yr) with asthma28
. Montelukast and UC had
similar safety profiles. Adverse events included asthma (42.7% and 46.2% in the
Montelukast and UC groups, respectively), cough (22.2% and 10.1%, respectively),
fever (36.5% and 28.6%, respectively), pharyngitis (22.9% and 16.8%,
respectively), and upper respiratory tract infection (40.6% and 40.3%, respectively).
The frequency of discontinuation because of adverse events was similar between
the groups. The authors concluded that Montelukast was well tolerated in
asthmatic children aged 2-5 yr28
.
Allergic rhinitis (AR) affects a large percentage of paediatric patients. With the
wide array of available agents, it has become a challenge to choose the most
appropriate treatment for patients. Second-generation antihistamines have become
increasingly popular because of their comparable efficacy and lower incidence of
adverse effects relative to their first-generation counterparts, and the safety and
efficacy of this drug class are established in the adult population. Data on the use
of the second-generation antihistamines oral Cetirizine, Levocetirizine, Loratadine,
Desloratadine and Fexofenadine, and the leukotriene receptor antagonist
Montelukast as well as Azelastine nasal spray in infants and children are evaluated
in this review29
. These agents have been found to be relatively safe and effective in
reducing symptoms associated with AR in children. Alternative dosage forms such
as liquids or oral disintegrating tablets are available for most agents, allowing ease
of administration to most young children and infants; however, limited data are
Page 51 of 70
available regarding use in infants for most agents, except Desloratadine, Cetirizine
and Montelukast. Unlike their predecessors, such as Astemizole and Terfenadine,
the newer second-generation antihistamines and Montelukast appear to be well
tolerated, with absence of cardiotoxicities. Comparative studies are limited to
Cetirizine versus Ketotifen, Oxatomide and/or Montelukast. Although second-
generation antihistamines and Montelukast are deemed relatively safe for use in
paediatric patients, there are some noteworthy drug interactions to consider when
selecting an agent. Given the wide variety of available agents for treatment of AR
in paediatric patients, the safety and efficacy data available for specific age groups,
type of AR, dosage form availability and cost should be considered when selecting
treatment for AR in infants and children29
.
In a meta-analysis, the clinical efficacy of leukotriene receptor antagonists,
including Montelukast, in the treatment of patients with allergic rhino sinusitis and
nasal polyposis was compared with that of placebo, antihistamines, and nasal
corticosteroids30
. A search of EMBASE, MEDLINE, and CINAHL for randomized
controlled trials found 94 abstracts, 14 eligible studies, and data from 8 trials, 6 of
which were parallel studies (n=2130 subjects). No trials were found that
specifically evaluated the effects of leukotriene receptor antagonists in patients
with sinusitis or nasal polyposis. The methodological quality of each included trial
was evaluated using Jadad's criteria (score 0-5). The composite daily rhinitis
symptoms scores in each trial were standardized for the maximum score and
pooled using the weighted mean difference (WMD) and 95% confidence intervals
(CI); this was accomplished by using a random effects model after assessing for
heterogeneity. According to the methodological quality analysis, the median
Jadad's score was 3. Among the trials included in the meta-analysis, 8 compared a
leukotriene receptor antagonist with a placebo (5 Montelukast trials, 2 Zafirlukast
trials, 1 L-649923 trial), 2 compared a leukotriene receptor antagonist with an
Page 52 of 70
antihistamine (both Montelukast vs Loratadine), and 4 compared a leukotriene
receptor antagonist with a nasal corticosteroid (1 Montelukast vs Mometasone, 1
Montelukast vs Budesonide, 1 Montelukast vs Fluticasone, 1 Zafirlukast vs
Beclomethasone). According to composite daily rhinitis symptoms scores,
leukotriene receptor antagonists were more effective than placebo (WMD -0.02,
95% CI -0.07 to -0.02), were as effective as antihistamines (WMD 0.02, 95% CI -
0.01 to 0.02), and were not as effective as nasal corticosteroids (WMD 0.22, 95%
CI 0.07 to 0.22). Quality of life and nasal peak flow improved with leukotriene
receptor antagonists when compared with placebo; this improvement was not seen
with nasal eosinophilia. The authors concluded that with regard to allergic rhinitis
symptom improvement, leukotriene receptor antagonists are more effective than
placebo, as effective as antihistamines, and inferior to nasal corticosteroids30
.
COST EFFECTIVENESS:
The cost effectiveness of Monteluakst is evaluated in Asthmatic patient mostly.
Considering the fact of link between Asthma and Allergic rhinitis, we therefore
included some data from those studies for the reference.
Asthma and allergic rhinitis are frequently co-morbid conditions. Montelukast is
effective in treating both diseases and may reduce total medication use among
children with asthma and allergic rhinitis. To determine the differences in
respiratory and allergy medication use and costs, as proxies for control, in pediatric
patients with asthma and allergy who initiated asthma controller therapy, a 24-
month, retrospective, pre-post cohort study using a pharmacy claims database of
children (age < 16 years) with 2 or more consecutive asthma controller
Page 53 of 70
prescriptions and 1 or more allergy prescription (within 12 months before initial
controller prescription). Children taking inhaled corticosteroids (ICSs) and
Montelukast were matched one to one based on age, days of prior allergic rhinitis
therapy supply, duration of controller therapy, and propensity score. Differences in
costs of rescue or acute asthma medications, prescription allergy medications,
other respiratory medications, and the number of days of rescue or acute asthma
medication use and allergy medication use were calculated. Results: A total of
1,236 children were matched into ICS and Montelukast groups (n = 618 each).
Montelukast patients had a smaller cost increase overall compared with ICS
patients (combined cost for rescue or acute asthma medications, allergy
medications, and other respiratory medications: USD5.55 vs USD12.08, P < .001).
Cost increase for rescue or acute asthma medications was significantly lower in the
Montelukast group (USD0.94 vs USD3.82, P = .003). The cost increase for allergy
medications (USD5.29 vs USD10.06, P < .001) was also significantly lower in the
Montelukast group. Patients taking Montelukast also had fewer days of therapy
with asthma rescue medication and allergy medication compared with patients
taking ICSs. The author concluded that Initiating therapy with Montelukast was
associated with better asthma and allergy control demonstrated via lower increase
in use and costs of asthma rescue and allergy medications compared with initiating
ICS therapy31
.
A 24-month, retrospective, longitudinal cohort study was conducted to investigate
the effects of initiating Montelukast or inhaled corticosteroids (ICS) on the use and
costs of respiratory and allergy medications in children with asthma and allergic
rhinitis31
. Data were obtained from a pharmacy administrative database (Medco
Health Solutions Inc. Information Warehouse) and published average wholesale
prices of medications. The cohort consisted of 3217 patients <16 yr of age who
initiated asthma controller therapy with either Montelukast or an ICS; after 1-to-1
Page 54 of 70
matching, 1236 patients were analyzed (618 in each group; 60% M, mean age 9.9
yr, >75% with mild asthma). The mean monthly per-patient cost for all asthma and
allergy medications increased significantly less in the Montelukast group than in
the ICS group (USUSD5.55 vs USD12.08, p<0.001). The increase in cost for all
asthma rescue medications was also lower in the Montelukast vs ICS group
(USD0.94 vs USD3.82, p=0.003), primarily because of a difference in the use of
short-acting b-agonists (USD1.79 with Montelukast vs USD3.34 with ICS,
p=0.008). The overall cost increase per month for all allergy medications was
lower in the Montelukast vs ICS group (USD5.29 vs USD10.06, p<0.001);
corresponding cost differences for antihistamines were USD4.44 vs USD7.43
(p=0.004) and for nasal steroids, USD0.85 vs USD2.63 (p<0.001). Overall, the
initiation of Montelukast vs ICS resulted in significant reductions in costs for other
medications (USD3.61 vs USD6.07 for asthma rescue agents and USD8.04 vs
USD12.00 for allergy medications [p<0.001 for both]). In a post-hoc analysis of a
matched cohort of patients who started Montelukast or fluticasone (n=282 each),
combined costs of allergy medications increased significantly less in the
Montelukast group than in the fluticasone group (USD4.50 vs USD9.45, p=0.005),
mainly because of less use of nasal steroids in the post-controller period. Patients
in the ICS group were 66% more likely to have more days of therapy with asthma
rescue agents and 2.3 times more likely to have more days taking short-acting b-
agonists than were those in the Montelukast group (odds ratio [OR] for ICS vs
Montelukast, 1.66 for all rescue agents, 2.31 for short-acting b-agonists, 1.27 for
all allergy medications, 1.78 for nasal steroids; all differences p=0.05). In both
groups, the odds of having a higher number of days of rescue therapy increased
with increasing age. Results showed that the initiation of Montelukast resulted in
significantly lower overall cost increases for asthma and allergy medications than
did initiation of ICS, suggesting better asthma control with Montelukast. The
Page 55 of 70
authors mentioned that these findings support the concept of "one airway" disease
for asthma and allergic rhinitis and that this is the first cost analysis of pediatric
asthma and allergy medication use based on a US pharmacy database31
.
Another retrospective cohort study was conducted in 88 Italian children (72% M,
aged 0-14 yr) with asthma and allergic rhinitis to determine usage of rescue or
acute asthma medication or allergy medication during treatment with Montelukast
or another asthma controller32
. Other controllers consisted of high-dose inhaled
corticosteroids (ICS) or ICS plus a long-acting b-agonist (LABA). Data were
obtained from an electronic database (PediaNET). Children with at least 2 yr of
follow-up (at least 1 yr before and after the index date) and who received at least 2
consecutive prescriptions for controller medication were included. The index date
was the date of the first controller prescription. Prescription medications and costs
were estimated for rescue medications (short-acting b-agonists), acute medications
(antibiotics or oral corticosteroids), allergy drugs (antihistamines or nasal steroids),
and other respiratory medications (such as cromones). The Montelukast cohort
comprised 23 children, with more than 78% also taking ICS. The other controller
cohort comprised 65 children, with 51% taking ICS and 49% taking ICS/LABA.
Although children taking Montelukast had more severe asthma than the other
cohort, this group still showed reductions in prescription rates for rescue, acute,
allergy, and other respiratory medications after starting Montelukast. In the other
controller cohort, prescription rates increased for all medication classes except
allergy medications and antibiotics, which showed reductions. Compared with the
other controller cohort, the Montelukast cohort had a 10-fold greater reduction in
overall crude monthly cost. Cost reductions (in euros) were 3.63 with Montelukast
and 0.03 with other controllers (p=0.11)32
.
As observational studies in children initiating GINA-Step 3 therapies are scarce, a
retrospective study evaluated outcomes and costs in a primary care cohort33
. This
Page 56 of 70
Two-yr retrospective cohort study included French children (age: 6-14)
continuously followed in BKL-Thalès database who received > or =2 consecutive
prescriptions for GINA-Step 3 therapy (=addition of Montelukast or other
controllers ('other'), such as increasing inhaled-corticosteroid dose (hICS), adding
long-acting beta agonist (LABA), or ICS + LABA). After matching on gender and
propensity score, medication use [rescue (short-acting beta agonists), acute
(antibiotics (AB), oral corticosteroids (OCS), allergy (antihistamines, nasal
steroids) and other respiratory] was estimated via mean number of prescriptions
and mean cost (per child/per month), and cost trends. During 12-month follow-up,
children adding Montelukast (n = 71) vs. 'other' (n = 213) had similar asthma
rescue/acute and allergy medication use. Subgroup with asthma and allergic
rhinitis (A + AR) adding Montelukast used less OCS and AB (p = 0.014). Two-yr
cost trends suggest stable asthma/allergy medication use in Montelukast group
(0.83 euro) compared with increase in 'other' (5.39 euro), which was driven by
nasal steroid use [0.32 euro ('other') vs. -0.04 euro (Montelukast), p = 0.0013]. In
subgroup with A + AR decline in asthma/allergy medication use in Montelukast
group (-0.47 euro) vs. increase in 'other' (11.05 euro), p = 0.015, was driven by
differences in AB and OCS (p = 0.04) and nasal steroid use (p = 0.001).
Concomitant asthma/allergy medication use was similar in children adding
Montelukast or 'other' controllers (hICS, LABA, ICS + LABA), while children
with allergic rhinitis on Montelukast used less AB. Concomitant medication costs
after addition of Montelukast remained stable, while 'other' group experienced
increase, especially in children with concomitant allergic rhinitis.
In this 2-yr retrospective, observational cohort study, the use and costs of asthma
and allergy medication were evaluated among 439 French children aged 6-14 yr
with asthma who initiated Global Initiative for Asthma (GINA) Step 3 therapy.
Approximately half of the patients had concomitant allergic rhinitis. The
Page 57 of 70
observation period consisted of 1 yr before the initiation of GINA Step 3 therapy
and 1 yr afterward. A total of 71 patients (47 M, 24 F, mean age 9.56 yr) added
Montelukast to their existing inhaled corticosteroid therapy, while 368 (234 M, 134
F, mean age 10.05 yr) used other controllers, including high-dose inhaled
corticosteroids, long-acting b-agonists, and inhaled corticosteroids plus long-acting
b-agonists. In the year after the introduction of GINA Step 3 therapy, the group
that added Montelukast and the group that used other controllers did not differ
significantly with respect to concomitant allergy/asthma medication use. In the
subgroup with allergic rhinitis, Montelukast was associated with significantly
lower use of allergy/asthma medications than were the other controllers (5.30 vs
7.62 prescriptions per patient per year; P=0.013). In the group as a whole and in
the subgroup with allergic rhinitis, the cost of asthma/allergy medications remained
stable in the Montelukast group over the 2-yr observation period. In the group
using other controllers, there was a slight increase in the cost of asthma/allergy
medications overall and a significant increase among patients with allergic rhinitis.
The authors concluded that Montelukast appears to provide asthma control
comparable to that of high-dose inhaled corticosteroids, long-acting b-agonists, and
inhaled corticosteroids plus long-acting b-agonists. Compared with the other
regimens, Montelukast may be associated with lower costs for concomitant
asthma/allergy medications33
.
A retrospective claims-based analysis of asthmatic children, 2-14 years old,
receiving a prescription (index) for Montelukast or Fluticasone between January 1,
1999 and June 30, 2000 was conducted to examine the impact of controller
monotherapy with Montelukast or Fluticasone on asthma-related health care
resource use among children aged 2-14 years old34
. Children were matched by age
and propensity score to obtain comparable treatment groups. The propensity score
was derived using patient demographics, pre-existing respiratory conditions, and
Page 58 of 70
asthma-related pharmacy and health service utilization (i.e. ambulatory visits,
emergency department visits and hospitalizations). Claims for asthma-related
emergent care and medication use were examined for the 12-month periods before
and after the index prescription. Treatment group comparisons of asthma-related
resource use were conducted for the total pediatric population and separately for
children 2-5 years and 6-14 years. Persistent controller medication use was
assessed at 6 and 12 months post-index. Results: A total of 2034 children were
matched (1017 in each treatment group). Post-index rates of asthma-related
resource use were similar among children treated with Montelukast or Fluticasone.
Among children 2-5 years old, fewer emergency department visits were observed
with Montelukast versus Fluticasone (relative risk = 0.52, 95% confidence interval
[CI]: 0.28-0.96); no significant difference was observed among children 6-14 years
old. No significant differences between Montelukast and Fluticasone cohorts in
hospitalizations or rescue medication fills were noted in either age group. Evidence
of at least one medication refill was significantly greater with Montelukast at both
6 and 12 months post-index. Conclusions: Similar levels of resource use were
achieved by children 2-14 years initiating Montelukast or Fluticasone, as indicated
by use of asthma-related emergent care and rescue/acute medications. Subgroup
analyses suggest a differential effect of age on the relationship between treatment
and asthma-related resource use, with children 2-5 years observed to have less
resource use while on Montelukast34
.
This retrospective cohort study34
was conducted to compare Montelukast and
Fluticasone propionate as controller monotherapy in children aged 2-14 yr) with
asthma. Data on 2034 children who received an index prescription for Montelukast
(n=1017) or Fluticasone (n=1017) between January 1, 1999 and June 30, 2000
were obtained from the administrative claims from 20 managed care plans in the
USA. Outcomes included visits to emergency departments, asthma-related
Page 59 of 70
hospitalizations, oral corticosteroid therapy, and short-acting beta-agonist therapy.
There was no difference between the 2 groups with respect to post index asthma-
related hospitalizations or rescue medication fills. Among children aged 2-5 yr,
fewer emergency department visits occurred in the Montelukast group compared
with the Fluticasone group. No differences were seen among those aged 6-14 yr.
The authors concluded that overall, patients in the Montelukast and Fluticasone
groups experienced similar therapeutic effects. However, they add that children
aged 2-5 yr had less resource use on Montelukast compared to fluticasone34
.
A 2-yr retrospective pre-post cohort study was conducted to evaluate use of asthma
rescue medications and allergy medications and costs in Italian children aged 0-14
yr with asthma who were receiving either Montelukast or other asthma controllers
(high-dose inhaled corticosteroids [h-d ICS] or ICS plus long-acting b-agonists) 35
.
Patients were registered for >=2 yr, received >=2 consecutive asthma-controller
prescriptions after 1 July 2001, and were followed-up through the PediaNET
(pediatrician network) database. Patients were enrolled in the cohort upon the
initial prescription for an asthma controller; patients with <1 yr of follow-up prior
to or after the index date were excluded. Estimates were made of pre-post
differences in mean per-child-per-month prescription costs and rates of rescue
medications (short-acting b-agonists, acute medications [antibiotics, oral
corticosteroids], allergy medications [antihistamines, nasal steroids], and other
respiratory medications). The cohort comprised 987 patients (61% M); 8.9% had a
recorded history of allergic rhinitis. The Montelukast cohort (about 75% with
Montelukast added to ICS) comprised 122 patients; the cohort receiving other
asthma controllers comprised 865 patients (ICS plus long-acting b-agonists,
n=187; h-d ICS, n=677 [sic]). Asthma was more severe and allergic rhinitis was
more common in the Montelukast cohort than in the cohort receiving other asthma
controllers. Nevertheless, the Montelukast cohort experienced a decrease in overall
Page 60 of 70
crude prescription rates and cost, while the cohort receiving other asthma
controllers experienced an increase in monthly costs (rescue medications, acute
medications, allergy medications, and other respiratory medications combined: -
1.52 Euros vs +1.50 Euros; p<0.012). Decreases in prescription rates and costs
were observed in the Montelukast cohort for rescue medications (p=0.064), acute
medications (NS), and allergy medications (p<0.001), whereas an increase was
observed in the cohort receiving other asthma controllers. The cost of use of other
asthma drugs increased in both cohorts but did not differ between the cohorts. In
conclusion, significant reductions in total use and costs of asthma rescue
medications, acute medications, and allergy medications were observed over a 2-
yr period among asthmatic children treated with Montelukast (75% added to ICS),
compared with those treated with either h-d ICS or ICS plus long-acting b-
agonists35
.
Another open-label study was conducted to compare the effects of long-term
treatment with Montelukast and usual care on health care resource use in children
with asthma36
. In the review it was noted that quite a few Pharmacoeconomic
studies mixed up allergic rhinitis with asthma. This has its basis on the fact that
there is a link between Asthma and AR. 80% of Asthma patient are having a
history of AR and 30% of AR patient may develop Asthma in their life. (Refer:
ARIA recommendations 2007)
Pediatric patients aged 2 to 5 years with asthma who had completed a 3-month,
double-blind; double-dummy clinical trial comparing Montelukast 4 mg and
placebo were asked to participate in an open-label, controlled extension study
comparing Montelukast 4 mg and usual care. Usual care was defined as Cromolyn
or inhaled corticosteroid therapy Health care resource utilization was measured in
terms of oral corticosteroid use and numbers of physician visits, emergency
department visits, and hospitalizations. Of 618 patients who completed the primary
Page 61 of 70
phase of the study, 506 (83.5%) participated in the extension study Data from 506
patients (302 without previous asthma maintenance therapy, 204 with) were
included in the analysis. During the extension phase, patients who received
Montelukast and had not used previous asthma maintenance therapy were followed
for a mean of 329.5 days; those who received usual care and In this open-label
study, pediatric patients aged 2 to 5 years with mild to moderate persistent asthma
receiving long-term therapy with Montelukast had similar rates of asthma-related
health care resource utilization compared with those receiving usual care with
Cromolyn or inhaled corticosteroids36
.
Also, this open-label, controlled extension of a 3-mo, double-blind, double-dummy
clinical trial was conducted to compare Montelukast 4 mg and usual care
(Cromolyn sodium or inhaled corticosteroids) with respect to health care resource
utilization in children aged 2-5 yr with mild-to-moderate persistent asthma36
. Of
the 689 patients enrolled in the original study, 506 participated in some portion of
the extension: 302 who had not used previous asthma maintenance therapy and 204
who had used maintenance therapy (Cromolyn or inhaled corticosteroids). Of the
302 who had not used previous maintenance therapy, 215 (122 M, 93 F) received
Montelukast and 87 (46 M, 41 F) received usual care in the extension. Of the 204
who had used maintenance therapy, 146 (88 M, 58 F) received Montelukast and
usual care and 58 (44 M, 14 F) received usual care during the extension. The mean
duration of follow-up in the extension phase was 329.5 days for those who
received Montelukast and had not used previous maintenance therapy, 314.6 days
for those who received usual care and had not used previous therapy, 319.7 days
for those who received Montelukast and had received previous therapy, and 289.4
days for those who received usual care and had received previous therapy. Among
patients who had not used previous asthma therapy, patients who received
Montelukast during the extension had lower rates of health care resource utilization
Page 62 of 70
than did patients who received usual care in terms of physician visits (1.50 vs
1.96/person-year) and emergency department visits (0.19 vs 0.39/person-year).
These differences, however, were not statistically significant. Hospitalization rates
were identical between Montelukast and usual care recipients. Among patients who
had used previous asthma therapy, patients who received Montelukast during the
extension had lower rates of health care resource utilization than did patients who
received usual care in terms of oral corticosteroid episodes (1.41 vs 1.59/person-
year), physician visits (1.64 vs 1.81/person-year), emergency department visits
(0.19 vs 0.28/person-year), and hospitalizations (0.07 vs 0.13/person-year). Again,
these differences were not statistically significant. The authors concluded that
among children aged 2-5 yr with mild-to-moderate persistent asthma, those who
received Montelukast had similar rates of asthma-related health care resource
utilization compared with those who received usual care with cromolyn or inhaled
corticosteroids36
.
An economic analysis of the PRE-EMPT study findings to assess the societal value
of short-course Montelukast for treatment of intermittent asthma in children was
conducted37
. The PRE-EMPT study, which was conducted in primary and
secondary care throughout Australia, compared Montelukast with placebo in 681
asthma episodes in 202 children aged 2-14 yr. The study showed that a short
course of Montelukast introduced at the first sign of viral upper respiratory tract
infection or asthma symptoms effectively reduced healthcare resource use,
symptom severity, time off from school, and parent time off from work. This cost
consequence analysis compared average costs per asthma episode for the
Montelukast and placebo study arms. The analysis considered costs in the
Australian and UK healthcare environments and took a societal perspective
including direct and indirect healthcare costs. The economic analysis showed that
the percent of episodes requiring healthcare resource use was significantly lower in
Page 63 of 70
the Montelukast arm than in the placebo arm. Average costs in Australian dollars
per episode in the Montelukast and placebo arms, respectively, were 5.72 and 5.95
for concomitant drugs (difference, -0.23); 15.73 and 0.00 for Montelukast drug
purchase (difference, +15.73); 67.08 and 90.93 for healthcare resources (including
general practitioner, specialist, emergency room attendance, hospital admission;
difference, -23.85); and 224.62 and 343.18 for parental work loss (difference, -
118.56). In conclusion, a short-course intervention with Montelukast significantly
reduced healthcare resource use. The costs associated with the Montelukast
intervention were substantially lower than those associated with placebo37
.
References:
1. Allergic Rhinitis David M. Lang Disease Management Project Clinical
Decisions Published: August 1, 2010
2. BMC Public Health; V.11; 2011; p437
3. The Lancet; V.378; 12/11; p2112.
4. The Journal of Laryngology and Otology; V.113; 1/99; p1)
5. European Journal of Allergy and Clinical Medicine; V.49 (Suppl); 1994; p6)
6. Epidemiology of Clinical Allergy. Monogr Allergy; Basel, Karger; 1993; V.31;
p61
Page 64 of 70
7. Incorvaia C et al, Allergologia, Istituti Clinici di Perfezionamento, Milan, Italy.
Pharmacoeconomics of subcutaneous allergen immunotherapy. Eur Ann Allergy
Clin. Immunol. 2007;39 Spec No:17-20.
8. Member Society Reports in: Pawankar R, Canonica GW, Holgate ST, and
Lockey RF, editors. WAO White Book on Allergy (World Allergy Organization),
2011.
9. Review Allergic rhinitis. Small and Kim Allergy, Asthma & Clinical
Immunology 2011 7(Suppl 1):S3 doi: 10.1186/1710-1492-7-S1-S3
10. A Kaliner, MD, Umer Najib, MD The Medscape Journal of Medicine (ISSN:
1934-1997), Updated: Sep 12, 2012
11. WPC of Montelukast (WPC-MK0476-MF-092011:
http://www.medsafe.govt.nz/profs/datasheet/s/Montelukasttab.pdf accessed on 10-
Dec-2012)
12. M. Kherkheulidze, N. Kavlashvili, I. Chkhaidze, E. Kandelaki, N. Adamia
Impact Of Anti-Leukotrienes On Course Of Seasonal Allergic Rhinitis In Children
Pediatr Allergy Immunol 20(20): 64; Abstr: LB6 34 2009. EAACI Pediatric
Allergy and Asthma Meeting, 12-14 November, Venice, Italy
13. Watanasomsiri, Apassorn; Poachanukoon, Orapan; Vichyanond, Pakit Efficacy
of Montelukast and Loratadine as Treatment for Allergic Rhinitis in Children
Asian Pacific J Allergy Immunol 26(2-3): 89-95 2008
Page 65 of 70
14. Chen S T, Lu K H, Sun H L, Chang W T, Lue K H and Chou M C Randomized
placebo-controlled trial comparing Montelukast and cetirizine for treating
perennial allergic rhinitis in children aged 2-6 yr Pediatr Allergy Immunol
17(1):49-54 2006
15. Razi C, Bakirtas A, Harmanci K, Turktas I, Erbas D. Effect of Montelukast on
symptoms and exhaled nitric oxide levels in 7- to 14-year-old children with
seasonal allergic rhinitis. Ann Allergy Asthma Immunol.97(6):767-74. 2006
16. Alul M E A study to determine the impact of rhinitis on sufferers' sleep and
daily routine with using nasal sprays or Montelukast drug XXV Congr Eur Acad of
Allerg and Clin Immun (EAACI), June 10-14, 2006, Vienna, Austria, Abst 1342
17. Storms W, Michele TM, Knorr B, Noonan G, Shapiro G, Zhang J, Shingo S,
Reiss TF Clinical safety and tolerability of Montelukast, a leukotriene receptor
antagonist, in controlled clinical trials in patients aged > or = 6 years. Clin Exp
Allergy. 31(1):77-87 2001
18. Hans Bisgaard, David Skoner, Maria L. Boza, Carol A. Tozzi, Kathleen
Newcomb, Theodore F. Reiss, Barbara Knorr and Gertrude Noonan BA Safety and
tolerability of Montelukast in placebo-controlled pediatric studies and their open-
label extensions. Pediatr Pulmonol Jun;44(6):568-79 2009
19. Christine A. Sorkness, PharmD,b Robert F. Lemanske, Jr, MD et al. Long-term
comparison of 3 controller regimens for mild-moderate persistent childhood
asthma: (J Allergy Clin Immunol 2007;119: 64-72).
Page 66 of 70
20. Tamesis GP, Covar RA. Long-term effects of asthma medications in children.
Curr Opin Allergy Clin Immunol. 8(2):163-7 2008
21. Barnes N, Thomas M, Price D and Tate H The national Montelukast survey J
Allergy Clin Immunol 115(1):47-54 2005
22. Karaman O, Sunneli L, Uzuner N, Islekel H, Turgut C S, Kose S, Tezcan D,
Coker C and Erbayraktar Z Evaluation of Montelukast in 8 to 14 year old children
with mild persistent asthma and compared with inhaled corticosteroids Allergol
Immunopathol Madr 32(1):21-27 2004
23. Kukreja S, Sanjay S, Ghosh G, Aggarwal K K and Moharana A Montelukast -
evaluation in 6 to 14 years old children with persistent asthma - pediatric
Montelukast study group Indian J Pediatr 71(9):811-815 2004
24. van Adelsberg J, Montalvo J, Liu N, Knorr B, Wei L X and Reiss T F Safety
and tolerability of Montelukast, a leukotriene receptor antagonist, in 6 to31-month-
old asthmatic patients: evaluation at 3 months Am Thoracic Soc 99th Inter Conf,
May 16-21, 2003, Seattle, Washington, USA, Abstract A117, Pos D74
25. van Adelsberg J, Wei L X, Knorr B, Kuna P, Wilhaber J H and Reiss T F .
Montelukast is safe and well tolerated in >=6 month to <2 year old patients 12th
European Respiratory Society Annual Congress, September 14-18, 2002,
Stockholm, Sweden, Abstract P3267
Page 67 of 70
26. Biswas P, Wilton L, Pearce G, et al Pharmacosurveillance and safety of the
leukotriene receptor antagonist (LTRA) Montelukast. Clin Exp Allergy Reviews
1(3):300-304 2001
27. Price D Tolerability of Montelukast Drugs 59 (Suppl. 1):35-42 2000
28. Bisgaard H, Franchi L M, Maspero J F, Sienra-Monge J, Keklikian E, Soto M,
Bratton D, Knorr B A, Nguyen H H, Reiss T F, Michele T M and the Montelukast
Preschool Pediatric Study Group Long-term safety of Montelukast in 2- to 5-year
old children with asthma Eur Respir Soc, Florence, Italy Abstr. 2152, Aug. 30-Sept.
3, 2000
29. Phan, Hanna; Moeller, Matthew L; Nahata, Milap C Treatment of allergic
rhinitis in infants and children: efficacy and safety of second-generation
antihistamines and the leukotriene receptor antagonist Montelukast. Drugs 69 18 :
2541-76 2009
30. Wilson A M, Parameswaran K and O'Byrne P M Leukotriene receptor
antagonists for allergic rhino-sinusitis: a systematic review and meta-analysis Eur
Respir J 22(Suppl. 45):Abstract P751 2003
31. Luskin A, Bukstein D, Sazonov Kocevar V and Yin D D Asthma rescue and
allergy medication use among asthmatic children with prior allergy prescriptions
who initiated asthma controller therapy. Ann Allergy Asthma Immunol 95(2):129-
136 2005
32. Sturkenboom M C J M Decline in use of asthma rescue/acute and allergy drugs
following treatment with Montelukast vs other controllers in Italian children with
Page 68 of 70
asthma and concomitant allergic rhinitis. XIX World Allergy Organization
Congress, June 26-July 1, 2005, Munich, Germany, Abstract 850
33. Sazonov-Kocevar V, Laforest L, Travier N, Yin D D and Van Ganse E Asthma
and allergy medication use and costs among pediatric primary care patients on
asthma controller therapy. Pediatr Allergy Immunol 17(8):620-628 2006
34. Allen-Ramey F C, Markson L E, Riedel A A, Sajjan S and Weiss K B Patterns
of asthma-related health care resource use in children treated with Montelukast of
fluticasone
Curr Med Res Opin 22(8):1453-1461 2006
35. Bonetto G Decreased use of asthma rescue and allergy medications in
asthmatic children receiving Montelukast versus other controllers in Italy
XIX World Allergy Organization Congress, June 26-July 1, 2005, Munich,
Germany, Abstract 854
36. Davies GM, Dasbach EJ, Santanello NC, Knorr BA, Bratton DL. The effect of
Montelukast versus usual care on health care resource utilization in children aged 2
to 5 years with asthma. Clin Ther. 26(11):1895-904 2004.
37. Price D, Robertson C F, Henry R L, Mellis C, Fitzgerald D, Glasgow N, Lee A,
Turner J, Schulz M and Noble I Short course Montelukast for intermittent asthma
in children: economic analysis of the PRE-EMPT study Eur Respir J 24(Suppl.
48):#P1984 2004
Page 69 of 70
Abbreviations Full terms
AB Antibiotics
A$ Australian Dollar
ARIA Allergic Rhinitis and its Impact on Asthma
AR Allergic Rhinitis
AUC Area Under Curve
b.i.d Bis in a day
CysLT Cysteinyl Leukotrienes
CAMP Childhood Asthma Management Program
CI Confidence Intervals
ECP Eosinophil Cationic Protein
F Female
FEV-1 Forced Expiratory Volume in 1 second
GINA Global Initiative for Asthma
h-d ICS High-Dose Inhaled Corticosteroids
ICSs Inhaled Corticosteroids
IPAG International Primary Care Airways Group
ISAAC International Study of Asthma and Allergies in Childhood
LABA Long-Acting Beta-Agonist
LTRA Leukotriene Receptor Antagonist
LTC 4 Cysteinyl Leukotrienes C-4
LTD 4 Cysteinyl Leukotrienes D-4
LTE 4 Cysteinyl Leukotrienes E-4
M Male
mcg Microgram
mg Milligram
NAR Nasal Airway Resistance
OCS Oral Corticosteroids
PDTS Percent change of the total daytime nasal symptom scores
PNTS Percent change of the total Night time nasal symptom scores
PES Percent change of daytime eyes symptom scores
PCS Percent change of composite symptom scores
PNSS Percentage change in nasal secretion score
PTSS Percentage change in turbinate swelling score
PNCS Percentage change in nasal congestion scores
PAR Perennial Allergic Rhinitis
PRQLQ Pediatric Rhinoconjunctivitis Quality of Life Questionnaire
PEAK Prevention of Early Asthma in Kids
PACT Pediatric Asthma Controller Trial
PEM Prescription Event Monitoring
PediaNET Pediatrician Network
QOL Quality of Life
Page 70 of 70
START Steroid Treatment As Regular Therapy in early asthma
TSS Total Symptom Score
UK United Kingdom
USA United States of America
US$ United States of America Dollar
UC Usual Care
WMD Weighted Mean Difference
$ Dollar
Appendix I
Safety, efficacy and tolerability study of Montelukast (Anti leukotrienes):
Ref. Study Design Inclusion
Criteria
Subjects Intervention primary outcome secondary outcome Results Authors conclusion
M.
Kherkheulidze
(2009)
NA Paediatric
patients aged
6–12 years
diagnosed
with seasonal
allergic
rhinitis
48
children
48 patients aged 6–12
years: from those 28
patients with already
diagnosed seasonal
allergic rhinitis
conducted main group
who received the
montelukast once per
day and 20 patients
without any previous
treatment consist the
second control group
Nasal symptom
severity scores and its
correlation to quality
of life questionnaire
(PRQLQ).
NA The most frequent symptom
was nasal secretion, but the
most serious or disturbing
symptom, that affects
quality of life was nasal
obstruction. The results
showed that in main group
all nasal symptom scores
(sneezing, nose blows, nasal
obstruction, interference
with daily living, and
symptom comparison with
the previous year) has
significantly less symptom
severity after the treatment
compared to control. All
subscales of PRQLQ
indicated higher scores for
group main group. The
quality of life scores depend
on treatment duration; the
longer the treatment period,
the higher the QOL score
The result showed
correlation between
severity of rhinitis and
quality of life and
effectiveness of using
anti-leukotrienes in
treatment for
improvement of nasal
symptom scores as
well as quality of life
of patients with
seasonal rhinitis
Watanasomsiri
et al (2008)
A randomized,
double-blind
placebo controlled
trial
Allergic
Rhinitis
patient of 6-15
years old
115
children
The patients were
randomly assigned to
receive montelukast and
loratadine (treatment
group) or placebo and
loratadine (control
group). Patients received
loratadine 5 or 10 mg
depending on weight and
montelukast 5 mg (n=56)
or loratadine plus
placebo (n=59) at
bedtime for 2 wk
The primary outcome
was the mean percent
change of the total
daytime nasal
symptom scores
(PDTS)
The secondary
outcomes were the
mean percent
changes of the
nighttime nasal,
daytime eye and
composite symptom
scores (PNTS, PES,
PCS), as well as the
nasal secretion,
turbinate swelling
and nasal
congestion scores
(PNSS, PTSS,
PNCS).
There were no significant
differences in the PDTS of
the 2 groups. The change in
the night time nasal
congestion score (PNTS-
congestion) was higher in
the treatment group, but not
statistically significant (p =
0.077). Only the mean per!
cent change in decreased
turbinate swelling was
significantly greater in the
montelukast and loratadine
group than the loratadine
alone group (-22 +/- 7 vs. -1
+/- 5, p < 0.05).
The authors conclude
that montelukast plus
loratadine had a
significant effect on
nasal congestion but
not on other
symptoms in children
with allergic rhinitis.
Chen S T etal.
(2006)
A randomized,
double-blind,
placebo-
controlled,
parallel-group
study
Children from
2 to 6 yr old
with perennial
allergic
rhinitis (PAR)
60
children
The patient were
randomly assigned to
Motelukast and Cetrizine
group. 20 patient were
assigned to receive oral
montelukast 4 mg once
daily at bedtime (n=20;
11 M, 9 F, mean age
4.49 yr) and 20 patients
were assigned to receive
oral cetirizine 5 mg once
daily at bedtime (n=20;
12 M, 8 F mean age 4.53
yr) for 12 wk (age 2-6
yr) and 20 children
received placebo.
The efficacy of the
three agents was
compared with the
Pediatric
Rhinoconjunctivitis
Quality of Life
Questionnaire
(PRQLQ) and Total
Symptom Score
(TSS) by diary.
In addition, serum
IgE, serum
eosinophil cationic
protein (ECP),
blood eosinophil
counts, nasal airway
resistance (NAR)
and eosinophil
percentage in nasal
smears were also
examined .
After 12 wk of therapy,
total symptoms scores had
decreased significantly in
the montelukast and
cetirizine groups (both
P<0.001); however, total
symptoms scores were
lower in the cetirizine group
than in the montelukast
group (P<0.05 between
groups). Nasal itching
decreased to a greater
degree in the cetirizine
group than in the
montelukast group, while
the quality of night sleep
improved more in the
montelukast group than in
the cetirizine group.
Pediatric
Rhinoconjunctivitis Quality
of Life Questionnaire scores
improved significantly in
the montelukast and
cetirizine groups over 12
wk of therapy (P=0.028 and
P<0.001, respectively).
There were no significant
changes in levels of serum
IgE, serum eosinophil
cationic protein, or blood
eosinophil counts over 12
wk of therapy with
montelukast or cetirizine.
Nasal airway resistance
values decreased
significantly in the
montelukast and cetirizine
groups after 8 (P=0.007 and
P=0.026, respectively) and
12 wk of therapy (P=0.007
and P=0.013, respectively).
Similarly, the number of
eosinophils in nasal smears
decreased significantly in
the montelukast and
cetirizine groups over 12
wk of therapy (P=0.045 and
P=0.004, respectively).
The authors
concluded that both
Montelukast and
Cetirizine are
effective for the
treatment of perennial
allergic rhinitis in
children
Razi C etal
(2006)
A randomized,
double-blind,
parallel-group
study
Children aged
7 to 14 years
with seasonal
allergic
rhinitis
57
children
The study comprised a 1-
week screening period, a
1-week run-in period,
and a 2-week treatment
period with once daily
Montelukast, 5 mg, or
matching placebo.
Improvements from
the baseline in the
daytime nasal,
composite, and
daytime eye
symptoms scores,
eNO levels, and
peripheral eosinophil
counts of children
with seasonal allergic
rhinitis during pollen
season
NA No significant difference at
baseline was found in
symptom scores, eNO
levels, and blood eosinophil
counts between the
treatment and placebo
groups. After 2 weeks of
Montelukast treatment,
improvements from the
baseline in the daytime
nasal, composite, and
daytime eye symptoms
scores were significantly
greater in the Montelukast
group compared with the
placebo group (P < .001, P
< .001, and P < .01,
respectively). A significant
decrease was also found in
eosinophil counts (P < .001)
in the Montelukast group
compared with the placebo
group after treatment.
Montelukast treatment did
not produce a significant
effect on eNO levels
compared with placebo (P
= .96).
The study results
concluded that
Montelukast treatment
provided significant
improvement in
symptoms and
peripheral eosinophil
counts of school-age
children with seasonal
allergic rhinitis;
however, it did not
show a significant
effect on eNO levels
Alul M E
(2006)
A retrospective
observational
study
Children (age
3-15 yr) with
rhinosinusitis
and seasonal
or perennial
allergic
rhinitis.
20
Children
A total of 10 of the
children received oral
montelukast, while the
other 10 received
corticosteroids in a nasal
spray formulation
NA NA A greater proportion of
children with perennial
rhinitis (with or without
seasonal allergic rhinitis)
than of children with only
seasonal allergic rhinitis
indicated that their
symptoms interfered with
their sleep patterns and
other activities of daily
living. Also, a greater
proportion of patients with
perennial rhinitis than of
patients with seasonal
rhinitis would agree to use
montelukast if symptom
control would be improved
with this agent
The authors
concluded that
children with
perennial rhinitis
experience substantial
disruptions of their
sleep patterns and
activities of daily
living
Storms W etal
(2001)
A meta-analysis of
11 multicenter,
randomized,
placebo-controlled
studies and 5
extension studies
Adults and
children with
chronic
asthma. Ten
of the 11
double-blind
studies were
Phase IIb/III
trials in 3386
adults aged
15-85; the
other study
was a Phase
III trial in 336
children aged
6-14 yr. Of
the 5
extension
studies, 4
were in adults
where
Montelukast
exposure
lasted up to
4.1 yr; the
other study
was in
children
where
Montelukast
exposure
lasted up to
1.8 yr.
A total of
3386
adult
patients
(aged 15-
85 years)
and 336
paediatric
patients
(aged 6-
14 years)
were
enrolled
in the
trials
2031 adults received
Montelukast for up to
4.1 years, and 257
children received
Montelukast for up to
1.8 years. Dosages
ranged from 2-200 mg
per day.
NA NA The overall incidence of
clinical and laboratory
adverse events among
montelukast-treated
patients, both adult and
paediatric, was similar to
that among patients
receiving placebo. There
were no clinically relevant
differences in individual
adverse events, including
infectious upper respiratory
conditions and transaminase
elevations, between
montelukast and placebo
groups. Discontinuations
due to adverse events
occurred with similar
frequencies during placebo,
montelukast and inhaled
beclomethasone therapy.
No dose-related adverse
effects of montelukast were
observed in adults treated
with dosages as high as 200
mg per day (20 times the
recommended dose) for 5
months.
The authors
concluded that
Montelukast is safe
for all age groups
during short-term and
long-term
administration, even
at doses substantially
higher than the
recommended dose
Hans Bisgaard
etal (2009)
A meta-analysis of
7 multicenter,
randomized,
placebo-
controlled, double-
blind registration
and post-
registration studies
and three active-
controlled open-
label
extension/extended
studies
These studies
evaluated
2,751
pediatric
patients 6
months to 14
years of age
with persistent
asthma,
intermittent
asthma
associated
with upper
respiratory
infection, or
allergic
rhinitis.
A total of
2751
paediatric
patients 6
months to
14 years
of age.
NA Review of the safety
and tolerability of
montelukast in
children
NA Montelukast was well
tolerated in all studies.
Clinical and laboratory
adverse experiences for
patients treated with
montelukast were generally
mild and transient. The
most frequent clinical
adverse events for all
treatments (placebo,
montelukast, active
control/usual care) in
virtually all studies were
upper respiratory infection,
worsening asthma,
pharyngitis, and fever.
The clinical and
laboratory safety
profile for
montelukast was
similar to that
observed for placebo
or active control/usual
care therapies. The
safety profile of
montelukast did not
change with long-
term use.
Tamesis GP
etal (2008)
In this review, the
authors discuss the
results of recent
studies of the long-
term effects of
inhaled
corticosteroids,
long-acting b-
agonists, and
leukotriene
receptor
antagonists on the
disease course of
asthma in children.
NA NA Several studies of
inhaled corticosteroids in
children with Asthma
i.e.Childhood Asthma
Management Program
[CAMP], inhaled Steroid
Treatment As Regular
Therapy in early asthma
[START], and
Prevention of Early
Asthma in Kids [PEAK]
Long-term outcomes
of controller asthma
medications
NA In the CAMP study,
budesonide improved lung
function to a greater extent
than did placebo while
children received
budesonide; but
measurements obtained for
asthma control and
bronchial
hyperresponsiveness in the
budesonide group after
treatment discontinuation
were similar to those
obtained for the placebo
group. In the START study,
initiating treatment with
budesonide in children who
had asthma for <2 yr
improved lung function test
results, but lung function
worsened later. In PEAK,
children at risk of
developing asthma received
fluticasone or placebo for 2
yr. During the 3rd year,
when study drugs were
discontinued, there was no
difference between the
fluticasone group and the
placebo group with respect
to the proportion of children
with active wheezing
The authors
concluded that
currently available
antiasthma agents can
decrease the incidence
of asthma
exacerbations in
children, but these
agents cannot delay or
prevent the natural
course of asthma.
Barnes N etal
(2005)
A retrospective,
cross-sectional,
observational
study of clinical
outcomes seen in
patients prescribed
montelukast for
asthma
Asthmatic
Patients
A total of
1351
patients
(597 M,
743 F,
age 1-88
yr, mean
age 35 yr)
seen at 56
centers
were
included
Patients taking
montelukast at the time
of the survey had been
taking it for a median of
15 mo (range, <1-38
mo), and patients who
had discontinued
montelukast had taken it
for a median of 3 mo
(range, <1-36 mo).
Information was
obtained by
questionnaires tailored
for patients, prescribing
physicians, and
independent observers
(respiratory nurse
trainers who answered
questions based on
patient records).
To examine the use,
effectiveness, and
tolerability of
montelukast in
clinical practice for
treating asthma and to
explore prognostic
factors that could
predict a favorable
response to the drug
NA Independent observer
assessments showed overall
improvement in asthma for
66.4% of patients, with
8.2% of patients having
very good or dramatic
improvement. Asthma was
much improved or
dramatically improved in a
larger proportion of
children (41.3%) than adults
(33.5%). Similar results
were found with physician
assessments. Among 211
patients who also had
rhinitis and had a response
recorded, 54.5% had
improvements in rhinitis.
Overall asthma responses to
montelukast were reported
by 292 patients, and the
results were similar to those
from independent observers
and physicians. Among 199
patients who were still
taking montelukast, 69.8%
reported that their asthma
was much better. Prognostic
factors that were
significantly associated with
a response to montelukast
were age, sex, other asthma
treatment at the start of
montelukast, activity-
induced asthma, and sleep
disturbance; only activity-
induced asthma remained
significant (P=0.002) in a
forward inclusion model.
Montelukast was well
tolerated, with records
showing drug-related
adverse events in 137
patients (9.3%). There was
only one serious adverse
event (diarrhea) that was
possibly related to
montelukast.
The authors
concluded that
montelukast is
effective and well
tolerated as asthma
therapy in routine
clinical practice.
Karaman O
etal (2004)
A 2-period, 14-wk,
randomized,
prospective,
parallel group
study
63 children
(36 M, 27 F,
age 8-14 yr)
with mild,
persistent
asthma.
The mean
duration of
asthma ranged
from 26.9 mo
to 28.4 mo.
63
children
Patients were
randomized to 1 of 3
groups: group 1,
montelukast 5-mg
chewable tablet
administered once daily
in the evening; group 2,
inhaled budesonide 400
mcg b.i.d.; and group 3,
montelukast plus
budesonide combination
therapy
To determine the
effectiveness,
reliability, and
tolerability of
montelukast therapy.
To compare the
effects of montelukast
therapy with those of
inhaled corticosteroid
therapy
NA Fifty-seven patients
completed the study: 1
patient from group 3
discontinued because of an
asthma attack; 2 patients in
group 2 discontinued
because of pneumonia; and
3 were lost to follow-up.
Treatment with montelukast
resulted in improvements in
airway obstruction, asthma
exacerbations, daily
symptom scores, nocturnal
awakenings, total daily B-
agonist therapy, and urinary
leukotriene E4 levels. The
FEV-1 values increased
with treatment when
compared to the baseline
values. Patients in all 3
groups had significant
improvements in morning
PEF measurements.
Monthly as-needed
treatment with beta-agonists
decreased significantly
among patients in all 3
groups. Improvements in
exercise capacity were
observed among patients in
all 3 groups
The authors conclude
that montelukast may
be an effective
treatment option for
pediatric patients with
mild, persistent
asthma.
Kukreja S etal
(2004)
An open,
prospective,
multicenter, non-
comparative,
Pediatric
Montelukast Study
Group
881 patients
(573 M, 308
F, age 6-14 yr,
mean age
11.83 yr) with
persistent
asthma
881
children
Oral montelukast 5 mg-
tablet once daily for 30
days
to evaluate the
tolerability and
efficacy of treatment
with oral montelukast
5mg tablet
NA With montelukast, the
daytime total asthma score
decreased from 9.55 to
3.59. The number of
nocturnal awakenings
decreased from 1.54 to
0.43. At the completion of
the study, physicians rated
montelukast tolerability:
46% as excellent; 28% as
very good; 20% as good;
6% as fair; and none as poor
The authors
concluded that
montelukast therapy
is well tolerated and
effective in pediatric
patients with
persistent asthma
Van
Adelsberg J
etal (2003)
A 3-mo,
multicenter, open-
label, controlled,
extension study
113 children
6-31 mo of
age with
asthma or
asthma-like
symptoms
who needed
controller
therapy based
on GINA
guidelines
113
children
A 6-wk, randomized,
double-blind, placebo-
controlled study.
Patient received either
oral granular
montelukast 4 mg once
daily (n=175) or placebo
(n=81).
The extension study
started after patients
were off active treatment
for a minimum of 2
month.
to evaluate the safety
and tolerability of oral
granular montelukast
4 mg once daily
NA children who received
montelukast were compared
with children who received
usual care (inhaled
controller therapy with
cromolyn, nedocromil, or
corticosteroids) there were
no differences regarding
clinical or laboratory
adverse experiences,
patients exceeding the
predefined limits of change
for laboratory tests, or
change in postexposure
transaminase levels relative
to baseline
The authors
concluded that in
asthmatic children 6-
31 mo of age, oral
granular montelukast
4 mg once daily is
generally well
tolerated over a 3-mo
period.
van Adelsberg
J etal (2002)
A multicenter,
randomized,
double-blind,
placebo-
controlled,
parallel-group
study
children aged
>=6 mo to <2
yr with
Asthma who
required
controller
therapy
NA Children were
randomized to receive
once-daily montelukast 4
mg with applesauce in
the evening for 6 wk
(n=175) or matching
placebo (n=81).
to determine the
safety and tolerability
of oral granular
montelukast
(sprinkles) in
children.
to evaluate the effects
of montelukast on the
use of b-agonists in
those at risk of
developing persistent
asthma
NA There were fewer episodes
of worsening asthma in the
montelukast group than in
the placebo group (18.9%
vs 22.2%).
The number of days without
b- agonist use was greater
in the subgroup of patients
at risk of developing
persistent asthma than in the
placebo group. Montelukast
was also superior to placebo
in a subgroup of patients
with atopic dermatitis,
allergic rhinitis, or a family
history of asthma.
The authors
concluded that oral
granular montelukast
4 mg for 6 wk is safe
and tolerable in
children aged >=6 mo
to <2 yr with asthma.
Biswas P etal
(2001)
A national
prescription event
monitoring (PEM)
study of
montelukast
NA 15,612
patients
A national prescription
event monitoring (PEM)
study of montelukast in
15,612 patients who had
prescriptions filled
between February 1998
and December 1998 in
England.
NA NA Age was not recorded for
2125 patients; however, for
the remaining 13,487
patients, the mean age was
48 yr. The most frequent
indications for the use of
montelukast were asthma
(55%) and chronic
obstructive airway disease
(3%); indications were
unspecified in 39% of the
patients. Treatment was
effective in 64%
(7826/12,248) of the
patients for whom an
opinion on effectiveness
was given. Six months after
initiating therapy, 56.2%
(8114/14,433) of the
patients were still receiving
montelukast. Events with
the highest incidence
density in the 1st month of
montelukast treatment (ID-1
per 1000 patient-mo of
treatment) were respiratory
tract infections (17.5),
improved condition (16.2),
headache/migraine (13.7),
nausea/vomiting (7.1),
nonsurgical admissions
(6.2), noncompliance (5.6),
and malaise/lassitude (5.5).
Specifically, the events with
the highest ID-1 in children
aged <6 yr (n=107) were
headache/migraine and
respiratory tract infection,
followed by abnormal
behavior and dizziness. In
children aged 6-14 yr
(n=1258), the event with the
highest ID-1 was
headache/migraine,
followed by
nausea/vomiting and
abdominal pain. General
practitioners reported 250
drug-related adverse events
in 191 (1.2%) patients. Of
the 250 adverse events, 62
were reported to the
The authors conclude
that montelukast is
well tolerated in this
cohort of patients
Committee on Safety of
Medicines. The most
frequently reported adverse
event was headache (n=35),
which was also the most
frequent reason for
discontinuing medication
(n=211). There were 11
reports of serious suspected
adverse events, including
Churg-Strauss syndrome (3
reports), angioedema (3
cases), allergy (2 cases),
facial edema (2 cases), and
anaphylaxis (1 case).
Adverse events that were
possibly related to
montelukast included
insomnia (36 cases),
abnormal dreams (8 cases),
dizziness (29 cases),
palpitations (9 cases),
worsened eczema (8 cases),
flu-like symptoms (7 cases),
depression (5 cases), drug
interaction (3 cases), and
allergy (2 cases). The
authors note that there were
5 reports of improved
eczema or urticaria that
were possibly related to the
use of montelukast. Among
the 53 women who reported
pregnancies, 38 had been
exposed to montelukast in
the 1st trimester. Pregnancy
outcomes included 21 live
births, 2 stillborns, 7
spontaneous abortions, 4
therapeutic terminations,
and 4 unknown outcomes.
No fetal malformations
were recorded. There were
305 deaths including 21
deaths due to asthma, 84
due to chronic obstructive
airways disease, 3 due to
status asthmaticus, 1 due to
multiorgan failure, 1 due to
hepatic failure, and 1 due to
an unspecified hepatic
disease. None of the deaths
were attributed to
montelukast
Bisgaard H
etal (2000)
An open-label,
extension study
children (age
2-5 yr) with
asthma.
NA Montelukast 4-mg
chewable tablets once
daily at bedtime (n=288)
or inhaled/nebulized
corticosteroids or
cromolyn sodium (usual
care (UC); n=119) for
26-409 days in children
(age 2-5 yr) with asthma.
To examine Long-
term safety of
montelukast 4mg
chewable tablets in 2-
to 5-year old children
with asthma
NA Montelukast and UC had
similar safety profiles.
Adverse events included
asthma (42.7% and 46.2%
in the montelukast and UC
groups, respectively), cough
(22.2% and 10.1%,
respectively), fever (36.5%
and 28.6%, respectively),
pharyngitis (22.9% and
16.8%, respectively), and
upper respiratory tract
infection (40.6% and
40.3%, respectively). The
frequency of
discontinuation because of
adverse events was similar
between the groups.
The authors
concluded that
montelukast was well
tolerated in asthmatic
children aged 2-5 yr
Wilson A M
etal (2003)
A meta-analysis of
data obtained
thorugh search of
EMBASE,
MEDLINE, and
CINAHL for
randomized
controlled trials
which revealed 94
abstracts, 14
eligible studies,
and data from 8
trials, 6 of which
were parallel
studies.
NA NA The methodological
quality of each included
trial was evaluated using
Jadad's criteria (score 0-
5). The composite daily
rhinitis symptoms scores
in each trial were
standardized for the
maximum score and
pooled using the
weighted mean
difference (WMD) and
95% confidence intervals
(CI); this was
accomplished by using a
random effects model
after assessing for
heterogeneity.
(According to the
methodological quality
analysis, the median
Jadad's score was 3).
To compare the
clinical efficacy of
leukotriene receptor
antagonists, including
montelukast, in the
treatment of patients
with allergic
rhinosinusitis and
nasal polyposis with
that of placebo,
antihistamines, and
nasal corticosteroids.
NA According to composite
daily rhinitis symptoms
scores, leukotriene receptor
antagonists were more
effective than placebo
(WMD -0.02, 95% CI -0.07
to -0.02), were as effective
as antihistamines (WMD
0.02, 95% CI -0.01 to 0.02),
and were not as effective as
nasal corticosteroids (WMD
0.22, 95% CI 0.07 to 0.22).
Quality of life and nasal
peak flow improved with
leukotriene receptor
antagonists when compared
with placebo; this
improvement was not seen
with nasal eosinophilia.
The authors conclude
that with regard to
allergic rhinitis
symptom
improvement,
leukotriene receptor
antagonists are more
effective than
placebo, as effective
as antihistamines, and
inferior to nasal
corticosteroids.
COST EFFECTIVENESS
Luskin A etal
(2005)
A 24-mo,
retrospective,
longitudinal cohort
study
The cohort
consisted of
3217 patients
<16 yr of age
who initiated
asthma
controller
therapy with
either
montelukast
or an ICS
After 1-to-1
matching,
1236 patients
were analyzed
(618 in each
group; 60%
M, mean age
9.9 yr, >75%
with mild
asthma
A 24-month,
retrospective, pre-post
cohort study using a
pharmacy claims
database of children
(age < 16 years) with 2
or more consecutive
asthma controller
prescriptions and 1 or
more allergy
prescription (within 12
months before initial
controller prescription).
Children taking inhaled
corticosteroids (ICSs)
and montelukast were
matched one to one
based on age, days of
prior allergic rhinitis
therapy supply, duration
of controller therapy,
and propensity score.
Differences in costs of
rescue or acute asthma
medications,
prescription allergy
medications, other
respiratory medications,
and the number of days
of rescue or acute
asthma medication use
and allergy medication
use were calculated
NA NA A total of 1,236 children were
matched into ICS and montelukast
groups (n = 618 each). Montelukast
patients had a smaller cost increase
overall compared with ICS patients
(combined cost for rescue or acute
asthma medications, allergy
medications, and other respiratory
medications: $5.55 vs $12.08, P
< .001). Cost increase for rescue or
acute asthma medications was
significantly lower in the montelukast
group ($0.94 vs $3.82, P = .003). The
cost increase for allergy medications
($5.29 vs $10.06, P < .001) was also
significantly lower in the montelukast
group. Patients taking montelukast
also had fewer days of therapy with
asthma rescue medication and allergy
medication compared with patients
taking ICSs.
The author concluded
Initiating therapy with
montelukast was
associated with better
asthma and allergy
control demonstrated
via lower increase in
use and costs of
asthma rescue and
allergy medications
compared with
initiating ICS therapy
Sturkenboom
M C J M
(2005)
A retrospective
cohort study
The cohort
consisted of
children (72%
M, aged 0-14
yr) with
asthma and
allergic
rhinitis
88 Italian
children (72%
M, aged 0-14
yr)
Data were obtained
from an electronic
database (PediaNET).
Children with at least 2
yr of follow-up (at least
1 yr before and after the
index date) and who
received at least 2
consecutive
prescriptions for
controller medication
were included. The
index date was the date
of the first controller
prescription.
The montelukast cohort
comprised 23 children,
NA NA Compared with the other controller
cohort, the montelukast cohort had a
10-fold greater reduction in overall
crude monthly cost. Cost reductions
(in euros) were 3.63 with montelukast
and 0.03 with other controllers
(p=0.11).
NA
with more than 78%
also taking ICS. The
other controller cohort
comprised 65 children,
with 51% taking ICS
and 49% taking
ICS/LABA
Sazonov-
Kocevar V
etal (2006)
A 2-yr
retrospective,
observational
cohort study
French
children (age:
6-14)
continuously
followed in
BKL-Thalès
database who
received > or
=2
consecutive
prescriptions
for GINA-
Step 3 therapy
(=addition of
montelukast
or other
controllers
('other'), such
as increasing
inhaled-
corticosteroid
dose (hICS),
adding long-
acting beta
agonist
(LABA), or
ICS + LABA
439 French
children aged
6-14 yr with
asthma who
initiated
Global
Initiative for
Asthma
(GINA) Step 3
therapy.
Approximately
half of the
patients had
concomitant
allergic
rhinitis.
A total of 71 patients
(47 M, 24 F, mean age
9.56 yr) added
montelukast to their
existing inhaled
corticosteroid therapy,
while 368 (234 M, 134
F, mean age 10.05 yr)
used other controllers,
including high-dose
inhaled corticosteroids,
long-acting b-agonists,
and inhaled
corticosteroids plus
long-acting b-agonists
NA NA In the year after the introduction of
GINA Step 3 therapy, the group that
added montelukast and the group that
used other controllers did not differ
significantly with respect to
concomitant allergy/asthma
medication use. In the subgroup with
allergic rhinitis, montelukast was
associated with significantly lower
use of allergy/asthma medications
than were the other controllers (5.30
vs 7.62 prescriptions per patient per
year; P=0.013). In the group as a
whole and in the subgroup with
allergic rhinitis, the cost of
asthma/allergy medications remained
stable in the montelukast group over
the 2-yr observation period. In the
group using other controllers, there
was a slight increase in the cost of
asthma/allergy medications overall
and a significant increase among
patients with allergic rhinitis.
The authors
concluded that
montelukast appears
to provide asthma
control comparable to
that of high-dose
inhaled
corticosteroids, long-
acting b-agonists, and
inhaled
corticosteroids plus
long-acting b-
agonists. Compared
with the other
regimens,
montelukast may be
associated with lower
costs for concomitant
asthma/allergy
medications.
Allen-Ramey
F C (2006)
A retrospective
cohort study
Asthmatic
children, 2-14
years old,
receiving a
prescription
(index) for
montelukast
or fluticasone
2034 children Children were matched
by age and propensity
score to obtain
comparable treatment
groups. The propensity
score was derived using
patient demographics,
pre-existing respiratory
conditions, and asthma-
related pharmacy and
health service
utilization (i.e.
ambulatory visits,
emergency department
visits and
hospitalizations).
Claims for asthma-
related emergent care
and medication use
were examined for the
12-month periods
before and after the
index prescription.
Treatment group
comparisons of asthma-
related resource use
were conducted for the
total pediatric
population and
separately for children
2-5 years and 6-14
years. Persistent
controller medication
use was assessed at 6
and 12 months post-
index.
Outcomes
included visits to
emergency
departments,
asthma-related
hospitalizations,
oral
corticosteroid
therapy, and
short-acting
beta-agonist
therapy.
NA A total of 2034 children were
matched (1017 in each treatment
group). Post-index rates of asthma-
related resource use were similar
among children treated with
montelukast or fluticasone. Among
children 2-5 years old, fewer
emergency department visits were
observed with montelukast versus
fluticasone (relative risk = 0.52, 95%
confidence interval [CI]: 0.28-0.96);
no significant difference was
observed among children 6-14 years
old. No significant differences
between montelukast and fluticasone
cohorts in hospitalizations or rescue
medication fills were noted in either
age group. Evidence of at least one
medication refill was significantly
greater with montelukast at both 6
and 12 months post-index.
The authors
concluded that
overall, patients in the
montelukast and
fluticasone groups
experienced similar
therapeutic effects.
However, they add
that children aged 2-5
yr had less resource
use on montelukast
compared to
fluticasone
Bonetto G
(2005)
A 2-yr
retrospective pre-
post cohort study
Italian
children aged
0-14 yr with
asthma who
were
receiving
either
montelukast
or other
asthma
controllers
(high-dose
inhaled
corticosteroids
[h-d ICS] or
ICS plus long-
acting b-
agonists)
The cohort
comprised 987
patients (61%
M); 8.9% had
a recorded
history of
allergic
rhinitis
Patients were registered
for >=2 yr, received
>=2 consecutive
asthma-controller
prescriptions after 1
July 2001, and were
followed-up through the
PediaNET (pediatrician
network) database.
Patients were enrolled
in the cohort upon the
initial prescription for
an asthma controller;
patients with <1 yr of
follow-up prior to or
after the index date
were excluded.
Estimates were made of
pre-post differences in
mean per-child-per-
month prescription
costs and rates of rescue
medications (short-
acting b-agonists, acute
medications
[antibiotics, oral
corticosteroids], allergy
medications
[antihistamines, nasal
steroids], and other
respiratory
medications). The
montelukast cohort
(about 75% with
montelukast added to
ICS) comprised 122
patients; the cohort
receiving other asthma
controllers comprised
865 patients (ICS plus
long-acting b-agonists,
n=187; h-d ICS, n=677
[sic]).
NA NA the montelukast cohort experienced a
decrease in overall crude prescription
rates and cost, while the cohort
receiving other asthma controllers
experienced an increase in monthly
costs (rescue medications, acute
medications, allergy medications, and
other respiratory medications
combined: -1.52 Euros vs +1.50
Euros; p<0.012). Decreases in
prescription rates and costs were
observed in the montelukast cohort
for rescue medications (p=0.064),
acute medications (NS), and allergy
medications (p<0.001), whereas an
increase was observed in the cohort
receiving other asthma controllers.
The cost of use of other asthma drugs
increased in both cohorts but did not
differ between the cohorts
The authors
concluded that
significant reductions
in total use and costs
of asthma rescue
medications, acute
medications, and
allergy medications
were observed over a
2-yr period among
asthmatic children
treated with
montelukast (75%
added to ICS),
compared with those
treated with either h-d
ICS or ICS plus long-
acting b-agonists.
Davies GM
etal (2004)
An open-label,
controlled
extension of a 3-
mo, double-blind,
double-dummy
clinical trial
Pediatric
patients aged
2 to 5 years
with asthma
who had
completed a
3-month,
double-blind,
double-
dummy
clinical trial
comparing
montelukast 4
mg and
placebo were
asked to
participate in
an open-label,
controlled
extension
study
comparing
montelukast 4
mg and usual
care
506
participated in
some portion
of the
extension
Of the 689 patients
enrolled in the original
study, 506 participated
in some portion of the
extension: 302 who had
not used previous
asthma maintenance
therapy and 204 who
had used maintenance
therapy (cromolyn or
inhaled corticosteroids).
Of the 302 who had not
used previous
maintenance therapy,
215 (122 M, 93 F)
received montelukast
and 87 (46 M, 41 F)
received usual care in
the extension. Of the
204 who had used
maintenance therapy,
146 (88 M, 58 F)
received montelukast
and usual care and 58
(44 M, 14 F) received
usual care during the
extension. The mean
duration of follow-up in
the extension phase was
329.5 days for those
who received
montelukast and had
not used previous
maintenance therapy,
314.6 days for those
who received usual care
and had not used
previous therapy, 319.7
days for those who
received montelukast
and had received
previous therapy, and
289.4 days for those
who received usual care
and had received
previous therapy.
NA NA Among patients who had not used
previous asthma therapy, patients
who received montelukast during the
extension had lower rates of health
care resource utilization than did
patients who received usual care in
terms of physician visits (1.50 vs
1.96/person-year) and emergency
department visits (0.19 vs
0.39/person-year). These differences,
however, were not statistically
significant. Hospitalization rates were
identical between montelukast and
usual care recipients. Among patients
who had used previous asthma
therapy, patients who received
montelukast during the extension had
lower rates of health care resource
utilization than did patients who
received usual care in terms of oral
corticosteroid episodes (1.41 vs
1.59/person-year), physician visits
(1.64 vs 1.81/person-year),
emergency department visits (0.19 vs
0.28/person-year), and
hospitalizations (0.07 vs 0.13/person-
year). Again, these differences were
not statistically significant.
The authors conclude
that among children
aged 2-5 yr with mild-
to-moderate persistent
asthma, those who
received montelukast
had similar rates of
asthma-related health
care resource
utilization compared
with those who
received usual care
with cromolyn or
inhaled
corticosteroids
Price D (2004) An economic
analysis of the
PRE-EMPT study
Children aged
2-14 yr with
intermittent
asthma
202 children
aged 2-14 yr.
Patients were divided
into two study groups:
Montelukast and
Placebo arm. A short
course of
(montelukast/Placebo)
introduced at the first
sign of viral upper
respiratory tract
infection or asthma
symptoms
To assess the
societal value of
short-course
montelukast for
treatment of
intermittent
asthma in
children
NA The economic analysis showed that
the percent of episodes requiring
healthcare resource use was
significantly lower in the montelukast
arm than in the placebo arm. Average
costs in Australian dollars per episode
in the montelukast and placebo arms,
respectively, were 5.72 and 5.95 for
concomitant drugs (difference, -0.23);
15.73 and 0.00 for montelukast drug
purchase (difference, +15.73); 67.08
and 90.93 for healthcare resources
(including general practitioner,
specialist, emergency room
attendance, hospital admission;
difference, -23.85); and 224.62 and
343.18 for parental work loss
(difference, -118.56).
The authors
concluded that a
short-course
intervention with
montelukast
significantly reduced
healthcare resource
use. The costs
associated with the
montelukast
intervention were
substantially lower
than those associated
with placebo
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